Mitotic G1 phase and G1/S transition (Homo sapiens)

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6, 10, 22, 42, 43, 76...401675512053, 147554012015962, 108, 22572, 83, 2258, 10966, 16623, 2396758, 99, 111, 122, 176...62, 108, 22514, 51, 168, 23767147, 22672, 225404012034, 190, 2101523718, 20, 29, 49, 71...120402616495, 2259021240, 12081225, 2274072, 2251591641846572, 222, 2251536, 76, 80, 161, 17512053, 120, 147214112, 14467122, 20434, 3717, 50, 85, 101, 116...157, 22521412040, 119, 131, 225153120, 224, 225, 22721241, 107, 16210254225119, 131, 22526152, 22528, 72, 22518, 29, 49, 71, 73...28, 72, 22595, 102, 225137, 184191224168, 188, 24346, 58, 99, 111, 158...1202790, 120168, 18817312, 16, 44, 45, 73...6723757, 6049, 57, 59, 71, 110...120105, 178, 24323, 159, 23979, 147, 226157, 22522, 42, 43, 176, 203...10152, 22552, 118, 199, 232cytosolnucleoplasmCCNA2 RBL2 p-T356-RB1 MCM4 TFDP2 ORC2 LIN37 LIN9 PSMA4 SKP1 TFDP1 LIN54 PRIM2 MYBL2 gene PPP2R1B p-T172-CDK4,p-T177-CDK6:CCND:CDKN1A,CDKN1B,(CDKN1C); p-T172-CDK4,p-T177-CDK6:CCND; (p-T172-CDK4,p-T177-CDK6:CCND:p-Y88-CDKN1B)PCNA gene MCM2-7CyclinE/A:p-T160-CDK2:p-S130-CDKN1A,p-T187-CDKN1BLIN37 CUL1 CDT1 MCM3 p-T356-RB1 PSMB9 E2F1:TFDP1,TFDP2:CDC6 geneUBA52(1-76) TFDP2 PPP2CA CCNE2 CDKN1C ORC1 CDK6 p-S788-RB1 CDKN1C CCND1 ORC1 p-T369,S640,S964,S975-RBL1CCNE1 CDK4,CDK6:CCNDCCND1 MCM6 RBL1 HDAC1:RBL2:E2F4,E2F5:TFDP1,TFDP2; HDAC1:RBL1:E2F4:TFDP1,TFDP2:E2F1 geneE2F4 UBC(457-532) POLA1 geneRBBP4 ORC6 E2F4 CDC45 gene GMNN p-T177-CDK6 ORC2 CCNE1 CDK2 RBL2 MCM10 TFDP1 E2F1 TK1 geneTOP2A geneUBC(457-532) POLA2 PSMD8 UBC(381-456) PSME1 CDK2 CCNE1 Cyclin B:CDK1CDKN1B CDK2 PP2Ap-Y88-CDKN1B CDKN1C PiTFDP2 TFDP2 POLE4 CCNE2 RBL2 CCND2 p-T187-CDKN1B MCM4 p-S28-LIN52 CCND2 E2F4 Ub-p-T401,S672,1035-RBL2HDAC1:RBL2:E2F4,E2F5:TFDP1,TFDP2; HDAC1:RBL1:E2F4:TFDP1,TFDP2:CDK1 geneFBXO5TFDP2 ORC3 p-T187-CDKN1B CCNA1 DHFR geneTFDP2 CCND1 CUL1:SKP1:SKP2:CKS1BRBBP4 TFDP2 MCM10 POLE MCM4 E2F1:TFDP1,TFDP2:CCNA1 geneLIN54 TFDP1 TFDP2 TFDP2 CDKN1B E2F5 TFDP2 p-T187-CDKN1B PCNA gene p-S807-RB1 LIN9 CDK4,CDK6:CCND:CDKN1A,CDKN1B,(CDKN1C); CDK4,CDK6:CCND; (CDK4,CDK6:CCND:p-Y88-CDKN1B)CDT1 ATPMCM5 CDK1 geneCDC45 geneSKP2 CCNEDBF4 ORC3 CDKN1A E2F4 UBC(305-380) UBC(1-76) RPA1 CDK6 TFDP2 RBL1 UBC(1-76) CDKN2D CCNE2 CDK:DDK:MCM10:activepre-replicativecomplex:CDC45E2F4:TFDP1,TFDP2E2F1:TFDP1,TFDP2:ORC1 geneCUL1 CCNE2 UBC(381-456) MCM5 UBC(305-380) E2F5 ADPCCND3 p-T,p-S-AKTLIN9 Senescence-Associated Secretory Phenotype (SASP)CDK1CDC25A gene TOP2Ap-T401,S672,S1035-RBL2 MCM4 CCNE2 CCNE1 CCNA2 POLE3 DBF4 E2F3 UbMCM5 HDAC1 MCM5 TFDP1 CCND2 UBC(457-532) UBC(77-152) LIN54 origin of replication HDAC1 FBXO5 geneE2F1 gene TFDP1 CUL1:SKP1:SKP2E2F5 p-T-CDKN1A/BORC5 Cyclin E:p-CDK2PSMD2 MCM3 TFDP2 TFDP1 Oxidative StressInduced SenescenceDREAM complex:CDC6geneDNA primer TFDP2 p-S608-RB1 CDC6 E2F4 E2F5 origin of replication E2F4 HDAC1 ORC6 LIN9 p-S230-RB1 RNA primer-DNAprimer:originduplex with DNAdamageRBBP4 TFDP2 RBL1 TFDP2 CDK2 CDT1 geneUBB(153-228) PiTFDP1 RBL1MCM3 p-Y77-CDKN1A TFDP2 UBC(533-608) ATPPSME2 CCNH CCNE1 CCNE2 CyclinB:CDK1:ORC:originof replicationCCNE:CDK2PSMC5 PSMA6 UBC(533-608) RBL2 E2F4,E2F5:TFDP1,TFDP2CDKN1A PRIM1 UBC(609-684) RBBP4 PSMB6 ATPCyclin E:p-T160-CDK2E2F1:TFDP1,TFDP2:FBXO5 genePSMA7 LIN54 MCM6 TFDP1 E2F3 CDKN2D TK1 gene RBL2:E2F4/5:DP1/2:Cyclin E/A:CDK2TFDP1 p-Y397-LYN RPA2 E2F1:TFDP1,TFDP2:TK1geneCCNA1 geneSKP2 H2OMCM5 DHFRPSMD7 RBL2 CDC7 TFDP2 TFDP1 CUL1 PPP2R2A HDAC1 RB1:RNA primer-DNAprimer:originduplex with DNAdamageLIN9 ADPCDC6 ADPATPTFDP1 TFDP1 TFDP1 CKS1B ORC1 ATPDREAM complex:TOP2Agenep16INK4A RPA4 CDC6 CDK4,CDK6CDKN1A ORC3 CDC7 MCM8 CCNE1 ORC2 E2F1 Pi CCNA1 DNA polymeraseepsilon:origincomplexPSMD4 ATPCDK4/6:CCND:p-Y77-CDKN1A,p-Y88-CDKN1B,(p-Y91-CDKN1C)GMNNCDKN2C CUL1 ATPORC4 RBL1 CCNE2 RNA primer-DNAprimer:originduplexPSMD6 RB1 UBB(153-228) E2F1 CKS1B DNA polymerasealpha:primaseH2OORC3 MCM7 RBL2 p-S252-RB1 DNA polymerasealpha:primase:DNApolymerasealpha:origincomplexCCND1 ORC4 TFDP2 Signaling by PTK6E2F4 ORC6 LIN37 E2F4 POLE p-T401,S672,S1035-RBL2CCNE1 CDKN1B RBL2 CCNA p-Y342-PTK6:CDKN1B:(CDK4:CCND1,(CDK2:CCNE1))UBC(533-608) p-T373-RB1 MCM7 TFDP1 PCNA geneCCNE1 PSMC3 CDK1 ORC6 RRM2 gene Aborted replicationcomplexLIN37 CDC25AE2F1 p-S28-LIN52 CDKN1A DNA primer RRM2 geneUBA52(1-76) LIN37 CCND3 p-Y88-CDKN1B CCNA PPP2CB ADPADPTranscriptionalactivity ofSMAD2/SMAD3:SMAD4heterotrimerPSMC1 E2F1 PPP2R1B CDKN1A,CDKN1BCyclinE/A:CDK2:p-S130-CDKN1A,p-T187-CDKN1B:CUL1:SKP1:SKP2:CKS1B:3xubiquitinE2F1:TFDP1,TFDP2:CDC45 geneCDC6 TFDP2 LIN37 DNA polymeraseepsilonCDKN1B:(CDK4:CCND1,(CDK2:CCNE1))CCND2 CDK6 PPP2R1A E2F5 TFDP2 E2F1 CDK2MCM6 p-Y342-PTK6 RBL2 E2F1:TFDP1,TFDP2:PCNA geneINK4PRIM2 ADPMCM6 p-S608-RB1 TFDP2 TFDP1 ORC:origin ofreplicationcyclin UBC(77-152) E2F1 CDC6 geneCDC25A gene ORC2 p-Y419-SRC ORC2 HDAC1:RBL2:E2F4,E2F5:TFDP1,TFDP2MCM6 MCM2 CDK2 TFDP2 ADPE2F1CDK4 E2F4 CDC6 p-T160-CDK2 ORC3 UBB(77-152) CDK4 MCM8 origin of replication RB1 UBC(381-456) E2F1:TFDP1,TFDP2:POLA1 geneRNA primer:origin duplex with DNA damage E2F4 E2F1 genep-T305,S472-AKT3 CDK1 gene E2F4 PCNARPS27A(1-76) SKP1 PPP2CA CCNE1 p-Y342-PTK6POLE2 RBL1:E2F4:DP1/2:Cyclin E/A:CDK2UBB(77-152) CDK6 TFDP2 ORC1 p-T826-RB1 E2F4 PPP2R3B RPA4 CCNB1 ATPCDC7 CUL1 p-MCM2-7Cyclin E PSMA3 E2F1 PRIM1 CDKPPP2CB p-S612-RB1 E2F1 p-S230-RB1 MYC RNA primer:origin duplex with DNA damage origin of replication ORC4 TFDP2 E2F5 E2F5 ORC5 E2F1 gene LIN9 PRIM1 E2F1:TFDP1,TFDP2:CDT1 genep-T821-RB1 ORC5 origin of replication MCM6 CCNA2 CDK4,CDK6:CCND:CDKN1A,CDKN1B,(CDKN1C); CDK4,CDK6:CCND; (CDK4,CDK6:CCND:p-Y88-CDKN1B)DYRK1ARBL1:E2F4:TFDP1,TFDP2POLE4 p-T160-CDK2 MCM4 CDK1 p-T160-CDK2 origin of replication MCM5 CDK2 RBL2 CDKN1A TFDP1 PSMB3 PSMA2 TFDP2 RBL1 POLA1 TFDP1 DREAM complexE2F6 CABLES1MuvB complexCCNA1CDKN1BH2ODDKCDC45POLA1 CDC7 CCNE1 gene CDC6 RRM2POLE4 TFDP1 CDKN2B MYBL2 geneMCM4 origin of replication p-Y91-CDKN1C CCNA1 gene MCM10:pre-replicative complexORC1 gene CCNE:p-T160-CDK2:hypophosphorylated RB1CCNE1 ORC1 ORC1TFDP2 CDK:DDK:MCM10:activepre-replicativecomplex:CDC45:RPA1-4CUL1:SKP1:SKP2:CKS1BUBC(229-304) TFDP1 ORC4 SKP1 PSMC6 UBA52(1-76) PSMD13 DREAM complex:CDC25AgeneUBC(381-456) CDK4 MCM3 MCM3 PSMD11 CDC6 gene MNAT1 MCM4 CDC6cyclin CCNA2 MCM8 MCM3 CCND3 CCNE2 TFDP1 E2F5 DBF4 RB1CDKN2C ADPDREAM complex:RBL1geneCDKN1A TFDP1 LIN9 CCND1 TFDP2 UBC(533-608) p-S28-LIN52 CDK2 POLE3 MCM4 CKS1B E2F1 MCM3 p-T172-CDK4 TFDP1 E2F5 p-T821-RB1 HDAC1:RBL2:E2F4,E2F5:TFDP1,TFDP2; HDAC1:RBL1:E2F4:TFDP1,TFDP2:MYBL2 geneCDK4 RBL1 gene HDAC1 ADPUBB(1-76) H2OPSMD1 CCNE2 TFDP1 CCNE1 CCNE1PSMB7 CDKN1A E2F1 p-S28-LIN52 CDK7 UBC(153-228) RBBP4 RPA1-4RPA2 ATPCDKN1BCDK2 p-S28-LIN52 pre-replicativecomplexCUL1 CCNA1 E2F5 CCND3 CCNA2 geneCCNA2 PSMB8 ORC6 DHFR gene CDKN1B ORC6 TOP2A gene E2F5 ATPLIN54 ORC2 UBB(153-228) RBL1 CCNA POLE2 CKS1B UBC(229-304) TFDP2 UBC(77-152) MCM5 POLE3 p-T401,S672,1035-RBL2:SCF(Skp2):Cks1p-Y226,Y393-ABL1 SKP2 RBBP4 E2F1:TFDP1,TFDP2:CDK1 geneCDKN1B CDC25A gene CDK4 CCNE2 RBL1:Cyclin E/A:CDK2RBL2:E2F4,E2F5:TFDP1,TFDP2MCM10ORC1 MCM2 p-S252-RB1 HDAC1RNA primer E2F1 PSMD10 PIP3 activates AKTsignalingE2F1 PSMF1 E2F1 Cyclin E/A:CDK2CKS1B MCM2 p-T373-RB1 ORC5 LIN54 UBC(153-228) TFDP1 CDK4,CDK6:INK4UBB(1-76) UBC(153-228) UBC(609-684) CCND3 RBL1 E2F4 TFDP2 p-Y88-CDKN1B:(CDK4:CCND1,(CDK2:CCNE1))UBB(77-152) p-T160-CDK2 TFDP1 TFDP1 MCM8 RNA primer:origin duplex with DNA damage E2F1,E2F2,E2F3:TFDP1,TFDP2CCNB1 CDKN1C RBL2 E2F4 PPP2R3B HDAC1:RBL2:E2F4,E2F5:TFDP1,TFDP2; HDAC1:RBL1:E2F4:TFDP1,TFDP2MCM7 CCNE:CDK2TFDP2 ORC6 p-S249-RB1 TFDP1 DREAM complex:PCNAgeneMCM10 E2F5 CCND2 RBL2 CDK2 UBC(457-532) RBL1CDK4 TFDP2 RBL2 HDAC1 ATPCDK2 CCND3 E2F4 UBA52(1-76) LIN37 CDK6 cyclin ORC4 CDK2 p-S811-RB1 CDK4 MCM8 CDK6 RRM2 gene RBL1:E2F4:TFDP1,TFDP2CDKN1A,CDKN1B,(CDKN1C)p-T308,S473-AKT1 CDC25A geneCDKN1AE2F1 UBB(153-228) PiMCM2 DNA primer E2F1 p-S788-RB1 CCNA2 gene RBBP4 p-S28-LIN52 RPA3 CDKN1B UBC(1-76) E2F1:TFDP1,TFDP2:DHFR geneORC5 LIN54 E2F1:TFDP1,TFDP2:CDC25A geneMCM8 CDK2 E2F4 Cdt1:gemininp-T160-CDK2 UBC(229-304) POLA1 gene RB1:E2F1,E2F2,E2F3:TFDP1,TFDP2:MCM8 TFDP2 CDK6 CDK2 MCM10 TFDP2 p-S780-RB1 CDKN2B E2F4 cyclin DREAM complex:E2F1geneORC3 MCM8 RBL2 RBL2:Cyclin E/A:CDK2p-CDK2 CCND1 PiE2F2 MCM2 CDT1ORC3 p-S28-LIN52 ORC4 CCND2 origin of replication CCNE1 ORC2 CDK4 PSMD9 UBC(229-304) p-T309,S474-AKT2 PPP2R1A E2F2 UBC(609-684) PSMD14 CCNE1 E2F1 HDAC1:RBL2:E2F4,E2F5:TFDP1,TFDP2; HDAC1:RBL1:E2F4:TFDP1,TFDP2:CCNA2 genep-T160-CDK2 UBC(305-380) CDT1 E2F1:TFDP1,TFDP2:RRM2 geneADPORC5 CDKN1C MCM10:activepre-replicativecomplexCDC6 gene LIN9 MCM6 monophosphorylatedRB1RB1 CyclinE/A:CDK2:p-S130-CDKN1A,p-T187-CDKN1B:CUL1:SKP1:SKP2:CKS1BMAX SKP1 p-T826-RB1 p-S795-RB1 CDKN1B MCM7 UbMCM7 CDKN1B CDK4 26S proteasomeE2F5 origin of replication CCNA MCM2 Cyclin E UBC(609-684) TFDP2 CCNE1 ORC1 POLA2 TFDP1 p-S780-RB1 CDKN1B p-S130-CDKN1A RBBP4 CCND1 CCNA p16INK4A SKP2 ORC2 TFDP1 E2F4 RPS27A(1-76) TYMSCDKN1A p-S130-CDKN1A TFDP1 TFDP2 RBL1 Oncogene InducedSenescenceORC6 CCND1 E2F4 UBB(1-76) p-S249-RB1 RBL1 RPS27A(1-76) TK1p-Y342-PTK6 POLA2 PSMB4 origin of replication PSME3 E2F5 UBC(305-380) PSMB2 p-Y88-CDKN1B CCNA2TFDP1 p-12Y-JAK2 RPS27A(1-76) TFDP1 TFDP2 TFDP1 E2F1:TFDP1,TFDP2hyperphosphorylatedRB1PSMC2 RBL2WEE1MCM7 E2F4 CDKN1B Cyclin E PSMD12 ORC1 MAX CDK4,CDK6:CCND:CDKN1A,CDKN1B,(CDKN1C)CCNA1 p-T157-CDKN1B RBL2 POLA1 CCNA1 p-S807-RB1 CCND1 CDT1 gene CDKN1ACCND3 TFDP1 POLA1p-T160-CDK2 ORC5 MCM2 E2F6:(TFDP1,TFDP2):RRM2 genePSMC4 TFDP2 TFDP2 ORC4 TFDP1 Cyclin E CDKN1A DNA primer LIN9 RBL1 UBC(77-152) origin of replication HDAC1:RBL1:E2F4:TFDP1,TFDP2ADPMCM5 PSMA5 p-Y88-CDKN1B CAKCDC45 PSMA1 (p-Y342-PTK6,p-Y397-LYN,p-Y226,Y393-ABL1,p-Y419-SRC,p-5Y-JAK2)CCND2 CDK2 SKP1 p-S795-RB1 TFDP2 LIN52 PSMB1 MCM3 ORC4 CCNA:p-T160-CDK2,CCNE:p-T160-CDK2DBF4 RBL2 CCNE2 CCND1 PP2AE2F1:TFDP1,TFDP2:CCNE1 genep-S612-RB1 ADPPOLE ATPp-T401,S672,S1035-RBL2 CDC45 CKS1BCCNE1 geneUBC(153-228) CDK:DDK:MCM10:activepre-replicativecomplexRBL1 geneUBC(1-76) MYC RBL2 p-T145-CDKN1A CDK2 POLE2 CDK1 gene p-MuvB complexMCM7 LIN54 MYC:MAXCyclin Dp-Y88-CDKN1B PSMD3 CCNE2 TFDP2 SHFM1 RPA1 SKP1 RPA3 E2F5 MYBL2p-S28-LIN52 E2F5 CyclinE:CDK2:CDKN1A,CDKN1Borigin ofreplicationCDKN1B p-S130-CDKN1A E2F4 PRIM2 PSMD5 MCM10 CCNE1 UBB(1-76) MCM7 RBBP4 HDAC1 E2F1 ORC5 LIN37 E2F4 TFDP1 FBXO5 gene E2F5 LIN54 MCM6 SKP2 RBL2:E2F4,E2F5:TFDP1,TFDP2ORC3 UBB(77-152) TYMS geneORC1 geneCDKN1A,CDKN1BATPTFDP1 MYC:MAX:CDC25A geneTFDP1 MCM2 RBL2p-S811-RB1 CDK4 TFDP1 SKP2 ADPLIN37 CyclinE/A:p-T160-CDK2:CDKN1A,CDKN1BPSMB10 RBL2 TFDP2 TFDP1 TFDP1 Cyclin E RB1PSMB5 1201204013, 24, 35, 48, 68...551204, 25, 36, 39, 47...225, 22712062, 108, 2252221846740157, 225119, 131, 22520940974012097, 133164184152, 225165, 171100, 12118, 49, 71177, 24012021, 31-33, 38...12072, 22540147, 22653, 14766, 1661, 3, 5, 7, 9...2, 78, 82, 92, 98...28, 72, 225224


Description

Mitotic G1-G1/S phase involves G1 phase of the mitotic interphase and G1/S transition, when a cell commits to DNA replication and divison genetic and cellular material to two daughter cells.

During early G1, cells can enter a quiescent G0 state. In quiescent cells, the evolutionarily conserved DREAM complex, consisting of the pocket protein family member p130 (RBL2), bound to E2F4 or E2F5, and the MuvB complex, represses transcription of cell cycle genes (reviewed by Sadasivam and DeCaprio 2013).<p>During early G1 phase in actively cycling cells, transcription of cell cycle genes is repressed by another pocket protein family member, p107 (RBL1), which forms a complex with E2F4 (Ferreira et al. 1998, Cobrinik 2005). RB1 tumor suppressor, the product of the retinoblastoma susceptibility gene, is the third member of the pocket protein family. RB1 binds to E2F transcription factors E2F1, E2F2 and E2F3 and inhibits their transcriptional activity, resulting in prevention of G1/S transition (Chellappan et al. 1991, Bagchi et al. 1991, Chittenden et al. 1991, Lees et al. 1993, Hiebert 1993, Wu et al. 2001). Once RB1 is phosphorylated on serine residue S795 by Cyclin D:CDK4/6 complexes, it can no longer associate with and inhibit E2F1-3. Thus, CDK4/6-mediated phosphorylation of RB1 leads to transcriptional activation of E2F1-3 target genes needed for the S phase of the cell cycle (Connell-Crowley et al. 1997). CDK2, in complex with cyclin E, contributes to RB1 inactivation and also activates proteins needed for the initiation of DNA replication (Zhang 2007). Expression of D type cyclins is regulated by extracellular mitogens (Cheng et al. 1998, Depoortere et al. 1998). Catalytic activities of CDK4/6 and CDK2 are controlled by CDK inhibitors of the INK4 family (Serrano et al. 1993, Hannon and Beach 1994, Guan et al. 1994, Guan et al. 1996, Parry et al. 1995) and the Cip/Kip family, respectively. View original pathway at Reactome.</div>

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Pathway is converted from Reactome ID: 453279
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Reactome version: 75
Reactome Author 
Reactome Author: Matthews, Lisa

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  159. Bell SP, Dutta A.; ''DNA replication in eukaryotic cells.''; PubMed Europe PMC Scholia
  160. Seidel JJ, Graves BJ.; ''An ERK2 docking site in the Pointed domain distinguishes a subset of ETS transcription factors.''; PubMed Europe PMC Scholia
  161. Hannon GJ, Beach D.; ''p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest.''; PubMed Europe PMC Scholia
  162. Avni D, Yang H, Martelli F, Hofmann F, ElShamy WM, Ganesan S, Scully R, Livingston DM.; ''Active localization of the retinoblastoma protein in chromatin and its response to S phase DNA damage.''; PubMed Europe PMC Scholia
  163. Nakajima T, Kinoshita S, Sasagawa T, Sasaki K, Naruto M, Kishimoto T, Akira S.; ''Phosphorylation at threonine-235 by a ras-dependent mitogen-activated protein kinase cascade is essential for transcription factor NF-IL6.''; PubMed Europe PMC Scholia
  164. Arata Y, Fujita M, Ohtani K, Kijima S, Kato JY.; ''Cdk2-dependent and -independent pathways in E2F-mediated S phase induction.''; PubMed Europe PMC Scholia
  165. Dhar SK, Delmolino L, Dutta A.; ''Architecture of the human origin recognition complex.''; PubMed Europe PMC Scholia
  166. Kumagai H, Sato N, Yamada M, Mahony D, Seghezzi W, Lees E, Arai K, Masai H.; ''A novel growth- and cell cycle-regulated protein, ASK, activates human Cdc7-related kinase and is essential for G1/S transition in mammalian cells.''; PubMed Europe PMC Scholia
  167. Masai H, Matsui E, You Z, Ishimi Y, Tamai K, Arai K.; ''Human Cdc7-related kinase complex. In vitro phosphorylation of MCM by concerted actions of Cdks and Cdc7 and that of a criticial threonine residue of Cdc7 bY Cdks.''; PubMed Europe PMC Scholia
  168. Tsvetkov LM, Yeh KH, Lee SJ, Sun H, Zhang H.; ''p27(Kip1) ubiquitination and degradation is regulated by the SCF(Skp2) complex through phosphorylated Thr187 in p27.''; PubMed Europe PMC Scholia
  169. Fang S, Jensen JP, Ludwig RL, Vousden KH, Weissman AM.; ''Mdm2 is a RING finger-dependent ubiquitin protein ligase for itself and p53.''; PubMed Europe PMC Scholia
  170. Fan G, Aleem S, Yang M, Miller WT, Tonks NK.; ''Protein-tyrosine Phosphatase and Kinase Specificity in Regulation of SRC and Breast Tumor Kinase.''; PubMed Europe PMC Scholia
  171. Vashee S, Simancek P, Challberg MD, Kelly TJ.; ''Assembly of the human origin recognition complex.''; PubMed Europe PMC Scholia
  172. Nelson ML, Kang HS, Lee GM, Blaszczak AG, Lau DK, McIntosh LP, Graves BJ.; ''Ras signaling requires dynamic properties of Ets1 for phosphorylation-enhanced binding to coactivator CBP.''; PubMed Europe PMC Scholia
  173. Desai D, Wessling HC, Fisher RP, Morgan DO.; ''Effects of phosphorylation by CAK on cyclin binding by CDC2 and CDK2.''; PubMed Europe PMC Scholia
  174. Matsuura H, Nishitoh H, Takeda K, Matsuzawa A, Amagasa T, Ito M, Yoshioka K, Ichijo H.; ''Phosphorylation-dependent scaffolding role of JSAP1/JIP3 in the ASK1-JNK signaling pathway. A new mode of regulation of the MAP kinase cascade.''; PubMed Europe PMC Scholia
  175. Guan KL, Jenkins CW, Li Y, Nichols MA, Wu X, O'Keefe CL, Matera AG, Xiong Y.; ''Growth suppression by p18, a p16INK4/MTS1- and p14INK4B/MTS2-related CDK6 inhibitor, correlates with wild-type pRb function.''; PubMed Europe PMC Scholia
  176. Connell-Crowley L, Harper JW, Goodrich DW.; ''Cyclin D1/Cdk4 regulates retinoblastoma protein-mediated cell cycle arrest by site-specific phosphorylation.''; PubMed Europe PMC Scholia
  177. Li Y, Asahara H, Patel VS, Zhou S, Linn S.; ''Purification, cDNA cloning, and gene mapping of the small subunit of human DNA polymerase epsilon.''; PubMed Europe PMC Scholia
  178. Wang W, Nacusi L, Sheaff RJ, Liu X.; ''Ubiquitination of p21Cip1/WAF1 by SCFSkp2: substrate requirement and ubiquitination site selection.''; PubMed Europe PMC Scholia
  179. Harbour JW, Luo RX, Dei Santi A, Postigo AA, Dean DC.; ''Cdk phosphorylation triggers sequential intramolecular interactions that progressively block Rb functions as cells move through G1.''; PubMed Europe PMC Scholia
  180. Liu S, Bolger JK, Kirkland LO, Premnath PN, McInnes C.; ''Structural and functional analysis of cyclin D1 reveals p27 and substrate inhibitor binding requirements.''; PubMed Europe PMC Scholia
  181. Parisi T, Pollice A, Di Cristofano A, Calabrò V, La Mantia G.; ''Transcriptional regulation of the human tumor suppressor p14(ARF) by E2F1, E2F2, E2F3, and Sp1-like factors.''; PubMed Europe PMC Scholia
  182. Hartupee J, Li X, Hamilton T.; ''Interleukin 1alpha-induced NFkappaB activation and chemokine mRNA stabilization diverge at IRAK1.''; PubMed Europe PMC Scholia
  183. Atwood AA, Sealy LJ.; ''C/EBPβ's role in determining Ras-induced senescence or transformation.''; PubMed Europe PMC Scholia
  184. Patel P, Asbach B, Shteyn E, Gomez C, Coltoff A, Bhuyan S, Tyner AL, Wagner R, Blain SW.; ''Brk/Protein tyrosine kinase 6 phosphorylates p27KIP1, regulating the activity of cyclin D-cyclin-dependent kinase 4.''; PubMed Europe PMC Scholia
  185. Coppé JP, Patil CK, Rodier F, Sun Y, Muñoz DP, Goldstein J, Nelson PS, Desprez PY, Campisi J.; ''Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor.''; PubMed Europe PMC Scholia
  186. Ishida N, Kitagawa M, Hatakeyama S, Nakayama K.; ''Phosphorylation at serine 10, a major phosphorylation site of p27(Kip1), increases its protein stability.''; PubMed Europe PMC Scholia
  187. Kato JY, Matsuoka M, Polyak K, Massagué J, Sherr CJ.; ''Cyclic AMP-induced G1 phase arrest mediated by an inhibitor (p27Kip1) of cyclin-dependent kinase 4 activation.''; PubMed Europe PMC Scholia
  188. Carrano AC, Eytan E, Hershko A, Pagano M.; ''SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27.''; PubMed Europe PMC Scholia
  189. Grimmler M, Wang Y, Mund T, Cilensek Z, Keidel EM, Waddell MB, Jäkel H, Kullmann M, Kriwacki RW, Hengst L.; ''Cdk-inhibitory activity and stability of p27Kip1 are directly regulated by oncogenic tyrosine kinases.''; PubMed Europe PMC Scholia
  190. Beijersbergen RL, Carlée L, Kerkhoven RM, Bernards R.; ''Regulation of the retinoblastoma protein-related p107 by G1 cyclin complexes.''; PubMed Europe PMC Scholia
  191. Izumi M, Yanagi K, Mizuno T, Yokoi M, Kawasaki Y, Moon KY, Hurwitz J, Yatagai F, Hanaoka F.; ''The human homolog of Saccharomyces cerevisiae Mcm10 interacts with replication factors and dissociates from nuclease-resistant nuclear structures in G(2) phase.''; PubMed Europe PMC Scholia
  192. Voncken JW, Niessen H, Neufeld B, Rennefahrt U, Dahlmans V, Kubben N, Holzer B, Ludwig S, Rapp UR.; ''MAPKAP kinase 3pK phosphorylates and regulates chromatin association of the polycomb group protein Bmi1.''; PubMed Europe PMC Scholia
  193. Sithanandam G, Latif F, Duh FM, Bernal R, Smola U, Li H, Kuzmin I, Wixler V, Geil L, Shrestha S.; ''3pK, a new mitogen-activated protein kinase-activated protein kinase located in the small cell lung cancer tumor suppressor gene region.''; PubMed Europe PMC Scholia
  194. Bracken AP, Kleine-Kohlbrecher D, Dietrich N, Pasini D, Gargiulo G, Beekman C, Theilgaard-Mönch K, Minucci S, Porse BT, Marine JC, Hansen KH, Helin K.; ''The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells.''; PubMed Europe PMC Scholia
  195. Young AR, Narita M.; ''SASP reflects senescence.''; PubMed Europe PMC Scholia
  196. Bockstaele L, Bisteau X, Paternot S, Roger PP.; ''Differential regulation of cyclin-dependent kinase 4 (CDK4) and CDK6, evidence that CDK4 might not be activated by CDK7, and design of a CDK6 activating mutation.''; PubMed Europe PMC Scholia
  197. Moiseeva O, Bourdeau V, Roux A, Deschênes-Simard X, Ferbeyre G.; ''Mitochondrial dysfunction contributes to oncogene-induced senescence.''; PubMed Europe PMC Scholia
  198. Le Gallic L, Virgilio L, Cohen P, Biteau B, Mavrothalassitis G.; ''ERF nuclear shuttling, a continuous monitor of Erk activity that links it to cell cycle progression.''; PubMed Europe PMC Scholia
  199. Chattopadhyay S, Bielinsky AK.; ''Human Mcm10 regulates the catalytic subunit of DNA polymerase-alpha and prevents DNA damage during replication.''; PubMed Europe PMC Scholia
  200. Gao Z, Zhang J, Bonasio R, Strino F, Sawai A, Parisi F, Kluger Y, Reinberg D.; ''PCGF homologs, CBX proteins, and RYBP define functionally distinct PRC1 family complexes.''; PubMed Europe PMC Scholia
  201. Ou L, Ferreira AM, Otieno S, Xiao L, Bashford D, Kriwacki RW.; ''Incomplete folding upon binding mediates Cdk4/cyclin D complex activation by tyrosine phosphorylation of inhibitor p27 protein.''; PubMed Europe PMC Scholia
  202. Tanizaki J, Okamoto I, Sakai K, Nakagawa K.; ''Differential roles of trans-phosphorylated EGFR, HER2, HER3, and RET as heterodimerisation partners of MET in lung cancer with MET amplification.''; PubMed Europe PMC Scholia
  203. Chellappan SP, Hiebert S, Mudryj M, Horowitz JM, Nevins JR.; ''The E2F transcription factor is a cellular target for the RB protein.''; PubMed Europe PMC Scholia
  204. Kelly BL, Wolfe KG, Roberts JM.; ''Identification of a substrate-targeting domain in cyclin E necessary for phosphorylation of the retinoblastoma protein.''; PubMed Europe PMC Scholia
  205. Niehof M, Streetz K, Rakemann T, Bischoff SC, Manns MP, Horn F, Trautwein C.; ''Interleukin-6-induced tethering of STAT3 to the LAP/C/EBPbeta promoter suggests a new mechanism of transcriptional regulation by STAT3.''; PubMed Europe PMC Scholia
  206. Lukong KE, Larocque D, Tyner AL, Richard S.; ''Tyrosine phosphorylation of sam68 by breast tumor kinase regulates intranuclear localization and cell cycle progression.''; PubMed Europe PMC Scholia
  207. Cheng M, Sexl V, Sherr CJ, Roussel MF.; ''Assembly of cyclin D-dependent kinase and titration of p27Kip1 regulated by mitogen-activated protein kinase kinase (MEK1).''; PubMed Europe PMC Scholia
  208. Atwood AA, Sealy L.; ''Regulation of C/EBPbeta1 by Ras in mammary epithelial cells and the role of C/EBPbeta1 in oncogene-induced senescence.''; PubMed Europe PMC Scholia
  209. Jiang W, Wells NJ, Hunter T.; ''Multistep regulation of DNA replication by Cdk phosphorylation of HsCdc6.''; PubMed Europe PMC Scholia
  210. Leng X, Noble M, Adams PD, Qin J, Harper JW.; ''Reversal of growth suppression by p107 via direct phosphorylation by cyclin D1/cyclin-dependent kinase 4.''; PubMed Europe PMC Scholia
  211. Zheng Y, Asara JM, Tyner AL.; ''Protein-tyrosine kinase 6 promotes peripheral adhesion complex formation and cell migration by phosphorylating p130 CRK-associated substrate.''; PubMed Europe PMC Scholia
  212. Orend G, Hunter T, Ruoslahti E.; ''Cytoplasmic displacement of cyclin E-cdk2 inhibitors p21Cip1 and p27Kip1 in anchorage-independent cells.''; PubMed Europe PMC Scholia
  213. Bagui TK, Jackson RJ, Agrawal D, Pledger WJ.; ''Analysis of cyclin D3-cdk4 complexes in fibroblasts expressing and lacking p27(kip1) and p21(cip1).''; PubMed Europe PMC Scholia
  214. Tedesco D, Lukas J, Reed SI.; ''The pRb-related protein p130 is regulated by phosphorylation-dependent proteolysis via the protein-ubiquitin ligase SCF(Skp2).''; PubMed Europe PMC Scholia
  215. Yu B, Lane ME, Pestell RG, Albanese C, Wadler S.; ''Downregulation of cyclin D1 alters cdk 4- and cdk 2-specific phosphorylation of retinoblastoma protein.''; PubMed Europe PMC Scholia
  216. Agger K, Cloos PA, Rudkjaer L, Williams K, Andersen G, Christensen J, Helin K.; ''The H3K27me3 demethylase JMJD3 contributes to the activation of the INK4A-ARF locus in response to oncogene- and stress-induced senescence.''; PubMed Europe PMC Scholia
  217. Ono H, Basson MD, Ito H.; ''PTK6 promotes cancer migration and invasion in pancreatic cancer cells dependent on ERK signaling.''; PubMed Europe PMC Scholia
  218. Reynisdóttir I, Massagué J.; ''The subcellular locations of p15(Ink4b) and p27(Kip1) coordinate their inhibitory interactions with cdk4 and cdk2.''; PubMed Europe PMC Scholia
  219. Dietrich N, Bracken AP, Trinh E, Schjerling CK, Koseki H, Rappsilber J, Helin K, Hansen KH.; ''Bypass of senescence by the polycomb group protein CBX8 through direct binding to the INK4A-ARF locus.''; PubMed Europe PMC Scholia
  220. Castro NE, Lange CA.; ''Breast tumor kinase and extracellular signal-regulated kinase 5 mediate Met receptor signaling to cell migration in breast cancer cells.''; PubMed Europe PMC Scholia
  221. Lundberg AS, Weinberg RA.; ''Functional inactivation of the retinoblastoma protein requires sequential modification by at least two distinct cyclin-cdk complexes.''; PubMed Europe PMC Scholia
  222. Bertoli C, Klier S, McGowan C, Wittenberg C, de Bruin RA.; ''Chk1 inhibits E2F6 repressor function in response to replication stress to maintain cell-cycle transcription.''; PubMed Europe PMC Scholia
  223. Bracken AP, Pasini D, Capra M, Prosperini E, Colli E, Helin K.; ''EZH2 is downstream of the pRB-E2F pathway, essential for proliferation and amplified in cancer.''; PubMed Europe PMC Scholia
  224. Galaktionov K, Chen X, Beach D.; ''Cdc25 cell-cycle phosphatase as a target of c-myc.''; PubMed Europe PMC Scholia
  225. DeGregori J, Kowalik T, Nevins JR.; ''Cellular targets for activation by the E2F1 transcription factor include DNA synthesis- and G1/S-regulatory genes.''; PubMed Europe PMC Scholia
  226. Ohtani K, DeGregori J, Leone G, Herendeen DR, Kelly TJ, Nevins JR.; ''Expression of the HsOrc1 gene, a human ORC1 homolog, is regulated by cell proliferation via the E2F transcription factor.''; PubMed Europe PMC Scholia
  227. Vigo E, Müller H, Prosperini E, Hateboer G, Cartwright P, Moroni MC, Helin K.; ''CDC25A phosphatase is a target of E2F and is required for efficient E2F-induced S phase.''; PubMed Europe PMC Scholia
  228. Chu I, Sun J, Arnaout A, Kahn H, Hanna W, Narod S, Sun P, Tan CK, Hengst L, Slingerland J.; ''p27 phosphorylation by Src regulates inhibition of cyclin E-Cdk2.''; PubMed Europe PMC Scholia
  229. Hiebert SW.; ''Regions of the retinoblastoma gene product required for its interaction with the E2F transcription factor are necessary for E2 promoter repression and pRb-mediated growth suppression.''; PubMed Europe PMC Scholia
  230. Goel RK, Lukong KE.; ''Tracing the footprints of the breast cancer oncogene BRK - Past till present.''; PubMed Europe PMC Scholia
  231. Ohtani N, Zebedee Z, Huot TJ, Stinson JA, Sugimoto M, Ohashi Y, Sharrocks AD, Peters G, Hara E.; ''Opposing effects of Ets and Id proteins on p16INK4a expression during cellular senescence.''; PubMed Europe PMC Scholia
  232. Remus D, Beuron F, Tolun G, Griffith JD, Morris EP, Diffley JF.; ''Concerted loading of Mcm2-7 double hexamers around DNA during DNA replication origin licensing.''; PubMed Europe PMC Scholia
  233. Ikeda O, Mizushima A, Sekine Y, Yamamoto C, Muromoto R, Nanbo A, Oritani K, Yoshimura A, Matsuda T.; ''Involvement of STAP-2 in Brk-mediated phosphorylation and activation of STAT5 in breast cancer cells.''; PubMed Europe PMC Scholia
  234. Ikeda O, Sekine Y, Mizushima A, Nakasuji M, Miyasaka Y, Yamamoto C, Muromoto R, Nanbo A, Oritani K, Yoshimura A, Matsuda T.; ''Interactions of STAP-2 with Brk and STAT3 participate in cell growth of human breast cancer cells.''; PubMed Europe PMC Scholia
  235. Zheng Y, Peng M, Wang Z, Asara JM, Tyner AL.; ''Protein tyrosine kinase 6 directly phosphorylates AKT and promotes AKT activation in response to epidermal growth factor.''; PubMed Europe PMC Scholia
  236. Chen HY, Shen CH, Tsai YT, Lin FC, Huang YP, Chen RH.; ''Brk activates rac1 and promotes cell migration and invasion by phosphorylating paxillin.''; PubMed Europe PMC Scholia
  237. Ganoth D, Bornstein G, Ko TK, Larsen B, Tyers M, Pagano M, Hershko A.; ''The cell-cycle regulatory protein Cks1 is required for SCF(Skp2)-mediated ubiquitinylation of p27.''; PubMed Europe PMC Scholia
  238. Vidal A, Koff A.; ''Cell-cycle inhibitors: three families united by a common cause.''; PubMed Europe PMC Scholia
  239. Walter J, Newport J.; ''Initiation of eukaryotic DNA replication: origin unwinding and sequential chromatin association of Cdc45, RPA, and DNA polymerase alpha.''; PubMed Europe PMC Scholia
  240. Li Y, Pursell ZF, Linn S.; ''Identification and cloning of two histone fold motif-containing subunits of HeLa DNA polymerase epsilon.''; PubMed Europe PMC Scholia
  241. Clifton AD, Young PR, Cohen P.; ''A comparison of the substrate specificity of MAPKAP kinase-2 and MAPKAP kinase-3 and their activation by cytokines and cellular stress.''; PubMed Europe PMC Scholia
  242. Ben-Levy R, Leighton IA, Doza YN, Attwood P, Morrice N, Marshall CJ, Cohen P.; ''Identification of novel phosphorylation sites required for activation of MAPKAP kinase-2.''; PubMed Europe PMC Scholia
  243. Montagnoli A, Fiore F, Eytan E, Carrano AC, Draetta GF, Hershko A, Pagano M.; ''Ubiquitination of p27 is regulated by Cdk-dependent phosphorylation and trimeric complex formation.''; PubMed Europe PMC Scholia
  244. Wu L, Timmers C, Maiti B, Saavedra HI, Sang L, Chong GT, Nuckolls F, Giangrande P, Wright FA, Field SJ, Greenberg ME, Orkin S, Nevins JR, Robinson ML, Leone G.; ''The E2F1-3 transcription factors are essential for cellular proliferation.''; PubMed Europe PMC Scholia
  245. Vijayachandra K, Lee J, Glick AB.; ''Smad3 regulates senescence and malignant conversion in a mouse multistage skin carcinogenesis model.''; PubMed Europe PMC Scholia
  246. Gao Y, Cimica V, Reich NC.; ''Suppressor of cytokine signaling 3 inhibits breast tumor kinase activation of STAT3.''; PubMed Europe PMC Scholia
  247. Takekawa M, Tatebayashi K, Saito H.; ''Conserved docking site is essential for activation of mammalian MAP kinase kinases by specific MAP kinase kinase kinases.''; PubMed Europe PMC Scholia
  248. Moiseeva O, Mallette FA, Mukhopadhyay UK, Moores A, Ferbeyre G.; ''DNA damage signaling and p53-dependent senescence after prolonged beta-interferon stimulation.''; PubMed Europe PMC Scholia
  249. Kotake Y, Cao R, Viatour P, Sage J, Zhang Y, Xiong Y.; ''pRB family proteins are required for H3K27 trimethylation and Polycomb repression complexes binding to and silencing p16INK4alpha tumor suppressor gene.''; PubMed Europe PMC Scholia
  250. Lal A, Kim HH, Abdelmohsen K, Kuwano Y, Pullmann R, Srikantan S, Subrahmanyam R, Martindale JL, Yang X, Ahmed F, Navarro F, Dykxhoorn D, Lieberman J, Gorospe M.; ''p16(INK4a) translation suppressed by miR-24.''; PubMed Europe PMC Scholia
  251. Kardinal C, Dangers M, Kardinal A, Koch A, Brandt DT, Tamura T, Welte K.; ''Tyrosine phosphorylation modulates binding preference to cyclin-dependent kinases and subcellular localization of p27Kip1 in the acute promyelocytic leukemia cell line NB4.''; PubMed Europe PMC Scholia
  252. Cobrinik D.; ''Pocket proteins and cell cycle control.''; PubMed Europe PMC Scholia
  253. Fan G, Lin G, Lucito R, Tonks NK.; ''Protein-tyrosine phosphatase 1B antagonized signaling by insulin-like growth factor-1 receptor and kinase BRK/PTK6 in ovarian cancer cells.''; PubMed Europe PMC Scholia
  254. Aprelikova O, Xiong Y, Liu ET.; ''Both p16 and p21 families of cyclin-dependent kinase (CDK) inhibitors block the phosphorylation of cyclin-dependent kinases by the CDK-activating kinase.''; PubMed Europe PMC Scholia
  255. Sgouras DN, Athanasiou MA, Beal GJ, Fisher RJ, Blair DG, Mavrothalassitis GJ.; ''ERF: an ETS domain protein with strong transcriptional repressor activity, can suppress ets-associated tumorigenesis and is regulated by phosphorylation during cell cycle and mitogenic stimulation.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
114646view16:11, 25 January 2021ReactomeTeamReactome version 75
113094view11:15, 2 November 2020ReactomeTeamReactome version 74
112328view15:25, 9 October 2020ReactomeTeamReactome version 73
112225view14:39, 2 October 2020DeSlOntology Term : 'M/G1 transition pathway' added !
101227view11:12, 1 November 2018ReactomeTeamreactome version 66
100765view20:38, 31 October 2018ReactomeTeamreactome version 65
100309view19:15, 31 October 2018ReactomeTeamreactome version 64
99855view15:59, 31 October 2018ReactomeTeamreactome version 63
99413view14:35, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93757view13:34, 16 August 2017ReactomeTeamreactome version 61
93279view11:19, 9 August 2017ReactomeTeamreactome version 61
86357view09:16, 11 July 2016ReactomeTeamreactome version 56
83315view10:46, 18 November 2015ReactomeTeamVersion54
81454view12:59, 21 August 2015ReactomeTeamVersion53
76928view08:20, 17 July 2014ReactomeTeamFixed remaining interactions
76633view12:00, 16 July 2014ReactomeTeamFixed remaining interactions
76130view12:48, 11 June 2014Anwesha
76129view12:44, 11 June 2014ReactomeTeamAdding missing reactome URL
75666view10:57, 10 June 2014ReactomeTeamReactome 48 Update
75021view13:53, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74665view08:43, 30 April 2014ReactomeTeamReactome46
68884view17:26, 8 July 2013MaintBotUpdated to 2013 gpml schema
44912view10:35, 6 October 2011MartijnVanIerselOntology Term : 'cell cycle pathway, mitotic' added !
42076view21:55, 4 March 2011MaintBotAutomatic update
39884view05:54, 21 January 2011MaintBotNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
(p-Y342-PTK6,p-Y397-LYN,p-Y226,Y393-ABL1,p-Y419-SRC,p-5Y-JAK2)ComplexR-HSA-8942611 (Reactome)
26S proteasomeComplexR-HSA-177750 (Reactome)
ADPMetaboliteCHEBI:456216 (ChEBI)
ATPMetaboliteCHEBI:30616 (ChEBI)
Aborted replication complexComplexR-HSA-113648 (Reactome)
CABLES1ProteinQ8TDN4 (Uniprot-TrEMBL)
CAKComplexR-HSA-69221 (Reactome)
CCNA R-HSA-75202 (Reactome)
CCNA1 ProteinP78396 (Uniprot-TrEMBL)
CCNA1 gene ProteinENSG00000133101 (Ensembl)
CCNA1 geneGeneProductENSG00000133101 (Ensembl)
CCNA1ProteinP78396 (Uniprot-TrEMBL)
CCNA2 ProteinP20248 (Uniprot-TrEMBL)
CCNA2 gene ProteinENSG00000145386 (Ensembl)
CCNA2 geneGeneProductENSG00000145386 (Ensembl)
CCNA2ProteinP20248 (Uniprot-TrEMBL)
CCNA:p-T160-CDK2,CCNE:p-T160-CDK2ComplexR-HSA-8848491 (Reactome)
CCNB1 ProteinP14635 (Uniprot-TrEMBL)
CCND1 ProteinP24385 (Uniprot-TrEMBL)
CCND2 ProteinP30279 (Uniprot-TrEMBL)
CCND3 ProteinP30281 (Uniprot-TrEMBL)
CCNE1 ProteinP24864 (Uniprot-TrEMBL)
CCNE1 gene ProteinENSG00000105173 (Ensembl)
CCNE1 geneGeneProductENSG00000105173 (Ensembl)
CCNE1ProteinP24864 (Uniprot-TrEMBL)
CCNE2 ProteinO96020 (Uniprot-TrEMBL)
CCNE:CDK2ComplexR-HSA-157594 (Reactome)
CCNE:CDK2ComplexR-HSA-68374 (Reactome)
CCNE:p-T160-CDK2:hypophosphorylated RB1ComplexR-HSA-188373 (Reactome)
CCNEComplexR-HSA-157462 (Reactome)
CCNH ProteinP51946 (Uniprot-TrEMBL)
CDC25A gene ProteinENSG00000164045 (Ensembl)
CDC25A geneGeneProductENSG00000164045 (Ensembl)
CDC25AProteinP30304 (Uniprot-TrEMBL)
CDC45 ProteinO75419 (Uniprot-TrEMBL)
CDC45 gene ProteinENSG00000093009 (Ensembl)
CDC45 geneGeneProductENSG00000093009 (Ensembl)
CDC45ProteinO75419 (Uniprot-TrEMBL)
CDC6 ProteinQ99741 (Uniprot-TrEMBL)
CDC6 gene ProteinENSG00000094804 (Ensembl)
CDC6 geneGeneProductENSG00000094804 (Ensembl)
CDC6ProteinQ99741 (Uniprot-TrEMBL)
CDC7 ProteinO00311 (Uniprot-TrEMBL)
CDK1 ProteinP06493 (Uniprot-TrEMBL)
CDK1 gene ProteinENSG00000170312 (Ensembl)
CDK1 geneGeneProductENSG00000170312 (Ensembl)
CDK1ProteinP06493 (Uniprot-TrEMBL)
CDK2 ProteinP24941 (Uniprot-TrEMBL)
CDK2ProteinP24941 (Uniprot-TrEMBL)
CDK4 ProteinP11802 (Uniprot-TrEMBL)
CDK4,CDK6:CCND:CDKN1A,CDKN1B,(CDKN1C); CDK4,CDK6:CCND; (CDK4,CDK6:CCND:p-Y88-CDKN1B)ComplexR-HSA-8949872 (Reactome)
CDK4,CDK6:CCND:CDKN1A,CDKN1B,(CDKN1C); CDK4,CDK6:CCND; (CDK4,CDK6:CCND:p-Y88-CDKN1B)ComplexR-HSA-8949874 (Reactome)
CDK4,CDK6:CCND:CDKN1A,CDKN1B,(CDKN1C)ComplexR-HSA-8941921 (Reactome)
CDK4,CDK6:CCNDComplexR-HSA-8941896 (Reactome)
CDK4,CDK6:INK4ComplexR-HSA-182579 (Reactome)
CDK4,CDK6ComplexR-HSA-69209 (Reactome)
CDK4/6:CCND:p-Y77-CDKN1A,p-Y88-CDKN1B,(p-Y91-CDKN1C)ComplexR-HSA-8942622 (Reactome)
CDK6 ProteinQ00534 (Uniprot-TrEMBL)
CDK7 ProteinP50613 (Uniprot-TrEMBL)
CDK:DDK:MCM10:active

pre-replicative

complex:CDC45:RPA1-4
ComplexR-HSA-68568 (Reactome)
CDK:DDK:MCM10:active

pre-replicative

complex:CDC45
ComplexR-HSA-68564 (Reactome)
CDK:DDK:MCM10:active

pre-replicative

complex
ComplexR-HSA-68561 (Reactome)
CDKN1A ProteinP38936 (Uniprot-TrEMBL)
CDKN1A,CDKN1B,(CDKN1C)ComplexR-HSA-8941923 (Reactome)
CDKN1A,CDKN1BComplexR-HSA-182504 (Reactome)
CDKN1A,CDKN1BComplexR-HSA-182558 (Reactome)
CDKN1AProteinP38936 (Uniprot-TrEMBL)
CDKN1B ProteinP46527 (Uniprot-TrEMBL)
CDKN1B:(CDK4:CCND1,(CDK2:CCNE1))ComplexR-HSA-8848419 (Reactome)
CDKN1BProteinP46527 (Uniprot-TrEMBL)
CDKN1C ProteinP49918 (Uniprot-TrEMBL)
CDKN2B ProteinP42772 (Uniprot-TrEMBL)
CDKN2C ProteinP42773 (Uniprot-TrEMBL)
CDKN2D ProteinP55273 (Uniprot-TrEMBL)
CDKComplexR-HSA-68380 (Reactome)
CDT1 ProteinQ9H211 (Uniprot-TrEMBL)
CDT1 gene ProteinENSG00000167513 (Ensembl)
CDT1 geneGeneProductENSG00000167513 (Ensembl)
CDT1ProteinQ9H211 (Uniprot-TrEMBL)
CKS1B ProteinP61024 (Uniprot-TrEMBL)
CKS1BProteinP61024 (Uniprot-TrEMBL)
CUL1 ProteinQ13616 (Uniprot-TrEMBL)
CUL1:SKP1:SKP2:CKS1BComplexR-HSA-187547 (Reactome)
CUL1:SKP1:SKP2ComplexR-HSA-187541 (Reactome)
Cdt1:gemininComplexR-HSA-156502 (Reactome)
Cyclin

B:CDK1:ORC:origin

of replication
ComplexR-HSA-113637 (Reactome)
Cyclin E/A:CDK2:p-S130-CDKN1A,p-T187-CDKN1B:CUL1:SKP1:SKP2:CKS1B:3xubiquitinComplexR-HSA-187568 (Reactome)
Cyclin E/A:CDK2:p-S130-CDKN1A,p-T187-CDKN1B:CUL1:SKP1:SKP2:CKS1BComplexR-HSA-187565 (Reactome)
Cyclin E/A:p-T160-CDK2:CDKN1A,CDKN1BComplexR-HSA-187516 (Reactome)
Cyclin E/A:p-T160-CDK2:p-S130-CDKN1A,p-T187-CDKN1BComplexR-HSA-187522 (Reactome)
Cyclin E:CDK2:CDKN1A,CDKN1BComplexR-HSA-68376 (Reactome)
Cyclin B:CDK1ComplexR-HSA-75032 (Reactome)
Cyclin DComplexR-HSA-182700 (Reactome)
Cyclin E R-HSA-187493 (Reactome)
Cyclin E/A:CDK2ComplexR-HSA-187496 (Reactome)
Cyclin E:p-CDK2ComplexR-HSA-68377 (Reactome)
Cyclin E:p-T160-CDK2ComplexR-HSA-188362 (Reactome)
DBF4 ProteinQ9UBU7 (Uniprot-TrEMBL)
DDKComplexR-HSA-68388 (Reactome)
DHFR gene ProteinENSG00000228716 (Ensembl)
DHFR geneGeneProductENSG00000228716 (Ensembl)
DHFRProteinP00374 (Uniprot-TrEMBL)
DNA polymerase

alpha:primase:DNA polymerase alpha:origin

complex
ComplexR-HSA-68510 (Reactome)
DNA polymerase alpha:primaseComplexR-HSA-68507 (Reactome)
DNA polymerase

epsilon:origin

complex
ComplexR-HSA-68485 (Reactome)
DNA polymerase epsilonComplexR-HSA-68483 (Reactome)
DNA primer R-ALL-68424 (Reactome)
DREAM complex:CDC25A geneComplexR-HSA-8964470 (Reactome)
DREAM complex:CDC6 geneComplexR-HSA-8964499 (Reactome)
DREAM complex:E2F1 geneComplexR-HSA-8964483 (Reactome)
DREAM complex:PCNA geneComplexR-HSA-8964464 (Reactome)
DREAM complex:RBL1 geneComplexR-HSA-8964487 (Reactome)
DREAM complex:TOP2A geneComplexR-HSA-8964478 (Reactome)
DREAM complexComplexR-HSA-1362264 (Reactome)
DYRK1AProteinQ13627 (Uniprot-TrEMBL)
E2F1 ProteinQ01094 (Uniprot-TrEMBL)
E2F1 gene ProteinENSG00000101412 (Ensembl)
E2F1 geneGeneProductENSG00000101412 (Ensembl)
E2F1,E2F2,E2F3:TFDP1,TFDP2ComplexR-HSA-1227905 (Reactome)
E2F1:TFDP1,TFDP2:CCNA1 geneComplexR-HSA-8961882 (Reactome)
E2F1:TFDP1,TFDP2:CCNE1 geneComplexR-HSA-8961838 (Reactome)
E2F1:TFDP1,TFDP2:CDC25A geneComplexR-HSA-8961960 (Reactome)
E2F1:TFDP1,TFDP2:CDC45 geneComplexR-HSA-8961906 (Reactome)
E2F1:TFDP1,TFDP2:CDC6 geneComplexR-HSA-8961621 (Reactome)
E2F1:TFDP1,TFDP2:CDK1 geneComplexR-HSA-8961924 (Reactome)
E2F1:TFDP1,TFDP2:CDT1 geneComplexR-HSA-8961945 (Reactome)
E2F1:TFDP1,TFDP2:DHFR geneComplexR-HSA-8961860 (Reactome)
E2F1:TFDP1,TFDP2:FBXO5 geneComplexR-HSA-8961690 (Reactome)
E2F1:TFDP1,TFDP2:ORC1 geneComplexR-HSA-8961672 (Reactome)
E2F1:TFDP1,TFDP2:PCNA geneComplexR-HSA-8961655 (Reactome)
E2F1:TFDP1,TFDP2:POLA1 geneComplexR-HSA-8961641 (Reactome)
E2F1:TFDP1,TFDP2:RRM2 geneComplexR-HSA-8961974 (Reactome)
E2F1:TFDP1,TFDP2:TK1 geneComplexR-HSA-8961992 (Reactome)
E2F1:TFDP1,TFDP2ComplexR-HSA-68653 (Reactome)
E2F1ProteinQ01094 (Uniprot-TrEMBL)
E2F2 ProteinQ14209 (Uniprot-TrEMBL)
E2F3 ProteinO00716 (Uniprot-TrEMBL)
E2F4 ProteinQ16254 (Uniprot-TrEMBL)
E2F4,E2F5:TFDP1,TFDP2ComplexR-HSA-1226072 (Reactome)
E2F4:TFDP1,TFDP2ComplexR-HSA-1362228 (Reactome)
E2F5 ProteinQ15329 (Uniprot-TrEMBL)
E2F6 ProteinO75461 (Uniprot-TrEMBL)
E2F6:(TFDP1,TFDP2):RRM2 geneComplexR-HSA-9007590 (Reactome)
FBXO5 gene ProteinENSG00000112029 (Ensembl)
FBXO5 geneGeneProductENSG00000112029 (Ensembl)
FBXO5ProteinQ9UKT4 (Uniprot-TrEMBL)
GMNN ProteinO75496 (Uniprot-TrEMBL)
GMNNProteinO75496 (Uniprot-TrEMBL)
H2OMetaboliteCHEBI:15377 (ChEBI)
HDAC1 ProteinQ13547 (Uniprot-TrEMBL)
HDAC1:RBL1:E2F4:TFDP1,TFDP2ComplexR-HSA-1227668 (Reactome)
HDAC1:RBL2:E2F4,E2F5:TFDP1,TFDP2; HDAC1:RBL1:E2F4:TFDP1,TFDP2:CCNA2 geneComplexR-HSA-8964582 (Reactome)
HDAC1:RBL2:E2F4,E2F5:TFDP1,TFDP2; HDAC1:RBL1:E2F4:TFDP1,TFDP2:CDK1 geneComplexR-HSA-8964568 (Reactome)
HDAC1:RBL2:E2F4,E2F5:TFDP1,TFDP2; HDAC1:RBL1:E2F4:TFDP1,TFDP2:E2F1 geneComplexR-HSA-8964553 (Reactome)
HDAC1:RBL2:E2F4,E2F5:TFDP1,TFDP2; HDAC1:RBL1:E2F4:TFDP1,TFDP2:MYBL2 geneComplexR-HSA-8964563 (Reactome)
HDAC1:RBL2:E2F4,E2F5:TFDP1,TFDP2; HDAC1:RBL1:E2F4:TFDP1,TFDP2ComplexR-HSA-8964549 (Reactome)
HDAC1:RBL2:E2F4,E2F5:TFDP1,TFDP2ComplexR-HSA-1227666 (Reactome)
HDAC1ProteinQ13547 (Uniprot-TrEMBL)
INK4ComplexR-HSA-182588 (Reactome)
LIN37 ProteinQ96GY3 (Uniprot-TrEMBL)
LIN52 ProteinQ52LA3 (Uniprot-TrEMBL)
LIN54 ProteinQ6MZP7 (Uniprot-TrEMBL)
LIN9 ProteinQ5TKA1 (Uniprot-TrEMBL)
MAX ProteinP61244 (Uniprot-TrEMBL)
MCM10 ProteinQ7L590 (Uniprot-TrEMBL)
MCM10:active

pre-replicative

complex
ComplexR-HSA-156564 (Reactome)
MCM10:pre-replicative complexComplexR-HSA-68560 (Reactome)
MCM10ProteinQ7L590 (Uniprot-TrEMBL)
MCM2 ProteinP49736 (Uniprot-TrEMBL)
MCM2-7ComplexR-HSA-68558 (Reactome)
MCM3 ProteinP25205 (Uniprot-TrEMBL)
MCM4 ProteinP33991 (Uniprot-TrEMBL)
MCM5 ProteinP33992 (Uniprot-TrEMBL)
MCM6 ProteinQ14566 (Uniprot-TrEMBL)
MCM7 ProteinP33993 (Uniprot-TrEMBL)
MCM8 ProteinQ9UJA3 (Uniprot-TrEMBL)
MNAT1 ProteinP51948 (Uniprot-TrEMBL)
MYBL2 gene ProteinENSG00000101057 (Ensembl)
MYBL2 geneGeneProductENSG00000101057 (Ensembl)
MYBL2ProteinP10244 (Uniprot-TrEMBL)
MYC ProteinP01106 (Uniprot-TrEMBL)
MYC:MAX:CDC25A geneComplexR-HSA-8932399 (Reactome)
MYC:MAXComplexR-HSA-188378 (Reactome)
MuvB complexComplexR-HSA-1362248 (Reactome)
ORC1 ProteinQ13415 (Uniprot-TrEMBL)
ORC1 gene ProteinENSG00000085840 (Ensembl)
ORC1 geneGeneProductENSG00000085840 (Ensembl)
ORC1ProteinQ13415 (Uniprot-TrEMBL)
ORC2 ProteinQ13416 (Uniprot-TrEMBL)
ORC3 ProteinQ9UBD5 (Uniprot-TrEMBL)
ORC4 ProteinO43929 (Uniprot-TrEMBL)
ORC5 ProteinO43913 (Uniprot-TrEMBL)
ORC6 ProteinQ9Y5N6 (Uniprot-TrEMBL)
ORC:origin of replicationComplexR-HSA-68540 (Reactome)
Oncogene Induced SenescencePathwayR-HSA-2559585 (Reactome) Oncogene-induced senescence (OIS) is triggered by high level of RAS/RAF/MAPK signaling that can be caused, for example, by oncogenic mutations in RAS or RAF proteins, or by oncogenic mutations in growth factor receptors, such as EGFR, that act upstream of RAS/RAF/MAPK cascade. Oncogene-induced senescence can also be triggered by high transcriptional activity of E2F1, E2F2 or E2F3 which can be caused, for example, by the loss-of-function of RB1 tumor suppressor.

Oncogenic signals trigger transcription of CDKN2A locus tumor suppressor genes: p16INK4A and p14ARF. p16INK4A and p14ARF share exons 2 and 3, but are expressed from different promoters and use different reading frames (Quelle et al. 1995). Therefore, while their mRNAs are homologous and are both translationally inhibited by miR-24 microRNA (Lal et al. 2008, To et al. 2012), they share no similarity at the amino acid sequence level and perform distinct functions in the cell. p16INK4A acts as the inhibitor of cyclin-dependent kinases CDK4 and CDK6 which phosphorylate and inhibit RB1 protein thereby promoting G1 to S transition and cell cycle progression (Serrano et al. 1993). Increased p16INK4A level leads to hypophosphorylation of RB1, allowing RB1 to inhibit transcription of E2F1, E2F2 and E2F3-target genes that are needed for cell cycle progression, which results in cell cycle arrest in G1 phase. p14-ARF binds and destabilizes MDM2 ubiquitin ligase (Zhang et al. 1998), responsible for ubiquitination and degradation of TP53 (p53) tumor suppressor protein (Wu et al. 1993, Fuchs et al. 1998, Fang et al. 2000). Therefore, increased p14-ARF level leads to increased level of TP53 and increased expression of TP53 target genes, such as p21, which triggers p53-mediated cell cycle arrest and, depending on other factors, may also lead to p53-mediated apoptosis. CDKN2B locus, which encodes an inhibitor of CDK4 and CDK6, p15INK4B, is located in the vicinity of CDKN2A locus, at the chromosome band 9p21. p15INK4B, together with p16INK4A, contributes to senescence of human T-lymphocytes (Erickson et al. 1998) and mouse fibroblasts (Malumbres et al. 2000). SMAD3, activated by TGF-beta-1 signaling, controls senescence in the mouse multistage carcinogenesis model through regulation of MYC and p15INK4B gene expression (Vijayachandra et al. 2003). TGF-beta-induced p15INK4B expression is also important for the senescence of hepatocellular carcinoma cell lines (Senturk et al. 2010).

MAP kinases MAPK1 (ERK2) and MAPK3 (ERK1), which are activated by RAS signaling, phosphorylate ETS1 and ETS2 transcription factors in the nucleus (Yang et al. 1996, Seidel et al. 2002, Foulds et al. 2004, Nelson et al. 2010). Phosphorylated ETS1 and ETS2 are able to bind RAS response elements (RREs) in the CDKN2A locus and stimulate p16INK4A transcription (Ohtani et al. 2004). At the same time, activated ERKs (MAPK1 i.e. ERK2 and MAPK3 i.e. ERK1) phosphorylate ERF, the repressor of ETS2 transcription, which leads to translocation of ERF to the cytosol and increased transcription of ETS2 (Sgouras et al. 1995, Le Gallic et al. 2004). ETS2 can be sequestered and inhibited by binding to ID1, resulting in inhibition of p16INK4A transcription (Ohtani et al. 2004).

Transcription of p14ARF is stimulated by binding of E2F transcription factors (E2F1, E2F2 or E2F3) in complex with SP1 to p14ARF promoter (Parisi et al. 2002).

Oncogenic RAS signaling affects mitochondrial metabolism through an unknown mechanism, leading to increased generation of reactive oxygen species (ROS), which triggers oxidative stress induced senescence pathway. In addition, increased rate of cell division that is one of the consequences of oncogenic signaling, leads to telomere shortening which acts as another senescence trigger.
While OIS has been studied to considerable detail in cultured cells, establishment of in vivo role of OIS has been difficult due to lack of specific biomarkers and its interconnectedness with other senescence pathways (Baek and Ryeom 2017, reviewed in Sharpless and Sherr 2015).

Oxidative Stress Induced SenescencePathwayR-HSA-2559580 (Reactome) Oxidative stress, caused by increased concentration of reactive oxygen species (ROS) in the cell, can happen as a consequence of mitochondrial dysfunction induced by the oncogenic RAS (Moiseeva et al. 2009) or independent of oncogenic signaling. Prolonged exposure to interferon-beta (IFNB, IFN-beta) also results in ROS increase (Moiseeva et al. 2006). ROS oxidize thioredoxin (TXN), which causes TXN to dissociate from the N-terminus of MAP3K5 (ASK1), enabling MAP3K5 to become catalytically active (Saitoh et al. 1998). ROS also stimulate expression of Ste20 family kinases MINK1 (MINK) and TNIK through an unknown mechanism, and MINK1 and TNIK positively regulate MAP3K5 activation (Nicke et al. 2005).


MAP3K5 phosphorylates and activates MAP2K3 (MKK3) and MAP2K6 (MKK6) (Ichijo et al. 1997, Takekawa et al. 2005), which act as p38 MAPK kinases, as well as MAP2K4 (SEK1) (Ichijo et al. 1997, Matsuura et al. 2002), which, together with MAP2K7 (MKK7), acts as a JNK kinase.


MKK3 and MKK6 phosphorylate and activate p38 MAPK alpha (MAPK14) and beta (MAPK11) (Raingeaud et al. 1996), enabling p38 MAPKs to phosphorylate and activate MAPKAPK2 (MK2) and MAPKAPK3 (MK3) (Ben-Levy et al. 1995, Clifton et al. 1996, McLaughlin et al. 1996, Sithanandam et al. 1996, Meng et al. 2002, Lukas et al. 2004, White et al. 2007), as well as MAPKAPK5 (PRAK) (New et al. 1998 and 2003, Sun et al. 2007).


Phosphorylation of JNKs (MAPK8, MAPK9 and MAPK10) by MAP3K5-activated MAP2K4 (Deacon and Blank 1997, Fleming et al. 2000) allows JNKs to migrate to the nucleus (Mizukami et al. 1997) where they phosphorylate JUN. Phosphorylated JUN binds FOS phosphorylated by ERK1 or ERK2, downstream of activated RAS (Okazaki and Sagata 1995, Murphy et al. 2002), forming the activated protein 1 (AP-1) complex (FOS:JUN heterodimer) (Glover and Harrison 1995, Ainbinder et al. 1997).


Activation of p38 MAPKs and JNKs downstream of MAP3K5 (ASK1) ultimately converges on transcriptional regulation of CDKN2A locus. In dividing cells, nucleosomes bound to the CDKN2A locus are trimethylated on lysine residue 28 of histone H3 (HIST1H3A) by the Polycomb repressor complex 2 (PRC2), creating the H3K27Me3 (Me3K-28-HIST1H3A) mark (Bracken et al. 2007, Kotake et al. 2007). The expression of Polycomb constituents of PRC2 (Kuzmichev et al. 2002) - EZH2, EED and SUZ12 - and thereby formation of the PRC2, is positively regulated in growing cells by E2F1, E2F2 and E2F3 (Weinmann et al. 2001, Bracken et al. 2003). H3K27Me3 mark serves as a docking site for the Polycomb repressor complex 1 (PRC1) that contains BMI1 (PCGF4) and is therefore named PRC1.4, leading to the repression of transcription of p16INK4A and p14ARF from the CDKN2A locus, where PCR1.4 mediated repression of p14ARF transcription in humans may be context dependent (Voncken et al. 2005, Dietrich et al. 2007, Agherbi et al. 2009, Gao et al. 2012). MAPKAPK2 and MAPKAPK3, activated downstream of the MAP3K5-p38 MAPK cascade, phosphorylate BMI1 of the PRC1.4 complex, leading to dissociation of PRC1.4 complex from the CDKN2A locus and upregulation of p14ARF transcription (Voncken et al. 2005). AP-1 transcription factor, formed as a result of MAP3K5-JNK signaling, as well as RAS signaling, binds the promoter of KDM6B (JMJD3) gene and stimulates KDM6B expression. KDM6B is a histone demethylase that removes H3K27Me3 mark i.e. demethylates lysine K28 of HIST1H3A, thereby preventing PRC1.4 binding to the CDKN2A locus and allowing transcription of p16INK4A (Agger et al. 2009, Barradas et al. 2009, Lin et al. 2012).


p16INK4A inhibits phosphorylation-mediated inactivation of RB family members by CDK4 and CDK6, leading to cell cycle arrest (Serrano et al. 1993). p14ARF inhibits MDM2-mediated degradation of TP53 (p53) (Zhang et al. 1998), which also contributes to cell cycle arrest in cells undergoing oxidative stress. In addition, phosphorylation of TP53 by MAPKAPK5 (PRAK) activated downstream of MAP3K5-p38 MAPK signaling, activates TP53 and contributes to cellular senescence (Sun et al. 2007).

PCNA gene ProteinENSG00000132646 (Ensembl)
PCNA geneGeneProductENSG00000132646 (Ensembl)
PCNAProteinP12004 (Uniprot-TrEMBL)
PIP3 activates AKT signalingPathwayR-HSA-1257604 (Reactome) Signaling by AKT is one of the key outcomes of receptor tyrosine kinase (RTK) activation. AKT is activated by the cellular second messenger PIP3, a phospholipid that is generated by PI3K. In ustimulated cells, PI3K class IA enzymes reside in the cytosol as inactive heterodimers composed of p85 regulatory subunit and p110 catalytic subunit. In this complex, p85 stabilizes p110 while inhibiting its catalytic activity. Upon binding of extracellular ligands to RTKs, receptors dimerize and undergo autophosphorylation. The regulatory subunit of PI3K, p85, is recruited to phosphorylated cytosolic RTK domains either directly or indirectly, through adaptor proteins, leading to a conformational change in the PI3K IA heterodimer that relieves inhibition of the p110 catalytic subunit. Activated PI3K IA phosphorylates PIP2, converting it to PIP3; this reaction is negatively regulated by PTEN phosphatase. PIP3 recruits AKT to the plasma membrane, allowing TORC2 to phosphorylate a conserved serine residue of AKT. Phosphorylation of this serine induces a conformation change in AKT, exposing a conserved threonine residue that is then phosphorylated by PDPK1 (PDK1). Phosphorylation of both the threonine and the serine residue is required to fully activate AKT. The active AKT then dissociates from PIP3 and phosphorylates a number of cytosolic and nuclear proteins that play important roles in cell survival and metabolism. For a recent review of AKT signaling, please refer to Manning and Cantley, 2007.
POLA1 ProteinP09884 (Uniprot-TrEMBL)
POLA1 gene ProteinENSG00000101868 (Ensembl)
POLA1 geneGeneProductENSG00000101868 (Ensembl)
POLA1ProteinP09884 (Uniprot-TrEMBL)
POLA2 ProteinQ14181 (Uniprot-TrEMBL)
POLE ProteinQ07864 (Uniprot-TrEMBL)
POLE2 ProteinP56282 (Uniprot-TrEMBL)
POLE3 ProteinQ9NRF9 (Uniprot-TrEMBL)
POLE4 ProteinQ9NR33 (Uniprot-TrEMBL)
PP2AComplexR-HSA-1362456 (Reactome)
PP2AComplexR-HSA-1363265 (Reactome)
PPP2CA ProteinP67775 (Uniprot-TrEMBL)
PPP2CB ProteinP62714 (Uniprot-TrEMBL)
PPP2R1A ProteinP30153 (Uniprot-TrEMBL)
PPP2R1B ProteinP30154 (Uniprot-TrEMBL)
PPP2R2A ProteinP63151 (Uniprot-TrEMBL)
PPP2R3B ProteinQ9Y5P8 (Uniprot-TrEMBL)
PRIM1 ProteinP49642 (Uniprot-TrEMBL)
PRIM2 ProteinP49643 (Uniprot-TrEMBL)
PSMA1 ProteinP25786 (Uniprot-TrEMBL)
PSMA2 ProteinP25787 (Uniprot-TrEMBL)
PSMA3 ProteinP25788 (Uniprot-TrEMBL)
PSMA4 ProteinP25789 (Uniprot-TrEMBL)
PSMA5 ProteinP28066 (Uniprot-TrEMBL)
PSMA6 ProteinP60900 (Uniprot-TrEMBL)
PSMA7 ProteinO14818 (Uniprot-TrEMBL)
PSMB1 ProteinP20618 (Uniprot-TrEMBL)
PSMB10 ProteinP40306 (Uniprot-TrEMBL)
PSMB2 ProteinP49721 (Uniprot-TrEMBL)
PSMB3 ProteinP49720 (Uniprot-TrEMBL)
PSMB4 ProteinP28070 (Uniprot-TrEMBL)
PSMB5 ProteinP28074 (Uniprot-TrEMBL)
PSMB6 ProteinP28072 (Uniprot-TrEMBL)
PSMB7 ProteinQ99436 (Uniprot-TrEMBL)
PSMB8 ProteinP28062 (Uniprot-TrEMBL)
PSMB9 ProteinP28065 (Uniprot-TrEMBL)
PSMC1 ProteinP62191 (Uniprot-TrEMBL)
PSMC2 ProteinP35998 (Uniprot-TrEMBL)
PSMC3 ProteinP17980 (Uniprot-TrEMBL)
PSMC4 ProteinP43686 (Uniprot-TrEMBL)
PSMC5 ProteinP62195 (Uniprot-TrEMBL)
PSMC6 ProteinP62333 (Uniprot-TrEMBL)
PSMD1 ProteinQ99460 (Uniprot-TrEMBL)
PSMD10 ProteinO75832 (Uniprot-TrEMBL)
PSMD11 ProteinO00231 (Uniprot-TrEMBL)
PSMD12 ProteinO00232 (Uniprot-TrEMBL)
PSMD13 ProteinQ9UNM6 (Uniprot-TrEMBL)
PSMD14 ProteinO00487 (Uniprot-TrEMBL)
PSMD2 ProteinQ13200 (Uniprot-TrEMBL)
PSMD3 ProteinO43242 (Uniprot-TrEMBL)
PSMD4 ProteinP55036 (Uniprot-TrEMBL)
PSMD5 ProteinQ16401 (Uniprot-TrEMBL)
PSMD6 ProteinQ15008 (Uniprot-TrEMBL)
PSMD7 ProteinP51665 (Uniprot-TrEMBL)
PSMD8 ProteinP48556 (Uniprot-TrEMBL)
PSMD9 ProteinO00233 (Uniprot-TrEMBL)
PSME1 ProteinQ06323 (Uniprot-TrEMBL)
PSME2 ProteinQ9UL46 (Uniprot-TrEMBL)
PSME3 ProteinP61289 (Uniprot-TrEMBL)
PSMF1 ProteinQ92530 (Uniprot-TrEMBL)
Pi MetaboliteCHEBI:43474 (ChEBI)
PiMetaboliteCHEBI:43474 (ChEBI)
RB1 ProteinP06400 (Uniprot-TrEMBL)
RB1:E2F1,E2F2,E2F3:TFDP1,TFDP2:ComplexR-HSA-68644 (Reactome)
RB1:RNA primer-DNA

primer:origin duplex with DNA

damage
ComplexR-HSA-113646 (Reactome)
RB1ProteinP06400 (Uniprot-TrEMBL)
RBBP4 ProteinQ09028 (Uniprot-TrEMBL)
RBL1 ProteinP28749 (Uniprot-TrEMBL)
RBL1 gene ProteinENSG00000080839 (Ensembl)
RBL1 geneGeneProductENSG00000080839 (Ensembl)
RBL1:Cyclin E/A:CDK2ComplexR-HSA-1363310 (Reactome)
RBL1:E2F4:DP1/2:Cyclin E/A:CDK2ComplexR-HSA-1363307 (Reactome)
RBL1:E2F4:TFDP1,TFDP2ComplexR-HSA-1226088 (Reactome)
RBL1ProteinP28749 (Uniprot-TrEMBL)
RBL2 ProteinQ08999 (Uniprot-TrEMBL)
RBL2:Cyclin E/A:CDK2ComplexR-HSA-1363301 (Reactome)
RBL2:E2F4,E2F5:TFDP1,TFDP2ComplexR-HSA-1226089 (Reactome)
RBL2:E2F4/5:DP1/2:Cyclin E/A:CDK2ComplexR-HSA-1363300 (Reactome)
RBL2ProteinQ08999 (Uniprot-TrEMBL)
RNA primer R-ALL-68422 (Reactome)
RNA primer-DNA

primer:origin duplex with DNA

damage
ComplexR-ALL-113656 (Reactome)
RNA primer-DNA

primer:origin

duplex
ComplexR-HSA-68425 (Reactome)
RNA primer:origin duplex with DNA damage R-ALL-113499 (Reactome)
RPA1 ProteinP27694 (Uniprot-TrEMBL)
RPA1-4ComplexR-HSA-68567 (Reactome)
RPA2 ProteinP15927 (Uniprot-TrEMBL)
RPA3 ProteinP35244 (Uniprot-TrEMBL)
RPA4 ProteinQ13156 (Uniprot-TrEMBL)
RPS27A(1-76) ProteinP62979 (Uniprot-TrEMBL)
RRM2 gene ProteinENSG00000171848 (Ensembl)
RRM2 geneGeneProductENSG00000171848 (Ensembl)
RRM2ProteinP31350 (Uniprot-TrEMBL)
SHFM1 ProteinP60896 (Uniprot-TrEMBL)
SKP1 ProteinP63208 (Uniprot-TrEMBL)
SKP2 ProteinQ13309 (Uniprot-TrEMBL)
Senescence-Associated Secretory Phenotype (SASP)PathwayR-HSA-2559582 (Reactome) The culture medium of senescent cells in enriched in secreted proteins when compared with the culture medium of quiescent i.e. presenescent cells and these secreted proteins constitute the so-called senescence-associated secretory phenotype (SASP), also known as the senescence messaging secretome (SMS). SASP components include inflammatory and immune-modulatory cytokines (e.g. IL6 and IL8), growth factors (e.g. IGFBPs), shed cell surface molecules (e.g. TNF receptors) and survival factors. While the SASP exhibits a wide ranging profile, it is not significantly affected by the type of senescence trigger (oncogenic signalling, oxidative stress or DNA damage) or the cell type (epithelial vs. mesenchymal) (Coppe et al. 2008). However, as both oxidative stress and oncogenic signaling induce DNA damage, the persistent DNA damage may be a deciding SASP initiator (Rodier et al. 2009). SASP components function in an autocrine manner, reinforcing the senescent phenotype (Kuilman et al. 2008, Acosta et al. 2008), and in the paracrine manner, where they may promote epithelial-to-mesenchymal transition (EMT) and malignancy in the nearby premalignant or malignant cells (Coppe et al. 2008). Interleukin-1-alpha (IL1A), a minor SASP component whose transcription is stimulated by the AP-1 (FOS:JUN) complex (Bailly et al. 1996), can cause paracrine senescence through IL1 and inflammasome signaling (Acosta et al. 2013).

Here, transcriptional regulatory processes that mediate the SASP are annotated. DNA damage triggers ATM-mediated activation of TP53, resulting in the increased level of CDKN1A (p21). CDKN1A-mediated inhibition of CDK2 prevents phosphorylation and inactivation of the Cdh1:APC/C complex, allowing it to ubiquitinate and target for degradation EHMT1 and EHMT2 histone methyltransferases. As EHMT1 and EHMT2 methylate and silence the promoters of IL6 and IL8 genes, degradation of these methyltransferases relieves the inhibition of IL6 and IL8 transcription (Takahashi et al. 2012). In addition, oncogenic RAS signaling activates the CEBPB (C/EBP-beta) transcription factor (Nakajima et al. 1993, Lee et al. 2010), which binds promoters of IL6 and IL8 genes and stimulates their transcription (Kuilman et al. 2008, Lee et al. 2010). CEBPB also stimulates the transcription of CDKN2B (p15-INK4B), reinforcing the cell cycle arrest (Kuilman et al. 2008). CEBPB transcription factor has three isoforms, due to three alternative translation start sites. The CEBPB-1 isoform (C/EBP-beta-1) seems to be exclusively involved in growth arrest and senescence, while the CEBPB-2 (C/EBP-beta-2) isoform may promote cellular proliferation (Atwood and Sealy 2010 and 2011). IL6 signaling stimulates the transcription of CEBPB (Niehof et al. 2001), creating a positive feedback loop (Kuilman et al. 2009, Lee et al. 2010). NF-kappa-B transcription factor is also activated in senescence (Chien et al. 2011) through IL1 signaling (Jimi et al. 1996, Hartupee et al. 2008, Orjalo et al. 2009). NF-kappa-B binds IL6 and IL8 promoters and cooperates with CEBPB transcription factor in the induction of IL6 and IL8 transcription (Matsusaka et al. 1993, Acosta et al. 2008). Besides IL6 and IL8, their receptors are also upregulated in senescence (Kuilman et al. 2008, Acosta et al. 2008) and IL6 and IL8 may be master regulators of the SASP.

IGFBP7 is also an SASP component that is upregulated in response to oncogenic RAS-RAF-MAPK signaling and oxidative stress, as its transcription is directly stimulated by the AP-1 (JUN:FOS) transcription factor. IGFBP7 negatively regulates RAS-RAF (BRAF)-MAPK signaling and is important for the establishment of senescence in melanocytes (Wajapeyee et al. 2008).

Please refer to Young and Narita 2009 for a recent review.

Signaling by PTK6PathwayR-HSA-8848021 (Reactome) PTK6 (BRK) is an oncogenic non-receptor tyrosine kinase that functions downstream of ERBB2 (HER2) (Xiang et al. 2008, Peng et al. 2015) and other receptor tyrosine kinases, such as EGFR (Kamalati et al. 1996) and MET (Castro and Lange 2010). Since ERBB2 forms heterodimers with EGFR and since MET can heterodimerize with both ERBB2 and EGFR (Tanizaki et al. 2011), it is not clear if MET and EGFR activate PTK6 directly or act through ERBB2. Levels of PTK6 increase under hypoxic conditions (Regan Anderson et al. 2013, Pires et al. 2014). The kinase activity of PTK6 is negatively regulated by PTPN1 phosphatase (Fan et al. 2013) and SRMS kinase (Fan et al. 2015), as well as the STAT3 target SOCS3 (Gao et al. 2012).

PTK6 activates STAT3-mediated transcription (Ikeda et al. 2009, Ikeda et al. 2010) and may also activate STAT5-mediated transcription (Ikeda et al. 2011). PTK6 promotes cell motility and migration by regulating the activity of RHO GTPases RAC1 (Chen et al. 2004) and RHOA (Shen et al. 2008), and possibly by affecting motility-related kinesins (Lukong and Richard 2008). PTK6 crosstalks with AKT1 (Zhang et al. 2005, Zheng et al. 2010) and RAS signaling cascades (Shen et al. 2008, Ono et al. 2014) and may be involved in MAPK7 (ERK5) activation (Ostrander et al. 2007, Zheng et al. 2012). PTK6 enhances EGFR signaling by inhibiting EGFR down-regulation (Kang et al. 2010, Li et al. 2012, Kang and Lee 2013). PTK6 may also enhance signaling by IGF1R (Fan et al. 2013) and ERBB3 (Kamalati et al. 2000).

PTK6 promotes cell cycle progression by phosphorylating and inactivating CDK inhibitor CDKN1B (p27) (Patel et al. 2015).

PTK6 activity is upregulated in osteopontin (OPN or SPP1)-mediated signaling, leading to increased VEGF expression via PTK6/NF-kappaB/ATF4 signaling path. PTK6 may therefore play a role in VEGF-dependent tumor angiogenesis (Chakraborty et al. 2008).

PTK6 binds and phosphorylates several nuclear RNA-binding proteins, including SAM68 family members (KHDRSB1, KHDRSB2 and KHDRSB3) (Derry et al. 2000, Haegebarth et al. 2004, Lukong et al. 2005) and SFPQ (PSF) (Lukong et al. 2009). The biological role of PTK6 in RNA processing is not known.

For a review of PTK6 function, please refer to Goel and Lukong 2015.

TFDP1 ProteinQ14186 (Uniprot-TrEMBL)
TFDP2 ProteinQ14188 (Uniprot-TrEMBL)
TK1 gene ProteinENSG00000167900 (Ensembl)
TK1 geneGeneProductENSG00000167900 (Ensembl)
TK1ProteinP04183 (Uniprot-TrEMBL)
TOP2A gene ProteinENSG00000131747 (Ensembl)
TOP2A geneGeneProductENSG00000131747 (Ensembl)
TOP2AProteinP11388 (Uniprot-TrEMBL)
TYMS geneGeneProductENSG00000176890 (Ensembl)
TYMSProteinP04818 (Uniprot-TrEMBL)
Transcriptional

activity of SMAD2/SMAD3:SMAD4

heterotrimer
PathwayR-HSA-2173793 (Reactome) In the nucleus, SMAD2/3:SMAD4 heterotrimer complex acts as a transcriptional regulator. The activity of SMAD2/3 complex is regulated both positively and negatively by association with other transcription factors (Chen et al. 2002, Varelas et al. 2008, Stroschein et al. 1999, Wotton et al. 1999). In addition, the activity of SMAD2/3:SMAD4 complex can be inhibited by nuclear protein phosphatases and ubiquitin ligases (Lin et al. 2006, Dupont et al. 2009).
UBA52(1-76) ProteinP62987 (Uniprot-TrEMBL)
UBB(1-76) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(153-228) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(77-152) ProteinP0CG47 (Uniprot-TrEMBL)
UBC(1-76) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(153-228) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(229-304) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(305-380) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(381-456) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(457-532) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(533-608) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(609-684) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(77-152) ProteinP0CG48 (Uniprot-TrEMBL)
Ub-p-T401,S672,1035-RBL2ComplexR-HSA-1363324 (Reactome)
UbComplexR-HSA-68524 (Reactome)
WEE1ProteinP30291 (Uniprot-TrEMBL)
cyclin R-HSA-68379 (Reactome)
hyperphosphorylated RB1ProteinP06400 (Uniprot-TrEMBL) The pRB C-terminus contains a cluster of seven candidate in vivo cdk phosphorylation sites (residues 795, 807, 811, 821, and 826) and is phosphorylated in vitro by cyclin A, cyclin E, and cyclin D-associated kinases.
monophosphorylated RB1ComplexR-HSA-9687348 (Reactome)
origin of replicationR-ALL-68419 (Reactome)
origin of replication R-ALL-68419 (Reactome)
p-12Y-JAK2 ProteinO60674 (Uniprot-TrEMBL)
p-CDK2 ProteinP24941 (Uniprot-TrEMBL)
p-MCM2-7ComplexR-HSA-68569 (Reactome)
p-MuvB complexComplexR-HSA-1362259 (Reactome)
p-S130-CDKN1A ProteinP38936 (Uniprot-TrEMBL)
p-S230-RB1 ProteinP06400 (Uniprot-TrEMBL)
p-S249-RB1 ProteinP06400 (Uniprot-TrEMBL)
p-S252-RB1 ProteinP06400 (Uniprot-TrEMBL)
p-S28-LIN52 ProteinQ52LA3 (Uniprot-TrEMBL)
p-S608-RB1 ProteinP06400 (Uniprot-TrEMBL)
p-S612-RB1 ProteinP06400 (Uniprot-TrEMBL)
p-S780-RB1 ProteinP06400 (Uniprot-TrEMBL)
p-S788-RB1 ProteinP06400 (Uniprot-TrEMBL)
p-S795-RB1 ProteinP06400 (Uniprot-TrEMBL)
p-S807-RB1 ProteinP06400 (Uniprot-TrEMBL)
p-S811-RB1 ProteinP06400 (Uniprot-TrEMBL)
p-T,p-S-AKTComplexR-HSA-202074 (Reactome)
p-T-CDKN1A/BComplexR-HSA-198605 (Reactome)
p-T145-CDKN1A ProteinP38936 (Uniprot-TrEMBL)
p-T157-CDKN1B ProteinP46527 (Uniprot-TrEMBL)
p-T160-CDK2 ProteinP24941 (Uniprot-TrEMBL)
p-T172-CDK4 ProteinP11802 (Uniprot-TrEMBL)
p-T172-CDK4,p-T177-CDK6:CCND:CDKN1A,CDKN1B,(CDKN1C); p-T172-CDK4,p-T177-CDK6:CCND; (p-T172-CDK4,p-T177-CDK6:CCND:p-Y88-CDKN1B)ComplexR-HSA-8949896 (Reactome)
p-T177-CDK6 ProteinQ00534 (Uniprot-TrEMBL)
p-T187-CDKN1B ProteinP46527 (Uniprot-TrEMBL)
p-T305,S472-AKT3 ProteinQ9Y243 (Uniprot-TrEMBL)
p-T308,S473-AKT1 ProteinP31749 (Uniprot-TrEMBL)
p-T309,S474-AKT2 ProteinP31751 (Uniprot-TrEMBL)
p-T356-RB1 ProteinP06400 (Uniprot-TrEMBL)
p-T369,S640,S964,S975-RBL1ProteinP28749 (Uniprot-TrEMBL)
p-T373-RB1 ProteinP06400 (Uniprot-TrEMBL)
p-T401,S672,1035-RBL2:SCF(Skp2):Cks1ComplexR-HSA-1363326 (Reactome)
p-T401,S672,S1035-RBL2 ProteinQ08999 (Uniprot-TrEMBL)
p-T401,S672,S1035-RBL2ProteinQ08999 (Uniprot-TrEMBL)
p-T821-RB1 ProteinP06400 (Uniprot-TrEMBL)
p-T826-RB1 ProteinP06400 (Uniprot-TrEMBL)
p-Y226,Y393-ABL1 ProteinP00519 (Uniprot-TrEMBL)
p-Y342-PTK6 ProteinQ13882 (Uniprot-TrEMBL)
p-Y342-PTK6:CDKN1B:(CDK4:CCND1,(CDK2:CCNE1))ComplexR-HSA-8848415 (Reactome)
p-Y342-PTK6ProteinQ13882 (Uniprot-TrEMBL)
p-Y397-LYN ProteinP07948 (Uniprot-TrEMBL)
p-Y419-SRC ProteinP12931-1 (Uniprot-TrEMBL)
p-Y77-CDKN1A ProteinP38936 (Uniprot-TrEMBL)
p-Y88-CDKN1B ProteinP46527 (Uniprot-TrEMBL)
p-Y88-CDKN1B:(CDK4:CCND1,(CDK2:CCNE1))ComplexR-HSA-8848441 (Reactome)
p-Y91-CDKN1C ProteinP49918 (Uniprot-TrEMBL)
p16INK4A ProteinP42771 (Uniprot-TrEMBL)
pre-replicative complexComplexR-HSA-68559 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
(p-Y342-PTK6,p-Y397-LYN,p-Y226,Y393-ABL1,p-Y419-SRC,p-5Y-JAK2)mim-catalysisR-HSA-8942607 (Reactome)
26S proteasomemim-catalysisR-HSA-187574 (Reactome)
ADPArrowR-HSA-1226094 (Reactome)
ADPArrowR-HSA-1226095 (Reactome)
ADPArrowR-HSA-1362270 (Reactome)
ADPArrowR-HSA-187520 (Reactome)
ADPArrowR-HSA-188350 (Reactome)
ADPArrowR-HSA-188390 (Reactome)
ADPArrowR-HSA-198613 (Reactome)
ADPArrowR-HSA-68954 (Reactome)
ADPArrowR-HSA-69195 (Reactome)
ADPArrowR-HSA-69227 (Reactome)
ADPArrowR-HSA-8848436 (Reactome)
ADPArrowR-HSA-8942607 (Reactome)
ADPArrowR-HSA-8942836 (Reactome)
ATPR-HSA-1226094 (Reactome)
ATPR-HSA-1226095 (Reactome)
ATPR-HSA-1362270 (Reactome)
ATPR-HSA-187520 (Reactome)
ATPR-HSA-188350 (Reactome)
ATPR-HSA-188390 (Reactome)
ATPR-HSA-198613 (Reactome)
ATPR-HSA-68954 (Reactome)
ATPR-HSA-69195 (Reactome)
ATPR-HSA-69227 (Reactome)
ATPR-HSA-8848436 (Reactome)
ATPR-HSA-8942607 (Reactome)
ATPR-HSA-8942836 (Reactome)
Aborted replication complexArrowR-HSA-113643 (Reactome)
CABLES1ArrowR-HSA-69195 (Reactome)
CAKmim-catalysisR-HSA-188350 (Reactome)
CAKmim-catalysisR-HSA-8942836 (Reactome)
CCNA1 geneR-HSA-8961888 (Reactome)
CCNA1 geneR-HSA-8961895 (Reactome)
CCNA1ArrowR-HSA-8961895 (Reactome)
CCNA2 geneR-HSA-8964580 (Reactome)
CCNA2 geneR-HSA-8964588 (Reactome)
CCNA2ArrowR-HSA-8964588 (Reactome)
CCNA:p-T160-CDK2,CCNE:p-T160-CDK2ArrowR-HSA-187574 (Reactome)
CCNE1 geneR-HSA-8961840 (Reactome)
CCNE1 geneR-HSA-8961846 (Reactome)
CCNE1ArrowR-HSA-8961846 (Reactome)
CCNE:CDK2ArrowR-HSA-157906 (Reactome)
CCNE:CDK2ArrowR-HSA-69191 (Reactome)
CCNE:CDK2ArrowR-HSA-69199 (Reactome)
CCNE:CDK2R-HSA-157906 (Reactome)
CCNE:CDK2R-HSA-188350 (Reactome)
CCNE:CDK2R-HSA-69195 (Reactome)
CCNE:CDK2R-HSA-69562 (Reactome)
CCNE:p-T160-CDK2:hypophosphorylated RB1ArrowR-HSA-188386 (Reactome)
CCNE:p-T160-CDK2:hypophosphorylated RB1R-HSA-188390 (Reactome)
CCNE:p-T160-CDK2:hypophosphorylated RB1mim-catalysisR-HSA-188390 (Reactome)
CCNER-HSA-69191 (Reactome)
CDC25A geneR-HSA-188345 (Reactome)
CDC25A geneR-HSA-8932400 (Reactome)
CDC25A geneR-HSA-8961961 (Reactome)
CDC25A geneR-HSA-8964471 (Reactome)
CDC25AArrowR-HSA-188345 (Reactome)
CDC25Amim-catalysisR-HSA-69199 (Reactome)
CDC45 geneR-HSA-8961907 (Reactome)
CDC45 geneR-HSA-8961915 (Reactome)
CDC45ArrowR-HSA-8961915 (Reactome)
CDC45R-HSA-68917 (Reactome)
CDC6 geneR-HSA-8961619 (Reactome)
CDC6 geneR-HSA-8961620 (Reactome)
CDC6 geneR-HSA-8964498 (Reactome)
CDC6ArrowR-HSA-8961619 (Reactome)
CDK1 geneR-HSA-8961920 (Reactome)
CDK1 geneR-HSA-8961934 (Reactome)
CDK1 geneR-HSA-8964567 (Reactome)
CDK1ArrowR-HSA-8961934 (Reactome)
CDK2R-HSA-69191 (Reactome)
CDK4,CDK6:CCND:CDKN1A,CDKN1B,(CDKN1C); CDK4,CDK6:CCND; (CDK4,CDK6:CCND:p-Y88-CDKN1B)ArrowR-HSA-8942803 (Reactome)
CDK4,CDK6:CCND:CDKN1A,CDKN1B,(CDKN1C); CDK4,CDK6:CCND; (CDK4,CDK6:CCND:p-Y88-CDKN1B)R-HSA-8942803 (Reactome)
CDK4,CDK6:CCND:CDKN1A,CDKN1B,(CDKN1C); CDK4,CDK6:CCND; (CDK4,CDK6:CCND:p-Y88-CDKN1B)R-HSA-8942836 (Reactome)
CDK4,CDK6:CCND:CDKN1A,CDKN1B,(CDKN1C)ArrowR-HSA-8941915 (Reactome)
CDK4,CDK6:CCND:CDKN1A,CDKN1B,(CDKN1C)R-HSA-8942607 (Reactome)
CDK4,CDK6:CCNDArrowR-HSA-8941895 (Reactome)
CDK4,CDK6:CCNDR-HSA-8941915 (Reactome)
CDK4,CDK6:INK4ArrowR-HSA-182594 (Reactome)
CDK4,CDK6:INK4TBarR-HSA-8941895 (Reactome)
CDK4,CDK6R-HSA-182594 (Reactome)
CDK4,CDK6R-HSA-8941895 (Reactome)
CDK4/6:CCND:p-Y77-CDKN1A,p-Y88-CDKN1B,(p-Y91-CDKN1C)ArrowR-HSA-8942607 (Reactome)
CDK:DDK:MCM10:active

pre-replicative

complex:CDC45:RPA1-4
ArrowR-HSA-68914 (Reactome)
CDK:DDK:MCM10:active

pre-replicative

complex:CDC45:RPA1-4
ArrowR-HSA-68916 (Reactome)
CDK:DDK:MCM10:active

pre-replicative

complex:CDC45:RPA1-4
ArrowR-HSA-68960 (Reactome)
CDK:DDK:MCM10:active

pre-replicative

complex:CDC45
ArrowR-HSA-68917 (Reactome)
CDK:DDK:MCM10:active

pre-replicative

complex:CDC45
R-HSA-68916 (Reactome)
CDK:DDK:MCM10:active

pre-replicative

complex
ArrowR-HSA-68918 (Reactome)
CDK:DDK:MCM10:active

pre-replicative

complex
R-HSA-68917 (Reactome)
CDKN1A,CDKN1B,(CDKN1C)R-HSA-8941915 (Reactome)
CDKN1A,CDKN1BR-HSA-198613 (Reactome)
CDKN1A,CDKN1BR-HSA-69562 (Reactome)
CDKN1A,CDKN1Bmim-catalysisR-HSA-69562 (Reactome)
CDKN1AArrowR-HSA-187828 (Reactome)
CDKN1AR-HSA-187828 (Reactome)
CDKN1B:(CDK4:CCND1,(CDK2:CCNE1))R-HSA-8848414 (Reactome)
CDKN1BArrowR-HSA-187506 (Reactome)
CDKN1BR-HSA-187506 (Reactome)
CDKR-HSA-68918 (Reactome)
CDT1 geneR-HSA-8961946 (Reactome)
CDT1 geneR-HSA-8961952 (Reactome)
CDT1ArrowR-HSA-68940 (Reactome)
CDT1ArrowR-HSA-8961952 (Reactome)
CDT1R-HSA-69299 (Reactome)
CKS1BR-HSA-187545 (Reactome)
CUL1:SKP1:SKP2:CKS1BArrowR-HSA-1363331 (Reactome)
CUL1:SKP1:SKP2:CKS1BArrowR-HSA-187545 (Reactome)
CUL1:SKP1:SKP2:CKS1BArrowR-HSA-187574 (Reactome)
CUL1:SKP1:SKP2:CKS1BR-HSA-1363328 (Reactome)
CUL1:SKP1:SKP2:CKS1BR-HSA-187552 (Reactome)
CUL1:SKP1:SKP2R-HSA-187545 (Reactome)
Cdt1:gemininArrowR-HSA-69299 (Reactome)
Cyclin

B:CDK1:ORC:origin

of replication
ArrowR-HSA-113638 (Reactome)
Cyclin E/A:CDK2:p-S130-CDKN1A,p-T187-CDKN1B:CUL1:SKP1:SKP2:CKS1B:3xubiquitinArrowR-HSA-187575 (Reactome)
Cyclin E/A:CDK2:p-S130-CDKN1A,p-T187-CDKN1B:CUL1:SKP1:SKP2:CKS1B:3xubiquitinR-HSA-187574 (Reactome)
Cyclin E/A:CDK2:p-S130-CDKN1A,p-T187-CDKN1B:CUL1:SKP1:SKP2:CKS1BArrowR-HSA-187552 (Reactome)
Cyclin E/A:CDK2:p-S130-CDKN1A,p-T187-CDKN1B:CUL1:SKP1:SKP2:CKS1BR-HSA-187575 (Reactome)
Cyclin E/A:CDK2:p-S130-CDKN1A,p-T187-CDKN1B:CUL1:SKP1:SKP2:CKS1Bmim-catalysisR-HSA-187575 (Reactome)
Cyclin E/A:p-T160-CDK2:CDKN1A,CDKN1BR-HSA-187520 (Reactome)
Cyclin E/A:p-T160-CDK2:CDKN1A,CDKN1Bmim-catalysisR-HSA-187520 (Reactome)
Cyclin E/A:p-T160-CDK2:p-S130-CDKN1A,p-T187-CDKN1BArrowR-HSA-187520 (Reactome)
Cyclin E/A:p-T160-CDK2:p-S130-CDKN1A,p-T187-CDKN1BR-HSA-187552 (Reactome)
Cyclin E:CDK2:CDKN1A,CDKN1BArrowR-HSA-69562 (Reactome)
Cyclin B:CDK1R-HSA-113638 (Reactome)
Cyclin DR-HSA-8941895 (Reactome)
Cyclin E/A:CDK2R-HSA-1363303 (Reactome)
Cyclin E/A:CDK2R-HSA-1363306 (Reactome)
Cyclin E/A:CDK2R-HSA-1363311 (Reactome)
Cyclin E/A:CDK2R-HSA-1363314 (Reactome)
Cyclin E:p-CDK2ArrowR-HSA-69195 (Reactome)
Cyclin E:p-CDK2R-HSA-69199 (Reactome)
Cyclin E:p-T160-CDK2ArrowR-HSA-188350 (Reactome)
Cyclin E:p-T160-CDK2ArrowR-HSA-188390 (Reactome)
Cyclin E:p-T160-CDK2R-HSA-188386 (Reactome)
Cyclin E:p-T160-CDK2TBarR-HSA-9018017 (Reactome)
DDKR-HSA-68918 (Reactome)
DDKmim-catalysisR-HSA-68954 (Reactome)
DHFR geneR-HSA-8961863 (Reactome)
DHFR geneR-HSA-8961874 (Reactome)
DHFRArrowR-HSA-8961874 (Reactome)
DNA polymerase

alpha:primase:DNA polymerase alpha:origin

complex
ArrowR-HSA-68914 (Reactome)
DNA polymerase alpha:primaseArrowR-HSA-113504 (Reactome)
DNA polymerase alpha:primaseR-HSA-68914 (Reactome)
DNA polymerase

epsilon:origin

complex
ArrowR-HSA-68960 (Reactome)
DNA polymerase

epsilon:origin

complex
R-HSA-68914 (Reactome)
DNA polymerase epsilonR-HSA-68960 (Reactome)
DREAM complex:CDC25A geneArrowR-HSA-8964471 (Reactome)
DREAM complex:CDC25A geneTBarR-HSA-188345 (Reactome)
DREAM complex:CDC6 geneArrowR-HSA-8964498 (Reactome)
DREAM complex:CDC6 geneTBarR-HSA-8961619 (Reactome)
DREAM complex:E2F1 geneArrowR-HSA-8964482 (Reactome)
DREAM complex:E2F1 geneTBarR-HSA-8964513 (Reactome)
DREAM complex:PCNA geneArrowR-HSA-8964465 (Reactome)
DREAM complex:PCNA geneTBarR-HSA-8961665 (Reactome)
DREAM complex:RBL1 geneArrowR-HSA-8964492 (Reactome)
DREAM complex:RBL1 geneTBarR-HSA-8964525 (Reactome)
DREAM complex:TOP2A geneArrowR-HSA-8964475 (Reactome)
DREAM complex:TOP2A geneTBarR-HSA-8964531 (Reactome)
DREAM complexArrowR-HSA-1362261 (Reactome)
DREAM complexR-HSA-8964465 (Reactome)
DREAM complexR-HSA-8964471 (Reactome)
DREAM complexR-HSA-8964475 (Reactome)
DREAM complexR-HSA-8964482 (Reactome)
DREAM complexR-HSA-8964492 (Reactome)
DREAM complexR-HSA-8964498 (Reactome)
DYRK1Amim-catalysisR-HSA-1362270 (Reactome)
E2F1 geneR-HSA-8964482 (Reactome)
E2F1 geneR-HSA-8964513 (Reactome)
E2F1 geneR-HSA-8964550 (Reactome)
E2F1,E2F2,E2F3:TFDP1,TFDP2R-HSA-9018017 (Reactome)
E2F1:TFDP1,TFDP2:CCNA1 geneArrowR-HSA-8961888 (Reactome)
E2F1:TFDP1,TFDP2:CCNA1 geneArrowR-HSA-8961895 (Reactome)
E2F1:TFDP1,TFDP2:CCNE1 geneArrowR-HSA-8961840 (Reactome)
E2F1:TFDP1,TFDP2:CCNE1 geneArrowR-HSA-8961846 (Reactome)
E2F1:TFDP1,TFDP2:CDC25A geneArrowR-HSA-188345 (Reactome)
E2F1:TFDP1,TFDP2:CDC25A geneArrowR-HSA-8961961 (Reactome)
E2F1:TFDP1,TFDP2:CDC45 geneArrowR-HSA-8961907 (Reactome)
E2F1:TFDP1,TFDP2:CDC45 geneArrowR-HSA-8961915 (Reactome)
E2F1:TFDP1,TFDP2:CDC6 geneArrowR-HSA-8961619 (Reactome)
E2F1:TFDP1,TFDP2:CDC6 geneArrowR-HSA-8961620 (Reactome)
E2F1:TFDP1,TFDP2:CDK1 geneArrowR-HSA-8961920 (Reactome)
E2F1:TFDP1,TFDP2:CDK1 geneArrowR-HSA-8961934 (Reactome)
E2F1:TFDP1,TFDP2:CDT1 geneArrowR-HSA-8961946 (Reactome)
E2F1:TFDP1,TFDP2:CDT1 geneArrowR-HSA-8961952 (Reactome)
E2F1:TFDP1,TFDP2:DHFR geneArrowR-HSA-8961863 (Reactome)
E2F1:TFDP1,TFDP2:DHFR geneArrowR-HSA-8961874 (Reactome)
E2F1:TFDP1,TFDP2:FBXO5 geneArrowR-HSA-8961688 (Reactome)
E2F1:TFDP1,TFDP2:FBXO5 geneArrowR-HSA-8961699 (Reactome)
E2F1:TFDP1,TFDP2:ORC1 geneArrowR-HSA-8961671 (Reactome)
E2F1:TFDP1,TFDP2:ORC1 geneArrowR-HSA-8961678 (Reactome)
E2F1:TFDP1,TFDP2:PCNA geneArrowR-HSA-8961651 (Reactome)
E2F1:TFDP1,TFDP2:PCNA geneArrowR-HSA-8961665 (Reactome)
E2F1:TFDP1,TFDP2:POLA1 geneArrowR-HSA-8961632 (Reactome)
E2F1:TFDP1,TFDP2:POLA1 geneArrowR-HSA-8961636 (Reactome)
E2F1:TFDP1,TFDP2:RRM2 geneArrowR-HSA-8961972 (Reactome)
E2F1:TFDP1,TFDP2:RRM2 geneArrowR-HSA-8961982 (Reactome)
E2F1:TFDP1,TFDP2:TK1 geneArrowR-HSA-8961991 (Reactome)
E2F1:TFDP1,TFDP2:TK1 geneArrowR-HSA-8962039 (Reactome)
E2F1:TFDP1,TFDP2ArrowR-HSA-8962050 (Reactome)
E2F1:TFDP1,TFDP2R-HSA-113643 (Reactome)
E2F1:TFDP1,TFDP2R-HSA-8961620 (Reactome)
E2F1:TFDP1,TFDP2R-HSA-8961636 (Reactome)
E2F1:TFDP1,TFDP2R-HSA-8961651 (Reactome)
E2F1:TFDP1,TFDP2R-HSA-8961671 (Reactome)
E2F1:TFDP1,TFDP2R-HSA-8961688 (Reactome)
E2F1:TFDP1,TFDP2R-HSA-8961840 (Reactome)
E2F1:TFDP1,TFDP2R-HSA-8961863 (Reactome)
E2F1:TFDP1,TFDP2R-HSA-8961888 (Reactome)
E2F1:TFDP1,TFDP2R-HSA-8961907 (Reactome)
E2F1:TFDP1,TFDP2R-HSA-8961920 (Reactome)
E2F1:TFDP1,TFDP2R-HSA-8961946 (Reactome)
E2F1:TFDP1,TFDP2R-HSA-8961961 (Reactome)
E2F1:TFDP1,TFDP2R-HSA-8961972 (Reactome)
E2F1:TFDP1,TFDP2R-HSA-8961991 (Reactome)
E2F1ArrowR-HSA-8964513 (Reactome)
E2F4,E2F5:TFDP1,TFDP2ArrowR-HSA-1226094 (Reactome)
E2F4:TFDP1,TFDP2ArrowR-HSA-1226095 (Reactome)
E2F6:(TFDP1,TFDP2):RRM2 geneTBarR-HSA-8961982 (Reactome)
FBXO5 geneR-HSA-8961688 (Reactome)
FBXO5 geneR-HSA-8961699 (Reactome)
FBXO5ArrowR-HSA-8961699 (Reactome)
GMNNR-HSA-69299 (Reactome)
H2OR-HSA-113503 (Reactome)
H2OR-HSA-1363274 (Reactome)
H2OR-HSA-1363276 (Reactome)
H2OR-HSA-69199 (Reactome)
HDAC1:RBL1:E2F4:TFDP1,TFDP2ArrowR-HSA-1227671 (Reactome)
HDAC1:RBL2:E2F4,E2F5:TFDP1,TFDP2; HDAC1:RBL1:E2F4:TFDP1,TFDP2:CCNA2 geneArrowR-HSA-8964580 (Reactome)
HDAC1:RBL2:E2F4,E2F5:TFDP1,TFDP2; HDAC1:RBL1:E2F4:TFDP1,TFDP2:CCNA2 geneTBarR-HSA-8964588 (Reactome)
HDAC1:RBL2:E2F4,E2F5:TFDP1,TFDP2; HDAC1:RBL1:E2F4:TFDP1,TFDP2:CDK1 geneArrowR-HSA-8964567 (Reactome)
HDAC1:RBL2:E2F4,E2F5:TFDP1,TFDP2; HDAC1:RBL1:E2F4:TFDP1,TFDP2:CDK1 geneTBarR-HSA-8961934 (Reactome)
HDAC1:RBL2:E2F4,E2F5:TFDP1,TFDP2; HDAC1:RBL1:E2F4:TFDP1,TFDP2:E2F1 geneArrowR-HSA-8964550 (Reactome)
HDAC1:RBL2:E2F4,E2F5:TFDP1,TFDP2; HDAC1:RBL1:E2F4:TFDP1,TFDP2:MYBL2 geneArrowR-HSA-8964561 (Reactome)
HDAC1:RBL2:E2F4,E2F5:TFDP1,TFDP2; HDAC1:RBL1:E2F4:TFDP1,TFDP2:MYBL2 geneTBarR-HSA-8978926 (Reactome)
HDAC1:RBL2:E2F4,E2F5:TFDP1,TFDP2; HDAC1:RBL1:E2F4:TFDP1,TFDP2R-HSA-8964550 (Reactome)
HDAC1:RBL2:E2F4,E2F5:TFDP1,TFDP2; HDAC1:RBL1:E2F4:TFDP1,TFDP2R-HSA-8964561 (Reactome)
HDAC1:RBL2:E2F4,E2F5:TFDP1,TFDP2; HDAC1:RBL1:E2F4:TFDP1,TFDP2R-HSA-8964567 (Reactome)
HDAC1:RBL2:E2F4,E2F5:TFDP1,TFDP2; HDAC1:RBL1:E2F4:TFDP1,TFDP2R-HSA-8964580 (Reactome)
HDAC1:RBL2:E2F4,E2F5:TFDP1,TFDP2ArrowR-HSA-1227670 (Reactome)
HDAC1R-HSA-1227670 (Reactome)
HDAC1R-HSA-1227671 (Reactome)
INK4R-HSA-182594 (Reactome)
MCM10:active

pre-replicative

complex
ArrowR-HSA-68940 (Reactome)
MCM10:active

pre-replicative

complex
R-HSA-68918 (Reactome)
MCM10:pre-replicative complexArrowR-HSA-68919 (Reactome)
MCM10:pre-replicative complexR-HSA-68940 (Reactome)
MCM10R-HSA-68919 (Reactome)
MCM2-7R-HSA-68954 (Reactome)
MYBL2 geneR-HSA-8964561 (Reactome)
MYBL2 geneR-HSA-8978926 (Reactome)
MYBL2ArrowR-HSA-8978926 (Reactome)
MYC:MAX:CDC25A geneArrowR-HSA-188345 (Reactome)
MYC:MAX:CDC25A geneArrowR-HSA-8932400 (Reactome)
MYC:MAXR-HSA-8932400 (Reactome)
MuvB complexR-HSA-1362270 (Reactome)
ORC1 geneR-HSA-8961671 (Reactome)
ORC1 geneR-HSA-8961678 (Reactome)
ORC1ArrowR-HSA-8961678 (Reactome)
ORC:origin of replicationR-HSA-113638 (Reactome)
PCNA geneR-HSA-8961651 (Reactome)
PCNA geneR-HSA-8961665 (Reactome)
PCNA geneR-HSA-8964465 (Reactome)
PCNAArrowR-HSA-8961665 (Reactome)
POLA1 geneR-HSA-8961632 (Reactome)
POLA1 geneR-HSA-8961636 (Reactome)
POLA1ArrowR-HSA-8961632 (Reactome)
PP2Amim-catalysisR-HSA-113503 (Reactome)
PP2Amim-catalysisR-HSA-1363274 (Reactome)
PP2Amim-catalysisR-HSA-1363276 (Reactome)
PiArrowR-HSA-113503 (Reactome)
PiArrowR-HSA-1363274 (Reactome)
PiArrowR-HSA-1363276 (Reactome)
PiArrowR-HSA-69199 (Reactome)
R-HSA-113503 (Reactome) Dephoshorylation of RB1 by the PP2A complex containing the regulatory subunit PPP2R3B (PR70) (Magenta et al. 2008) is needed for loading of RB1 to the DNA damage sites during S phase of the cell cycle. RB1 suppresses replication of damaged DNA during S phase (Knudsen et al. 2000, Avni et al. 2003).
R-HSA-113504 (Reactome) At the beginning of this reaction, 1 molecule of 'RNA primer-DNA primer:origin duplex' is present. At the end of this reaction, 1 molecule of 'DNA polymerase alpha:primase', and 1 molecule of 'RNA primer-DNA primer:origin duplex with DNA damage' are present.
This reaction takes place in the 'nucleus' (Gambus et al. 2009, Remus et al. 2009, Chattopadhyay et al.2007, Fien et al. 2004).
R-HSA-113638 (Reactome) This event is inferred from the fission yeast. Cyclin B activity is thought to inhibit pre-RC formation by first associating with ORC during DNA replication.
R-HSA-113643 (Reactome) This set of events is inferred from annotated events in Drosophila.

Rb1 is normally hyperphosphorylated by CycD/CDK4/CDK6 and Cyclin E/CDK2 for transition into S-phase. PP2A can then reverse this reaction, in this case, in response to DNA damage induced checkpoint.
R-HSA-1226094 (Reactome) At G1 entry from G0, p130 (RBL2) is phosphorylated on three threonine and serine residues by cyclin D1 dependent kinases CDK4 and/or CDK6, leading to dissociation of p130 (RBL2) from complexes it formed with E2F4 or E2F5 and DP1 or DP2. This is thought to promote translocation of E2F4 and E2F5, which lack nuclear localization signals, to the cytosol, allowing activating E2Fs (E2F1, E2F2 and E2F3) to bind E2F promoters and activate transcription of genes needed for G1 progression.
R-HSA-1226095 (Reactome) In late G1, cyclin D dependent kinases CDK4 and CDK6 phosphorylate RBL1 (p107) on four serine and threonine residues (S964, S975, T369 and S640), leading to dissociation of phosphorylated RBL1 (p107) from E2F4 in complex with either DP-1 or DP-2. E2F4, which lacks nuclear localization signal, is then thought to translocate to the cytosol, allowing E2F promoter sites to become occupied by activating E2Fs (E2F1, E2F2, and E2F3), resulting in transcription of E2F targets needed for cell cycle progression.
R-HSA-1227670 (Reactome) p130 (RBL2) in complex with E2F4 or E2F5 and DP1 or DP2 recruits histone deacetylase HDAC1, probably in complex with other chromatin modification factors, and represses transcription of E2F target promoters during G0 in quiescent cells.
R-HSA-1227671 (Reactome) p107 (RBL1) in complex with E2F4 and DP1 or DP2 recruits histone deacetylase HDAC1 (possibly in complex with other chromatin modification proteins) through LXCXE-like motif, shared by pocket proteins, to repress transcription of E2F target genes in early G1.
R-HSA-1362261 (Reactome) In G0 and early G1, p130 (RBL2) bound to E2F4 or E2F5 and DP1 or DP2 associates with the MuvB complex, consisting of LIN9, LIN37, LIN52, LIN54 and RBBP4 to form evolutionarily conserved DREAM complex. Phosphorylation of LIN52 on serine residue S28 is critical for association of MuvB complex with p130 (RBL2).
R-HSA-1362270 (Reactome) LIN52 subunit of MuvB complex is phosphorylated by the protein kinase DYRK1A on the serine residue S28, promoting association of MuvB with p130 (RBL2). From model organism studies, DYRK proteins are known to function in cell cycle regulation, differentiation and stress response.
R-HSA-1363274 (Reactome) Dephosphorylation of p107 (RBL1) by PP2A complex containing either PPP2R3B (B" beta) or PPP2R2A (B alpha) regulatory subunit plays a role in maintaining the equilibrium of hyperphosphorylated and hypophosphorylated p107 (RBL1), through counteracting action of cyclin dependent kinases (CDKs) throughout the cell cycle. It is assumed that PP2A dephosphorylates p107 (RBL1) on all four phosphorylation sites, but further experiments are needed to confirm this.
R-HSA-1363276 (Reactome) Dephosphorylation of p130 (RBL2) by PP2A complex containing either PPP2R3B (B" beta) or PPP2R2A (B alpha) regulatory subunit plays a role in maintaining the equilibrium of hyperphosphorylated and hypophosphorylated p130 (RBL2), through counteracting action of cyclin dependent kinases (CDKs). It is assumed that PP2A dephosphorylates p130 (RBL2) on all three phosphorylation sites, but further experiments are needed to confirm this.
R-HSA-1363303 (Reactome) p130 (RBL2) in complex with E2F4/5 and DP1/2 binds to cyclin A or cyclin E in complex with CDK2 through its conserved LFG pocket domain motif and amino terminus, leading to inhibition of CDK2 kinase activity and suppression of cellular growth.
R-HSA-1363306 (Reactome) p130 (RBL2) is able to bind complexes of CDK2 with either cyclin A or cyclin E through the cyclin-binding LFG motif within the pocket domain, which is conserved in p107 (RBL1) and p21/WAF1/Cip1 family of cyclin-dependent kinases. In addition to LFG motif, amino terminal region of p130 (RBL2), conserved in p107 (RBL1), is necessary for inhibition of CDK2 kinase activity. Presence of E2F is not required for this interaction.
R-HSA-1363311 (Reactome) p107 (RBL1) in complex with E2F4 and DP1/2 binds to cyclin A or cyclin E in complex with CDK2 through its conserved LFG pocket domain motif and amino terminus, leading to inhibition of CDK2 kinase activity and suppression of cellular growth.
R-HSA-1363314 (Reactome) p107 (RBL1) is able to bind complexes of CDK2 with either cyclin A or cyclin E, through cyclin-binding LFG motif in the pocket domain, which is conserved in p130 (RBL2) and p21/WAF1/Cip1 family of cyclin-dependent kinase inhibitors. In addition to the LFG motif, the amino terminal sequence conserved in the p107 (RBL1) and p130 (RBL2) is needed for inhibition of CDK2 kinase activity. Presence of E2F is not required for this interaction.
R-HSA-1363328 (Reactome) Phosphorylated p130 (RBL2) binds SCF (Skp2) ubiquitin ligase in complex with Cks1. Phosphorylation of p130 (RBL2) serine residue S672 by CDK4/6 is critical for this interaction.
R-HSA-1363331 (Reactome) As quiescent G0 cells reenter the cell cycle, p130 (RBL2) is phosphorylated by CDK4/6. This phosphorylated p130 (RBL2) binds ubiquitin ligase SCF (Skp2) in complex with Cks1, and is subsequently ubiquitinated and degraded similarly to p27, which is another target of SCF (Skp2).
R-HSA-157906 (Reactome) Follow their formation, the Cyclin E:Cdk2 complexes are translocated to the nucleus.
R-HSA-182594 (Reactome) Prior to mitogen activation, the inhibitory proteins of the INK4 family (p15, p16, p18, and p19) associate with the catalytic domains of free CDK4 and CDK6, preventing their association with D type cyclins (CCND1, CCND2 and CCND3), and thus their activation and their inhibitory phosphorylation of the RB family (Serrano et al. 1993, Hannon and Beach 1994, Guan et al. 1994, Guan et al. 1996, Parry et al. 1995). Inactivation and defects of RB1 strongly upregulate p16INK4A (Parry et al. 1995).
R-HSA-187506 (Reactome) p27 translocates to the nucleoplasm where it associates with CyclinE:Cdk2 complexes. Localization of p27 to the nucleus is necessary to inhibit Cdk activation by Cdk-activating kinase.
R-HSA-187520 (Reactome) The interaction between the Skp2 subunit of the SCF(Skp2) complex and p27 is dependent upon Cdk2:Cyclin A/E mediated phosphorylation of p27 at Thr 187 (Carrano et al, 1999; Tsvetkov et al, 1999). There is evidence that Cyclin A/B:Cdk1 can also bind and phosphorylate p27 on Thr 187 (Nakayama et al., 2004). This phosphorylation is also essential for the subsequent ubiquitination of p27.
R-HSA-187545 (Reactome) The accessory protein, Cks1 promotes efficient interaction between phosphorylated p27 and the SCF (Skp2) complex (Ganoth et al., 2001; Spruck et al., 2001). Cks1 binds to Skp2 in the leucine-rich repeat (LRR) domain and C-terminal tail (Hao et al., 2005). The phosphorylated Thr187 side chain of p27 associates with a phosphate binding site on Cks1, and the side chain containing Glu185 is positioned in the interface between Skp2 and Cks1 where it interacts with both (Hao et al., 2005).
R-HSA-187552 (Reactome) The association of Cks1 with both Skp2 and phosphorylated p27 promotes a tight interaction between p27 and the SCF complex (Hao et al., 2005).
R-HSA-187574 (Reactome) Following ubiquitination by the SCF(Skp2):Cks1 complex, phospho-p27/p21 is degraded by the 26S proteasome.
R-HSA-187575 (Reactome) Once in tight contact with the SCF (Skp2):Cks1 complex, phosphorylated p27/p21 is ubiquitinated.
R-HSA-187828 (Reactome) p21 associates with and inhibits Cyclin:Cdk complexes in the nucleus.
R-HSA-188345 (Reactome) Binding of the MYC:MAX heterodimer to MYC response elements in the first and second intron of the CDC25A gene activates CDC25A transcription in mid to late G1 (Galaktionov et al. 1996).
Transcription of the CDC25A gene can be directly activated by E2F1 (DeGregori et al. 1995, Vigo et al. 1999).
Transcription of the CDC25A gene is directly inhibited by the DREAM complex (Litovchick et al. 2007).
R-HSA-188350 (Reactome) Phosphorylation of cyclin-dependent kinases (CDKs) by the CDK-activating kinase (CAK) is required for the activation of the CDK kinase activity. The association of p21/p27 with the Cyclin A/E:Cdk2 complex prevents CAK mediated phosphorylation of Cdk2 (Aprelikova et al., 1995).
R-HSA-188386 (Reactome) pRB contains, in its C terminus, a cyclin-cdk interaction motif like that found in E2F1 and p21 that enables it to be recognized and phosphorylated by cyclin-cdk complexes.
R-HSA-188390 (Reactome) Cyclin E (CCNE1 or CCNE2) forms a complex with CDK2 and collaborates with the cyclin D-dependent kinases CDK4 and CDK6 in phosphorylating RB1 (Kelly et al.1998, Adams et al.1999). CDK4/CDK6-mediated monophosphorylation of RB1 is a pre-requisite for hyperphosphorylation and full inactivation of RB1 mediated by the CCNE:CDK2 complex (Connell-Crowley et al. 1997, Lundberg and Weinberg 1998, Brown et al. 1999, Harbour et al. 1999, Yu et al. 2000, Ezhevsky et al. 2001), with monophosphorylated RB1 being phosphorylated on 14 CDK sites out of 16 predicted sites (Narasimha et al. 2014).
R-HSA-198613 (Reactome) Phosphorylation of p27Kip1 at T157 and of p21Cip1 at T145 by AKT leads to their retention in the cytoplasm, segregating these cyclin-dependent kinase (CDK) inhibitors from cyclin-CDK complexes.
R-HSA-68914 (Reactome) DNA polymerase alpha:primase is comprised of four subunits, p180, p70, p58, and p49. The two primase subunits, p58 and p49, form a tight complex. The p49 subunit contains the DNA primase activity and one role of p58 appears to be tethering p49 to p180, the DNA polymerase catalytic subunit. The fourth subunit, p70, binds p180 and may tether the DNA polymerase alpha:primase complex to Cdc45.
R-HSA-68916 (Reactome) After pre-RC assembly and Cdc45 association with the origin of replication, Replication Protein A (RPA) also associates with chromatin. RPA is a heterotrimeric complex containing p70, p34, and p11 subunits, and also is required for DNA recombination and DNA repair. The p70 subunit of RPA binds to the primase subunits of Pol alpha:primase. The p70 and p34 subunits of RPA are phosphorylated in a cell cycle-dependent manner. RPA is a single-strand DNA (ssDNA) binding protein and its association with chromatin at this stage suggests that DNA is partially unwound. This suggestion has been confirmed by detection of ssDNA in budding yeast origins of replication using chemical methods.
R-HSA-68917 (Reactome) Once the Mcm2-7 complex has been assembled onto the origin of replication, the next step is the assembly of Cdc45, an essential replication protein, in late G1. The assembly of Cdc45 onto origins of replication forms a complex distinct from the pre-replicative complex, sometimes called the pre-initiation complex. The assembly of Cdc45 onto origins correlates with the time of initiation. Like the Mcm2-7 proteins, Cdc45 binds specifically to origins in the G1 phase of the cell cycle and then to non-origin DNA during S phase and is therefore thought to travel with the replication fork. Indeed, S. cerevisiae Cdc45 is required for DNA replication elongation as well as replication initiation. Cdc45 is required for the association of alpha DNA polymerase:primase with chromatin. Based on this observation and the observation that in S. cerevisiae, cCdc45 has been found in large complexes with some components of Mcm2-7 complex, it has been suggested that Cdc45 plays a scaffolding role at the replication fork, coupling Pol-alpha:primase to the replication fork through the helicase. Association of Cdc45 with origin DNA is regulated in the cell cycle and its association is dependent on the activity of cyclin-dependent kinases but not the Cdc7/Dbf4 kinase. In Xenopus egg extracts, association of Cdc45 with chromatin is dependent on Xmus101. TopBP1, the human homolog of Xmus1, is essential for DNA replication and interacts with DNA polymerase epsilon, one of the polymerases involved in replicating the genome. TopBP1 homologs have been found in S. cerevisiae and S. pombe. Sld3, an additional protein required for Cdc45 association with chromatin in S. cerevisiae and S. pombe, has no known human homolog.
R-HSA-68918 (Reactome) At the beginning of this reaction, 1 molecule of 'Mcm10:active pre-replicative complex', 1 molecule of 'DDK', and 1 molecule of 'CDK' are present. At the end of this reaction, 1 molecule of 'CDK:DDK:Mcm10:pre-replicative complex' is present.

This reaction takes place in the 'nucleus'.

R-HSA-68919 (Reactome) MCM10 is required for human DNA replication. In S. cerevisiae, Mcm10, like Mcm2-7, is required for minichromosome maintenance, but Mcm10 has no sequence homology with these other proteins (Merchant et al., 1997). Genetic studies have demonstrated that Mcm10 is required for DNA replication in S. pombe (Aves et al., 1998) and S. cerevisiae cells (Homesley et al., 2000) and immunodepletion of XlMcm10 interferes with DNA replication in Xenopus egg extracts (Wohlschlegel et al., 2002). Human Mcm10 interacts with chromatin in G1 phase and then dissociates during G2 phase. In S. cerevisiae, Mcm10 has been shown to localize to origins during G1 (Ricke and Bielinsky, 2004), and it may stabilize the association of Mcm2-7 with the pre-replicative complex (Sawyer et al., 2004). This timing of association is consistent with studies that demonstrate that, in Xenopus egg extracts, Mcm10 is required for association of Cdc45, but not Mcm2-7 with chromatin. Biochemical evidence that Mcm10 plays a direct role in the activation of the pre-replicative complex includes the requirement for SpMcm10 in the phosphorylation of the Mcm2-7 complex by DDK (Lee et al., 2004) and the fact that SpMcm10 binds and stimulates DNA polymerase alpha activity (Fien et al., 2004).
R-HSA-68940 (Reactome) At the beginning of this reaction, 1 molecule of 'Mcm10:pre-replicative complex' is present. At the end of this reaction, 1 molecule of 'Mcm10:active pre-replicative complex', and 1 molecule of 'CDT1' are present.

This reaction takes place in the 'nucleus'.

R-HSA-68954 (Reactome) At the beginning of this reaction, 1 molecule of 'Mcm2-7 complex', and 1 molecule of 'ATP' are present. At the end of this reaction, 1 molecule of 'phosphorylated Mcm2-7 complex', and 1 molecule of 'ADP' are present.

This reaction takes place in the 'nucleus' and is mediated by the 'kinase activity' of 'DDK'.

R-HSA-68960 (Reactome) At the beginning of this reaction, 1 molecule of 'origin of replication', and 1 molecule of 'DNA polymerase epsilon' are present. At the end of this reaction, 1 molecule of 'DNA polymerase epsilon:origin complex' is present.



R-HSA-69191 (Reactome) The E-type cyclins and Cyclin Dependent Kinase 2 control the transition from G1 to S phase. Cdk2 is competent to carry out the necessary reactions only when complexed with Cyclin E.
R-HSA-69195 (Reactome) WEE1 phosphorylates CDK2, inhibiting entry into S-phase (Watanabe et al., 1995; Wu et al., 2001). WEE1-mediated phosphorylation of CDK2 is enhanced in the presence of CABLES1, which can form a complex with CDK2 bound to cyclin E (CCNE) or cyclin A (CCNA) (Wu et al. 2001).
R-HSA-69199 (Reactome) Cdc25A dephosphorylates Cdk2 and activates cyclin E-Cdk2 and cyclin A-Cdk2 kinases (Blomberg and Hoffmann, 1999).
R-HSA-69227 (Reactome) CDK4 and CDK6, in complex with D type cyclins (CCND1, CCND2 or CCND3) monophosphorylate RB1 (Narasimha et al. 2014). In G1, any serine or threonine residue on RB1 can be monophosphorylated by CDK4/CDK6 in complex with cyclin D. Studies have implicated progressive phosphorylation of RB1 by CDK2. CDK4/CDK6-mediated monophosphorylation is a pre-requisite for hyperphosphorylation of RB1 mediated by the complex of CDK2 and E type cyclins (CCNE1 or CCNE2) (Connell-Crowley et al. 1997, Lundberg and Weinberg 1998, Brown et al. 1999, Harbour et al. 1999, Yu et al. 2000, Ezhevsky et al. 2001). Some studies imply that CDK4/CDK6 activity results in RB1 hyperphosphorylation in late G1 phase, while the CDK2:CCNE complex takes over the role of RB1 hyperphosphorylation at S phase entry (Chung et al. 2019). Several studies have shown that the complex of CDK4/CDK6 and cyclin D monophosphorylates RB1 on any of the fourteen in vivo phosphorylated RB1 residues (out of sixteen predicted CDK-target sites). Monophosphorylation at different residues has different consequences on RB1 protein-protein interactions (Narasimha et al. 2014, Sanidas et al. 2019).
R-HSA-69299 (Reactome) At the beginning of this reaction, 1 molecule of 'geminin', and 1 molecule of 'CDT1' are present. At the end of this reaction, 1 molecule of 'Cdt1:geminin' is present.

This reaction takes place in the 'nucleoplasm'.

R-HSA-69562 (Reactome) During G1, the activity of cyclin-dependent kinases (CDKs) is controlled by the CDK inhibitors (CKIs) CDKN1A (p21) and CDKN1B (p27), thereby preventing premature entry into S phase (see Guardavaccaro and Pagano, 2006). The efficient recognition and ubiquitination of p27 by the SCF (Skp2) complex requires the formation of a trimeric complex containing p27 and cyclin E/A:Cdk2.
R-HSA-8848414 (Reactome) Activated PTK6 (BRK) binds to CDKN1B (p27KIP1) that is in a complex with CDK4 and cyclin D1 (CCND1). Since PTK6 increases cyclin E1 (CCNE1) levels downstream of ERBB2 while decreasing CDKN1B levels, PTK6 probably also associates with CDKN1B bound to the complex of CCNE1 and CDK2 (Xiang et al. 2008).
R-HSA-8848436 (Reactome) PTK6 (BRK) phosphorylates CDKN1B (p27KIP1) bound to the complex of CDK4 and CCND1 (cyclin D1) on tyrosine residue Y88 and possibly other tyrosines (e.g. Y89) (Patel et al. 2015). Based on the finding that PTK6 promotes ERBB2-induced increase in cyclin E1 (CCNE1) levels and decrease in CDKN1B levels (Xiang et al. 2008), and supported by the analogy with other SRC family kinases that phosphorylate CDKN1B (Grimmler et al. 2007), PTK6 is likely to also phosphorylate CDKN1B bound to the complex of CCNE1 and CDK2. Phosphorylation of CDKN1B (p27KIP1) on tyrosine residue Y88 by SRC family kinases dislodges the 3-10 helix of CDKN1B from the active site of CDK2 or CDK4, thus converting CDKN1B from a bound inhibitor to a bound non-inhibitor (Grimmler et al. 2007, Ray et al. 2009).
R-HSA-8932400 (Reactome) The MYC:MAX heterodimer binds to MYC response elements in the first and second intron of the CDC25A gene (Galaktionov et al. 1996).
R-HSA-8941895 (Reactome) The cyclin dependent kinase CDK4 or CDK6 forms a complex with one of the cyclin D family (CCND) members: cyclin D1 (CCND1), cyclin D2 (CCND2) or cyclin D3 (CCND3) (Matsushime et al. 1992, Meyerson and Harlow 1994, La Baer et al. 1997, Bagui et al. 2003, Cerqueira et al. 2014). This association is regulated by mitogenic pathways (Cheng et al. 1998, Depoortere et al. 1998). While the binding of Cip/Kip CDK-inhibitors (CDKIs) (CDKNA1 - p21Cip, CDKN1B - p27Kip or CDKN1C - p57Kip2) stabilizes CDK4/6:CCND complexes by decreasing their dissociation rate (La Baer et al. 1997; reviewed by Sherr and Roberts 1999), CIP/KIP CDKIs are not needed for binding of CDK4 or CDK6 to CCNDs and activity of CDK4/6:CCND complexes (Bagui et al. 2000, Sugimoto et al. 2002, Bagui et al. 2003, Cerqueira et al. 2014; reviewed by Bockstaele et al 2006).
R-HSA-8941915 (Reactome) Binding of CDK inhibitors of the Cip/Kip family, CDKNA1 (p21Cip), CDKN1B (p27Kip) or CDKN1C (p57Kip2) to the complex of CDK4 or CDK6 and cyclin D family members (CCND1, CCND2 or CCND3), inhibits kinase activity of the CDK4/6:CCND complexes but at the same time increases their stability and, hence, their abundance (La Baer et al. 1997, Bagui et al. 2003, Cerqueira et al. 2014; reviewed by Bockstaele et al. 2006). Based on structural studies of CDKN1B, Cip/Kip inhibitors simultaneously interact with CDK4/6 and CCNDs (Liu et al. 2010). Phosphorylation of CDKN1B on threonine residues T157 and T198 by activated AKT in early G1 may precede binding of CDKN1B to CDK4/6:CCND complexes (Larrea et al. 2008).
R-HSA-8942607 (Reactome) Phosphorylation of Cip/Kip cyclin-dependent kinase (CDK) inhibitors CDKN1A (p21Cip), CDKN1B (p27Kip1) and CDKN1C (p57Kip2) on conserved tyrosine residues Y77, Y88 and Y91, respectively, can convert them from bound inhbitors to bound non-inhibitors of CDK4 or CDK6 complexes with D cyclins by dislodging them from the active site of CDK4 or CDK6. This mechanism was studied in most detail on the example of CDKN1B associated with the CDK2:CCNA complex (Grimmler et al. 2007) and the CDK4:CCND1 complex (James et al. 2008, Patel et al. 2015). For a review of this topic, please refer to Blain 2008.
CDKN1A can be phosphorylated at tyrosine residue Y77 by protein tyrosine kinase ABL1 (Hukkelhoven et al. 2012). CDKN1B can be phosphorylated at tyrosine residue Y88, and probably also at the adjacent Y89, by protein tyrosine kinases ABL1 (Grimmler et al. 2007, James et al. 2008, Ray et al. 2009, Ou et al. 2011), LYN (Grimmler et al. 2007), SRC (Larrea et al. 2008), JAK2 (Jakel et al. 2011) and PTK6 (Patel et al. 2015). CDKN1C can be phosphorylated at tyrosine residue Y91 by protein tyrosine kinase ABL1 (Borriello et al. 2011).
Dislodgment of the tyrosine phosphorylated 3-10 helix of Cip/Kip CDK inhibitors from the active site of cyclin D-bound CDK4 or CDK6 results in increased catalytic activity of CDK4 or CDK6 by allowing ATP binding to the active site, but also by enabling activating phosphorylation of the T-loop of CDK4 or CDK6 phosphorylation by CDK7 in complex with cyclin H (Ray et al. 2009).
SRC-mediated phosphorylation of CDKN1B on tyrosine residue Y88 was shown to reduce protein stability of CDKN1B (Chu et al. 2007).
Without overexpression of BCR-ABL or SRC-family tyrosine kinases in several cell systems, tyrosine phosphorylated p27 is either undetectable or a very low abundance species (Ishida et al. 2000, Jaimes et al. 2008, Grimmler et al. 2007) that does not bind preferentially to CDK4 (Jaimes et al. 2008). Therefore, tyrosine phosphorylation of p27 is unlikely to be the sole explanation of the full activity of p27-bound CDK4:CCND complexes reported in previous studies (Blain et al. 1997, Coulonval et al. 2003, Bockstaele et al. 2006). It has been proposed that stoichiometry of the Cip/Kip complex with CDK4 or CDK6 and cyclin D, in addition to or alternative to tyrosine phosphorylation of Cip/Kip CDK inhibitors, determines their inhibitory role where binding of more than one molecule of CDKN1A, CDKN1B or CDKN1C would be needed to achieve inhibition of the CDK4/6:CCND complex (reviewed by Paternot et al. 2010).
R-HSA-8942803 (Reactome) Cyclin D:CDK4/6 complexes translocate to the nucleus from the cytoplasm at G1/S transition (Wang et al. 2008). This nuclear accumulation requires the binding to the Cip/Kip cyclin-dependent kinase (CDK) inhibitors CDKN1A (p21Cip), CDKN1B (p27Kip1) and probably also CDKN1C (p57Kip2), and the C-terminal NLS sequence of Cip/Kip proteins (LaBaer et al. 1997, Reynisdottir and Massagué 1997). Phosphorylations close to the NLS (at T145 in CDKN1A and T157 in CDKN1B) impede the nuclear localization of Cip/Kip proteins (Zhou et al. 2001, Shin et al. 2005) and potentially of CDK4/6:CCND complexes. One study suggested that tyrosine phosphorylation of p27 (CDKN1B) could facilitate the nuclear import of p27-bound CDK4 (Kardinal et al. 2006). However, others observed that endogenous Y88-phosphorylated p27Kip1, as well as overexpressed p27Kip1 phosphorylated by JAK2 was predominantly cytoplasmic (Jäkel et al. 2011). Effects of tyrosine phosphorylation of CDKN1A and CDKN1C on their localization have not been investigated.
In the absence of Cip/Kip proteins, a small number of CDK4/6:CCND complexes enter the nucleus through an unknown mechanism and phosphorylate target proteins (Bagui et al. 2003).
R-HSA-8942836 (Reactome) T-loop phosphorylation of CDK4 and CDK6 on threonine residues T172 and T177, respectively, is necessary for catalytic activity of complexes of CDK4 and CDK6 with D-type cyclins (CCND1, CCND2 and CCND3) (Kato, Matsuoka, Strom and Sherr 1994, Merzel-Schachter et al. 2013, Bisteau et al. 2013). These phosphorylations depend on prior D type cyclin binding (Kato, Matsuoka, Polyak et al. 1994, Bockstaele et al. 2006). The T-loop phosphorylation is not precluded by the association of CDK4/6:CCND complexes to Cip/Kip cyclin-dependent kinase (CDK) inhibitors CDKN1A (p21Cip) and CDKN1B (p27Kip1), however high expression levels of CDKN1B reduce the T172 phosphorylation of CDK4 (Kato, Matsuoka, Polyak et al. 1994, Bockstaele et al. 2006, Ray et al. 2009). Phosphorylation at tyrosine residue Y89 of CDKN1B (p27Kip1) bound to CDK4:CCND complexes was found to be necessary for phosphorylation of CDK4 by the CAK complex (composed of CDK7, CCNH and MAT1) in vitro, but not for the phosphorylation by CSK1 of S. pombe (Ray et al. 2009). T-loop phosphorylations of CDK4 and CDK6 are differentially regulated (Bockstaele et al. 2009). Especially, the T172 phosphorylation of CDK4 is strictly controlled by mitogenic and antimitogenic pathways (Paternot and Roger 2009), and it can be differentially regulated in cyclin D1:CDK4 and cyclin D3:CDK4 complexes (reviewed by Paternot et al. 2010). The T-loop T172 phosphorylation motif of CDK4 differs from the other cell cycle CDKs, including CDK6, by the presence of an adjacent proline residue (P173) that is evolutionarily conserved. This proline residue is required for T172 phosphorylation of CDK4 in vivo, but not for its in vitro phosphorylation by CAK. This indicates that CDK4 might be activated by other proline-directed kinases in vivo (Bockstaele et al. 2009). Nevertheless, in HCT116 colon carcinoma cell line, the activity of CDK7 is required for the T172 phosphorylation of CDK4 and the activity of CDK4/6:CCND complexes (Merzel Schachter et al. 2013, Bisteau et al. 2013). T170 phosphorylation of CDK7 facilitates the activity of CAK on CDK4 (Merzel Schachter et al. 2013). However, CDK7 inhibition in HCT116 cells does not preclude the T172 phosphorylation of CDK4:CCND complexes that are not associated with CDKN1A (Bisteau et al. 2013).
Phosphorylation of CDKN1A at serine residue S130 by CDK4/6 and CDK2 has been implicated as a pre-requisite for CAK-mediated phosphorylation of CDKN1A-bound CDK4 (Bisteau et al. 2013). Other kinases involved in phosphorylation of CDK4 at T172 remain to be defined (Bockstaele et al. 2009, Bisteau et al. 2013, reviewed by Paternot et al. 2010).
R-HSA-8961619 (Reactome) E2F1 directly stimulates transcription of the CDC6 gene (Yan et al., 1998; Ohtani et al., 1998). CDC6 is required to recruit the MCM2-7 replication helicases.
Transcription of the CDC6 gene is directly repressed by the DREAM complex (Litovchick et al. 2007).
R-HSA-8961620 (Reactome) E2F1 binds to E2F binding sites in the promoter of the CDC6 gene (Yan et al., 1998; Ohtani et al., 1998). CDC6 is required to recruit the MCM2-7 replication helicases.
R-HSA-8961632 (Reactome) E2F1 binds to E2F binding sites in the promoter of the POLA1 gene, stimulating POLA1 transcription. POLA1 encodes the catalytic subunit p180 of the DNA polymerase alpha (DeGregori et al. 1995, Giangrande et al. 2004). Activation of POLA1 by E2F1 has also been demonstrated in Drosophila (Ohtani and Nevins 1994).
R-HSA-8961636 (Reactome) E2F1 binds to E2F binding sites in the promoter of the POLA1 gene, encoding the DNA polymerase alpha catalytic subunit p180 (DeGregori et al. 1995, Giangrande et al. 2004).
R-HSA-8961651 (Reactome) E2F1 binds to E2F binding sites in the promoter of the PCNA gene, encoding the proliferating cell nuclear antigen, a component of the DNA polymerase complex involved in eukaryotic DNA replication (DeGregori et al. 1995, Li et al. 2003).
R-HSA-8961665 (Reactome) E2F1 directly stimulates transcription of the PCNA gene, which encodes the proliferating cell nuclear antigen, a component of the DNA polymerase complex involved in eukaryotic DNA replication (DeGregori et al. 1995, Li et al. 2003).
The PCNA gene transcription is directly repressed by the DREAM complex (Litovchick et al. 2007).
R-HSA-8961671 (Reactome) E2F1 binds to E2F binding sites in the promoter of the ORC1 gene (Ohtani et al. 1996, Ohtani et al. 1998). It has been observed in Drosophila that E2F1 regulated expression of Orc1 stimulates ORC1-6 complex formation and binding to the origin of replication (Asano and Wharton, 1999).
R-HSA-8961678 (Reactome) E2F1 directly stimulates transcription of the ORC1 gene (Ohtani et al. 1996, Ohtani et al. 1998). E2F1 regulated expression of Orc1 stimulates ORC1-6 complex formation and binding to the origin of replication in Drosophila (Asano and Wharton, 1999).
R-HSA-8961688 (Reactome) E2F1 binds to E2F binding sites in the promoter of the FBXO5 (Emi1) gene (Hsu et al. 2002).
R-HSA-8961699 (Reactome) E2F1 directly stimulates transcription of the FBXO5 (Emi1) gene (Hsu et al. 2002).
R-HSA-8961840 (Reactome) E2F1 binds to E2F binding sites in the promoter of the CCNE1 gene, encoding cyclin E1 (DeGregori et al. 1995, Ohtani et al. 1995).
R-HSA-8961846 (Reactome) E2F1 directly stimulates transcription of the CCNE1 gene, encoding cyclin E1 (DeGregori et al. 1995, Ohtani et al. 1995).Cyclin E proteins play an important role in the transition from G1 to S-phase by associating with CDK2.
R-HSA-8961863 (Reactome) E2F1 binds to E2F binding sites in the promoter of the DHFR gene, encoding dihydrofolate reductase. DHFR is involved in folate metabolism and synthesis of DNA bases (DeGregori et al. 1995, Wells et al. 1997, Darbinian et al. 1999).
R-HSA-8961874 (Reactome) E2F1 directly stimulates transcription of the DHFR gene, encoding dihydrofolate reductase. DHFR is involved in folate metabolism and synthesis of DNA bases (DeGregori et al. 1995, Wells et al. 1997, Darbinian et al. 1999).
R-HSA-8961888 (Reactome) E2F1 binds to E2F binding sites in the promoter of the CCNA1 gene, encoding cyclin A1 (DeGregori et al. 1995, Liu et al. 1998).
R-HSA-8961895 (Reactome) E2F1 directly stimulates transcription of the CCNA1 gene, encoding cyclin A1 (DeGregori et al. 1995, Liu et al. 1998).
R-HSA-8961907 (Reactome) E2F1 binds to E2F binding sites in the promoter of the CDC45 gene (Arata et al. 2000).
R-HSA-8961915 (Reactome) E2F1 directly stimulates transcription of the CDC45 gene (Arata et al. 2000), encoding Cell division control protein 45 homolog, which is required for initiation of DNA replication.
R-HSA-8961920 (Reactome) E2F1 binds to E2F binding sites in the promoter of the CDK1 gene, encoding cyclin-dependent kinase 1 (Cdc2) (Furukawa et al. 1994, DeGregori et al. 1995, Zhu et al. 2004).
R-HSA-8961934 (Reactome) E2F1 directly stimulates transcription of the CDK1 gene, encoding cyclin-dependent kinase 1 (Cdc2) (Furukawa et al. 1994, DeGregori et al. 1995, Zhu et al. 2004). Transcription of the CDK1 gene is directly inhibited by complexes of HDAC1 and RBL1 (p107) or RBL2 (p130) in G1 and G0, respectively (Rayman et al. 2002).
R-HSA-8961946 (Reactome) E2F1 binds to E2F binding sites in the promoter of the CDT1 gene, encoding DNA replication factor Cdt1 (Yoshida and Inoue 2004).
R-HSA-8961952 (Reactome) E2F1 directly stimulates transcription of the CDT1 gene, encoding DNA replication factor Cdt1 (Yoshida and Inoue 2004).
R-HSA-8961961 (Reactome) E2F1 binds to E2F binding sites in the promoter of the CDC25A gene, encoding M-phase inducer phosphatase 1 (DeGregori et al. 1995, Vigo et al. 1999).
R-HSA-8961972 (Reactome) E2F1 binds to E2F binding sites in the promoter of the RRM2 gene, encoding Ribonucleoside-diphosphate reductase subunit M2 (DeGregori et al. 1995, Giangrande et al. 2004).
R-HSA-8961982 (Reactome) E2F1 directly stimulates transcription of the RRM2 gene, encoding Ribonucleoside-diphosphate reductase subunit M2 (DeGregori et al. 1995, Giangrande et al. 2004). Binding of E2F6 to the RRM2 gene promoter inhibits RRM2 transcription (Bertoli et al. 2013).
R-HSA-8961991 (Reactome) E2F1 binds to E2F binding sites in the promoter of the TK1 gene, encoding thymidine kinase (Dou et al. 1994, DeGregori et al. 1995, Giangrande et al. 2004).
R-HSA-8962039 (Reactome) E2F1 directly stimulates transcription of the TK1 gene, encoding thymidine kinase (Dou et al. 1994, DeGregori et al. 1995, Giangrande et al. 2004).
R-HSA-8962050 (Reactome) Expression of the TYMS gene, encoding thymidylate synthase, is positively regulated by E2F1, but direct regulation has not been demonstrated (DeGregori et al. 1995).
R-HSA-8964465 (Reactome) The DREAM complex binds the promoter of the PCNA gene (Litovchick et al. 2007).
R-HSA-8964471 (Reactome) The DREAM complex binds the promoter of the CDC25A gene (Litovchick et al. 2007).
R-HSA-8964475 (Reactome) The DREAM complex binds the promoter of the TOP2A gene (Litovchick et al. 2007).
R-HSA-8964482 (Reactome) The DREAM complex binds the promoter of the E2F1 gene (Litovchick et al. 2007).
R-HSA-8964492 (Reactome) The DREAM complex binds the RBL1 (p107) gene promoter (Litovchick et al. 2007).
R-HSA-8964498 (Reactome) The DREAM complex binds the promoter of the CDC6 gene (Litovchick et al. 2007).
R-HSA-8964513 (Reactome) Transcription of the E2F1 gene is directly inhibited by the DREAM complex (Litovchick et al. 2007). E2F1 transcription is also directly inhibited by the complex of HDAC1 and RBL1 (p107) or RBL2 (p130) (Rayman et al. 2002).
R-HSA-8964525 (Reactome) The DREAM complex directly represses transcription of the RBL1 gene (Litovchick et al. 2007).
R-HSA-8964531 (Reactome) The DREAM complex directly represses the TOP2A gene transcription (Litovchick et al. 2007).
R-HSA-8964550 (Reactome) In G0 and early G1, complexes containing p130 (RBL2) and p107 (RBL1), respectively, and histone deacetylase HDAC1 bind the promoter of the E2F1 gene (Rayman et al. 2002).
R-HSA-8964561 (Reactome) In G0 and early G1, complexes containing p130 (RBL2) and p107 (RBL1), respectively, and histone deacetylase HDAC1 bind the promoter of the MYBL2 gene (Rayman et al. 2002).
R-HSA-8964567 (Reactome) In G0 and early G1, complexes containing p130 (RBL2) and p107 (RBL1), respectively, and histone deacetylase HDAC1 bind the promoter of the CDK1 gene (Rayman et al. 2002).
R-HSA-8964580 (Reactome) In G0 and early G1, complexes containing p130 (RBL2) and p107 (RBL1), respectively, and histone deacetylase HDAC1 bind the promoter of the CCNA2 gene (Rayman et al. 2002).
R-HSA-8964588 (Reactome) In G0 and early G1, complexes containing p130 (RBL2) and p107 (RBL1), respectively, and histone deacetylase HDAC1 bind the promoter of the CCNA2 gene (Rayman et al. 2002).
R-HSA-8978926 (Reactome) In G0 and early G1, complexes containing p130 (RBL2) and p107 (RBL1), respectively, and histone deacetylase HDAC1 directly inhibit transcription from the MYBL2 gene (Rayman et al. 2002).
R-HSA-9018017 (Reactome) RB1 tumor suppressor, the product of the retinoblastoma susceptibility gene, binds to E2F transcription factors E2F1, E2F2 and E2F3, presumably heterodimerized with TFDP1 or TFDP2. The interaction involves the pocket domain of RB1. RB1 binding inhibits transcriptional activity of E2F1/2/3:TFDP1/2 complexes, resulting in prevention of G1/S transition (Chellappan et al. 1991, Bagchi et al. 1991, Chittenden et al. 1991, Lees et al. 1993, Hiebert 1993, Wu et al. 2001). Once RB1 is phosphorylated on serine residue S795 by Cyclin D:CDK4/6 complexes, it can no longer associate with and inhibit E2F1/2/3:TFDP1/2 complexes. Thus, CDK4/6-mediated phosphorylation of RB1 leads to transcriptional activation of E2F1/2/3 target genes needed for the S phase of the cell cycle (Connell-Crowley et al. 1997).
R-HSA-9659820 (Reactome) Amino acid residues 860-876 in the C terminal part of RB1 constitute a bipartite nuclear localization signal (NLS), needed for translocation of RB1 from the cytosol to the nucleus. In the absence of the NLS, only a small portion of RB1 translocates to the nucleus, while a large portion of RB1 is retained in the cytosol (Zacksenhaus et al. 1993).
RB1:E2F1,E2F2,E2F3:TFDP1,TFDP2:ArrowR-HSA-9018017 (Reactome)
RB1:RNA primer-DNA

primer:origin duplex with DNA

damage
ArrowR-HSA-113503 (Reactome)
RB1:RNA primer-DNA

primer:origin duplex with DNA

damage
R-HSA-113643 (Reactome)
RB1ArrowR-HSA-9659820 (Reactome)
RB1R-HSA-69227 (Reactome)
RB1R-HSA-9018017 (Reactome)
RB1R-HSA-9659820 (Reactome)
RBL1 geneR-HSA-8964492 (Reactome)
RBL1 geneR-HSA-8964525 (Reactome)
RBL1:Cyclin E/A:CDK2ArrowR-HSA-1363314 (Reactome)
RBL1:E2F4:DP1/2:Cyclin E/A:CDK2ArrowR-HSA-1363311 (Reactome)
RBL1:E2F4:TFDP1,TFDP2R-HSA-1226095 (Reactome)
RBL1:E2F4:TFDP1,TFDP2R-HSA-1227671 (Reactome)
RBL1:E2F4:TFDP1,TFDP2R-HSA-1363311 (Reactome)
RBL1ArrowR-HSA-1363274 (Reactome)
RBL1ArrowR-HSA-8964525 (Reactome)
RBL1R-HSA-1363314 (Reactome)
RBL2:Cyclin E/A:CDK2ArrowR-HSA-1363306 (Reactome)
RBL2:E2F4,E2F5:TFDP1,TFDP2R-HSA-1226094 (Reactome)
RBL2:E2F4,E2F5:TFDP1,TFDP2R-HSA-1227670 (Reactome)
RBL2:E2F4,E2F5:TFDP1,TFDP2R-HSA-1362261 (Reactome)
RBL2:E2F4,E2F5:TFDP1,TFDP2R-HSA-1363303 (Reactome)
RBL2:E2F4/5:DP1/2:Cyclin E/A:CDK2ArrowR-HSA-1363303 (Reactome)
RBL2ArrowR-HSA-1363276 (Reactome)
RBL2R-HSA-1363306 (Reactome)
RNA primer-DNA

primer:origin duplex with DNA

damage
ArrowR-HSA-113504 (Reactome)
RNA primer-DNA

primer:origin duplex with DNA

damage
R-HSA-113503 (Reactome)
RNA primer-DNA

primer:origin

duplex
R-HSA-113504 (Reactome)
RPA1-4R-HSA-68916 (Reactome)
RRM2 geneR-HSA-8961972 (Reactome)
RRM2 geneR-HSA-8961982 (Reactome)
RRM2ArrowR-HSA-8961982 (Reactome)
TBarR-HSA-8964513 (Reactome)
TK1 geneR-HSA-8961991 (Reactome)
TK1 geneR-HSA-8962039 (Reactome)
TK1ArrowR-HSA-8962039 (Reactome)
TOP2A geneR-HSA-8964475 (Reactome)
TOP2A geneR-HSA-8964531 (Reactome)
TOP2AArrowR-HSA-8964531 (Reactome)
TYMS geneR-HSA-8962050 (Reactome)
TYMSArrowR-HSA-8962050 (Reactome)
Ub-p-T401,S672,1035-RBL2ArrowR-HSA-1363331 (Reactome)
UbArrowR-HSA-187574 (Reactome)
UbR-HSA-1363331 (Reactome)
UbR-HSA-187575 (Reactome)
WEE1mim-catalysisR-HSA-69195 (Reactome)
hyperphosphorylated RB1ArrowR-HSA-188390 (Reactome)
hyperphosphorylated RB1R-HSA-113503 (Reactome)
monophosphorylated RB1ArrowR-HSA-69227 (Reactome)
monophosphorylated RB1R-HSA-188386 (Reactome)
origin of replicationR-HSA-68960 (Reactome)
p-MCM2-7ArrowR-HSA-68954 (Reactome)
p-MuvB complexArrowR-HSA-1362270 (Reactome)
p-MuvB complexR-HSA-1362261 (Reactome)
p-T,p-S-AKTmim-catalysisR-HSA-198613 (Reactome)
p-T-CDKN1A/BArrowR-HSA-198613 (Reactome)
p-T172-CDK4,p-T177-CDK6:CCND:CDKN1A,CDKN1B,(CDKN1C); p-T172-CDK4,p-T177-CDK6:CCND; (p-T172-CDK4,p-T177-CDK6:CCND:p-Y88-CDKN1B)ArrowR-HSA-8942836 (Reactome)
p-T172-CDK4,p-T177-CDK6:CCND:CDKN1A,CDKN1B,(CDKN1C); p-T172-CDK4,p-T177-CDK6:CCND; (p-T172-CDK4,p-T177-CDK6:CCND:p-Y88-CDKN1B)TBarR-HSA-9018017 (Reactome)
p-T172-CDK4,p-T177-CDK6:CCND:CDKN1A,CDKN1B,(CDKN1C); p-T172-CDK4,p-T177-CDK6:CCND; (p-T172-CDK4,p-T177-CDK6:CCND:p-Y88-CDKN1B)mim-catalysisR-HSA-1226094 (Reactome)
p-T172-CDK4,p-T177-CDK6:CCND:CDKN1A,CDKN1B,(CDKN1C); p-T172-CDK4,p-T177-CDK6:CCND; (p-T172-CDK4,p-T177-CDK6:CCND:p-Y88-CDKN1B)mim-catalysisR-HSA-1226095 (Reactome)
p-T172-CDK4,p-T177-CDK6:CCND:CDKN1A,CDKN1B,(CDKN1C); p-T172-CDK4,p-T177-CDK6:CCND; (p-T172-CDK4,p-T177-CDK6:CCND:p-Y88-CDKN1B)mim-catalysisR-HSA-69227 (Reactome)
p-T369,S640,S964,S975-RBL1ArrowR-HSA-1226095 (Reactome)
p-T369,S640,S964,S975-RBL1R-HSA-1363274 (Reactome)
p-T401,S672,1035-RBL2:SCF(Skp2):Cks1ArrowR-HSA-1363328 (Reactome)
p-T401,S672,1035-RBL2:SCF(Skp2):Cks1R-HSA-1363331 (Reactome)
p-T401,S672,1035-RBL2:SCF(Skp2):Cks1mim-catalysisR-HSA-1363331 (Reactome)
p-T401,S672,S1035-RBL2ArrowR-HSA-1226094 (Reactome)
p-T401,S672,S1035-RBL2R-HSA-1363276 (Reactome)
p-T401,S672,S1035-RBL2R-HSA-1363328 (Reactome)
p-Y342-PTK6:CDKN1B:(CDK4:CCND1,(CDK2:CCNE1))ArrowR-HSA-8848414 (Reactome)
p-Y342-PTK6:CDKN1B:(CDK4:CCND1,(CDK2:CCNE1))R-HSA-8848436 (Reactome)
p-Y342-PTK6:CDKN1B:(CDK4:CCND1,(CDK2:CCNE1))mim-catalysisR-HSA-8848436 (Reactome)
p-Y342-PTK6ArrowR-HSA-8848436 (Reactome)
p-Y342-PTK6R-HSA-8848414 (Reactome)
p-Y88-CDKN1B:(CDK4:CCND1,(CDK2:CCNE1))ArrowR-HSA-8848436 (Reactome)
pre-replicative complexR-HSA-68919 (Reactome)

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