Factors involved in megakaryocyte development and platelet production (Homo sapiens)

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2, 9, 134235152937201012, 3124341117, 18, 30, 32, 356, 228, 193716, 33213714128Rabenosyn-5:VPS-45[endosome membrane]ZFPM1, ZFPM2[nucleoplasm]Small Maf familymembers[nucleoplasm]IRF3-P:IRF7-P[nucleoplasm]Dual-specificAKAPs:PKA tetramer[cytosol]RAD51B:RAD51C:Single-strandedDNA [nucleoplasm]F-actin cappingprotein:f-actin[cytosol]PKA catalyticsubunit [cytosol]IRF1:Promoter regionof IFN beta[nucleoplasm]F-actin cappingprotein [cytosol]SH2Bfamily:p(Y813)-JAK2[cytosol]PKA regulatorysubunit [cytosol]RAC1, CDC42[cytosol]Dual-specific AKAPs[cytosol]SH2B family[cytosol]F-actin cappingprotein alphasubunit [cytosol]NF-E2 [nucleoplasm]REST:REST DNAbinding sites[nucleoplasm]RAD51B:RAD51C[nucleoplasm]LRRC16A:F-actincapping protein[cytosol]F-actin cappingprotein alphasubunit [cytosol]IRF2:Promoter regionof INF beta[nucleoplasm]PKA catalyticsubunit [cytosol]NF-E2:Promoterregion ofbeta-globin[nucleoplasm]GATA proteins[nucleoplasm]DOCK-GEFs:RAC1,CDC42 [cytosol]C-terminal EH domaincontainingproteins:Rabenosyn-5[endosome membrane]CDK2:CABLES1:Wee-1[nucleoplasm]cytosolp-2S-IRF7:p-2S-IRF7[nucleoplasm]CTNNA1 [plasmamembrane]VAF/pIRF7:CBP/p300[nucleoplasm]Promoter region oftype-I IFN genes[nucleoplasm]IRF2:Promoter regionof INF alpha[nucleoplasm]VAF/pIRF7:CBP/p300bound to type I IFNgene promoter[nucleoplasm]IRF2:promoters ofINF alpha, INF beta[nucleoplasm]Histone H3methylated atlysine-9[nucleoplasm]F-actin cappingprotein [cytosol]REST:REST DNAbinding sites[nucleoplasm]PKA regulatorysubunit [cytosol]PKA tetramer[cytosol]PKA tetramer[cytosol]p53:MYB:SIN3A[nucleoplasm]NF-E2 [nucleoplasm]F-actin cappingprotein alphasubunit [cytosol]F-actin cappingprotein [cytosol]IRF-1:IFN-alphapromoter[nucleoplasm]CDK5:CABLES:ABL[cytosol]HP1alpha:Histone H3methylated at K9[nucleoplasm]CBP/p300[nucleoplasm]Small Maf familymembers[nucleoplasm]VAF (virus-activatedfactor)[nucleoplasm]nucleoplasmZFPM proteins:GATAproteins[nucleoplasm]BHCcomplex:REST:RESTDNA binding sites[nucleoplasm]CBP/p300:pIRF7:pIRF7[nucleoplasm]Mitofusin complex[mitochondrial outermembrane]C-terminal EH domaincontaining proteins[endosome membrane]mitochondrial matrixNectin:afadincomplex (name copiedfrom entity in Homosapiens) [plasmamembrane]RAD51B:RAD51C[nucleoplasm]endosome lumenIRF1:Promotors ofIFN alpha, IFN beta[nucleoplasm]IRF2 [nucleoplasm]ATPHBG1IRF1:Promotors ofIFN alpha, IFN betaJMJD1CNFE2Dual-specific AKAPsWEE1 [nucleoplasm]IFN alpha/beta(IFNA/B)PRKAR2B [cytosol]RCOR1 [nucleoplasm]RAB5A(2-215)[endosome membrane]TP53 [nucleoplasm]AKAP10 [cytosol]RAC1, CDC42DOCK-GEFs:RAC1,CDC42HBDI(1,3,4)P3RAC1 [cytosol]RAD51C [nucleoplasm]GDPVPS45RAD51C [nucleoplasm]PRKAR2A [cytosol]Dual-specificAKAPs:PKA tetramerRAD51B [nucleoplasm]MAFK [nucleoplasm]GATA2 [nucleoplasm]Promotor region ofbeta-globinSIN3AIRF1PRKAR1B [cytosol]RAD51B:RAD51C:Single-strandedDNAp-4S,T404-IRF3[nucleoplasm]ZFYVE20(2-784)CDK5 [cytosol]Single-stranded DNA[nucleoplasm]MitofusinsF-actin cappingproteinSIN3A [nucleoplasm]C-terminal EH domaincontaining proteinsPRKACB [cytosol]Rabenosyn-5:VPS-45GATA4 [nucleoplasm]CDK5PRKAR2A [cytosol]EHD3 [endosomemembrane]MYB [nucleoplasm]PRKACG [cytosol]CAPZA2 [cytosol]Histone H3 mono ordi-methylated at K9SH2Bfamily:p(Y813)-JAK2ZFPM1, ZFPM2MeK-HIST2H3A[nucleoplasm]PRKACB [cytosol]SH2B3 [cytosol]MAFG [nucleoplasm]CBX5 [nucleoplasm]HBE1MAFK [nucleoplasm]NFE2 [nucleoplasm]AKAP1 [cytosol]CDK5:CABLES:ABLp53:MYB:SIN3AIRF2ITPK1ATPPRKACG [cytosol]ZFYVE20(2-784)[endosome membrane]Promotor region ofinterferon betaHDAC1 [nucleoplasm]Histone H3 mono- orunmethylated at K9PRKAR1A(1-381)[cytosol]RCOR1 [nucleoplasm]I(1,3,4,5,6)P5VAF/pIRF7:CBP/p300bound to type I IFNgene promoterRAD51BHDAC2 [nucleoplasm]GATA5 [nucleoplasm]TP53PRKACA [cytosol]BHC complexCAPZA1 [cytosol]C-terminal EH domaincontainingproteins:Rabenosyn-5CAPZA2 [cytosol]ABL1 [cytosol]SH2B familyRAD51B [nucleoplasm]CDK2IRF2:promoters ofINF alpha, INF betaSH2B1 [cytosol]WEE1RAD51CZFPM1 [nucleoplasm]MAFF [nucleoplasm]GATA6 [nucleoplasm]CABLESGTPPRKAR2B [cytosol]Histone H3methylated atlysine-9PRKAR1A(1-381)[cytosol]EHD1 [endosomemembrane]CDC42 [cytosol]SH2B2 [cytosol]Single-stranded DNANFE2 [nucleoplasm]F-actin cappingprotein alphasubunitHMG20B [nucleoplasm]KDM1A [nucleoplasm]ABL1KinesinsCREBBP(2-2442)[nucleoplasm]I(1,3,4,5)P4ADPCDK2 [nucleoplasm]NF-E2:Promoterregion ofbeta-globinCAPZBRAD51B:RAD51CDOCK-GEFsMeK-H3F3A[nucleoplasm]GATA proteinsLRRC16A [cytosol]ADPGATA1 [nucleoplasm]I(1,3,4,6)P4MAFF [nucleoplasm]ZFPM proteins:GATAproteinsCBX5MYBZFPM2 [nucleoplasm]AMPREST:REST DNAbinding sitesHBBp-Y813-JAK2[cytosol]F-actin cappingprotein:f-actinLRRC16APHF21A [nucleoplasm]CAPZB [cytosol]CAPZB [cytosol]ZFYVE20(2-784)[endosome membrane]CAPZA1 [cytosol]EHD2 [endosomemembrane]PRKACA [cytosol]I(3,4,5,6)P4f-actinCAPZB [cytosol]MeK-HIST1H3A[nucleoplasm]CAPZA2 [cytosol]Promotor region ofinterferon alphaMAFG [nucleoplasm]CABLES1CAPZA1 [cytosol]NF-E2PKA tetramerCDK2:CABLES1:Wee-1p-Y813-JAK2LRRC16A:F-actincapping proteinBHCcomplex:REST:RESTDNA binding sitesp-S477,S479-IRF7[nucleoplasm]AK3VPS45 [endosomemembrane]GATA3 [nucleoplasm]CABLES1[nucleoplasm]RAB5A(2-215)EP300(1-2414)[nucleoplasm]Mitofusin complexIRF1 [nucleoplasm]ADPPRKAR1B [cytosol]Small Maf familymembersHBG2HP1alpha:Histone H3methylated at K925-27, 3634


Description

Megakaryocytes (MKs) give rise to circulating platelets (thrombocytes) through terminal differentiation of MKs which release cytoplasmic fragments as circulating platelets. As MKs mature they undergo endoreduplication (polyploidisation) and expansion of cytoplasmic mass to cell sizes larger than 50-100 microns, and ploidy ranges up to 128 N. As MK's mature, the polyploid nucleus becomes horseshoe-shaped, the cytoplasm expands, and platelet organelles and the demarcation membrane system are amplified. Proplatelet projections form which give rise to de novo circulating platelets (Deutsch & Tomer 2006).
The processes of megakaryocytopoiesis and platelet production occur within a complex microenvironment where chemokines, cytokines and adhesive interactions play major roles (Avecilla et al. 2004). Megakaryocytopoiesis is regulated at several levels including proliferation, differentiation and platelet release (Kaushansky 2003). Thrombopoietin (TPO/c-Mpl ligand) is the most potent cytokine stimulating proliferation and maturation of MK progenitors (Kaushansky 2005) but many other growth factors are involved. MK development is controlled by the action of multiple Transcriptin Factors, many MK-specific genes are co-regulated by GATA and friend of GATA (FOG), RUNX1 and ETS proteins. Nuclear factor erythroid 2 (NF-E2) which has an MK-erythroid specific 45-kDa subunit controls terminal MK maturation, proplatelet formation and platelet release (Schulze & Shivdasani 2004). NF-E2 deficient mice have profound thrombocytopenia (Shiraga et al. 1999). c-myb functions with p300 as a negative regulator of thrombopoiesis (Metcalf et al. 2005). During MK maturation, internal membrane systems, granules and organelles are assembled. Cytoplasmic fragmentation requires changes in the MK cytoskeleton and formation of organelles and channels. Individual organelles migrate from the cell body to the proplatelet ends, with approximately 30 percent of organelles/granules in motion at any given time (Richardson et al. 2005).Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=983231

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Bibliography

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History

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CompareRevisionActionTimeUserComment
114719view16:20, 25 January 2021ReactomeTeamReactome version 75
113164view11:23, 2 November 2020ReactomeTeamReactome version 74
112392view15:32, 9 October 2020ReactomeTeamReactome version 73
101296view11:18, 1 November 2018ReactomeTeamreactome version 66
100833view20:49, 31 October 2018ReactomeTeamreactome version 65
100374view19:24, 31 October 2018ReactomeTeamreactome version 64
99921view16:07, 31 October 2018ReactomeTeamreactome version 63
99476view14:40, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99130view12:40, 31 October 2018ReactomeTeamreactome version 62
93897view13:43, 16 August 2017ReactomeTeamreactome version 61
93470view11:24, 9 August 2017ReactomeTeamreactome version 61
87443view13:42, 22 July 2016MkutmonOntology Term : 'hemostasis pathway' added !
86564view09:21, 11 July 2016ReactomeTeamreactome version 56
83188view10:19, 18 November 2015ReactomeTeamVersion54
81558view13:05, 21 August 2015ReactomeTeamVersion53
77027view08:32, 17 July 2014ReactomeTeamFixed remaining interactions
76732view12:09, 16 July 2014ReactomeTeamFixed remaining interactions
76057view10:12, 11 June 2014ReactomeTeamRe-fixing comment source
75767view11:27, 10 June 2014ReactomeTeamReactome 48 Update
75117view14:06, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74764view08:51, 30 April 2014ReactomeTeamReactome46
42038view21:52, 4 March 2011MaintBotAutomatic update
39841view05:52, 21 January 2011MaintBotNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
ABL1 [cytosol]ProteinP00519 (Uniprot-TrEMBL)
ABL1ProteinP00519 (Uniprot-TrEMBL)
ADPMetaboliteCHEBI:16761 (ChEBI)
AK3ProteinQ9UIJ7 (Uniprot-TrEMBL)
AKAP1 [cytosol]ProteinQ92667 (Uniprot-TrEMBL)
AKAP10 [cytosol]ProteinO43572 (Uniprot-TrEMBL)
AMPMetaboliteCHEBI:16027 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
BHC

complex:REST:REST

DNA binding sites		ComplexREACT_25596 (Reactome)
BHC complexComplexREACT_26743 (Reactome)
C-terminal EH domain

containing

proteins:Rabenosyn-5		ComplexREACT_26657 (Reactome)
C-terminal EH domain containing proteinsProteinREACT_26767 (Reactome)
CABLES1 [nucleoplasm]ProteinQ8TDN4 (Uniprot-TrEMBL)
CABLES1ProteinQ8TDN4 (Uniprot-TrEMBL)
CABLESProteinREACT_26006 (Reactome)
CAPZA1 [cytosol]ProteinP52907 (Uniprot-TrEMBL)
CAPZA2 [cytosol]ProteinP47755 (Uniprot-TrEMBL)
CAPZB [cytosol]ProteinP47756 (Uniprot-TrEMBL)
CAPZBProteinP47756 (Uniprot-TrEMBL)
CBX5 [nucleoplasm]ProteinP45973 (Uniprot-TrEMBL)
CBX5ProteinP45973 (Uniprot-TrEMBL)
CDC42 [cytosol]ProteinP60953 (Uniprot-TrEMBL)
CDK2 [nucleoplasm]ProteinP24941 (Uniprot-TrEMBL)
CDK2:CABLES1:Wee-1ComplexREACT_25979 (Reactome)
CDK2ProteinP24941 (Uniprot-TrEMBL)
CDK5 [cytosol]ProteinQ00535 (Uniprot-TrEMBL)
CDK5:CABLES:ABLComplexREACT_26864 (Reactome)
CDK5ProteinQ00535 (Uniprot-TrEMBL)
CREBBP(2-2442) [nucleoplasm]ProteinQ92793 (Uniprot-TrEMBL)
DOCK-GEFs:RAC1, CDC42ComplexREACT_25414 (Reactome)
DOCK-GEFsProteinREACT_26129 (Reactome)
Dual-specific AKAPs:PKA tetramerComplexREACT_25534 (Reactome)
Dual-specific AKAPsProteinREACT_25713 (Reactome)
EHD1 [endosome membrane]ProteinQ9H4M9 (Uniprot-TrEMBL)
EHD2 [endosome membrane]ProteinQ9NZN4 (Uniprot-TrEMBL)
EHD3 [endosome membrane]ProteinQ9NZN3 (Uniprot-TrEMBL)
EP300(1-2414) [nucleoplasm]ProteinQ09472 (Uniprot-TrEMBL)
F-actin capping

protein alpha

subunit		ProteinREACT_25420 (Reactome)
F-actin capping protein:f-actinComplexREACT_26552 (Reactome)
F-actin capping proteinComplexREACT_26977 (Reactome)
GATA proteinsProteinREACT_26707 (Reactome)
GATA1 [nucleoplasm]ProteinP15976 (Uniprot-TrEMBL)
GATA2 [nucleoplasm]ProteinP23769 (Uniprot-TrEMBL)
GATA3 [nucleoplasm]ProteinP23771 (Uniprot-TrEMBL)
GATA4 [nucleoplasm]ProteinP43694 (Uniprot-TrEMBL)
GATA5 [nucleoplasm]ProteinQ9BWX5 (Uniprot-TrEMBL)
GATA6 [nucleoplasm]ProteinQ92908 (Uniprot-TrEMBL)
GDPMetaboliteCHEBI:17552 (ChEBI)
GTPMetaboliteCHEBI:15996 (ChEBI)
HBBProteinP68871 (Uniprot-TrEMBL)
HBDProteinP02042 (Uniprot-TrEMBL)
HBE1ProteinP02100 (Uniprot-TrEMBL)
HBG1ProteinP69891 (Uniprot-TrEMBL)
HBG2ProteinP69892 (Uniprot-TrEMBL)
HDAC1 [nucleoplasm]ProteinQ13547 (Uniprot-TrEMBL)
HDAC2 [nucleoplasm]ProteinQ92769 (Uniprot-TrEMBL)
HMG20B [nucleoplasm]ProteinQ9P0W2 (Uniprot-TrEMBL)
HP1alpha:Histone H3 methylated at K9ComplexREACT_27026 (Reactome)
Histone H3

methylated at

lysine-9		ProteinREACT_25651 (Reactome)
Histone H3 mono or di-methylated at K9ProteinREACT_27055 (Reactome)
Histone H3 mono- or unmethylated at K9ProteinREACT_27021 (Reactome)
I(1,3,4)P3MetaboliteCHEBI:18228 (ChEBI)
I(1,3,4,5)P4MetaboliteCHEBI:16783 (ChEBI)
I(1,3,4,5,6)P5MetaboliteCHEBI:16322 (ChEBI)
I(1,3,4,6)P4MetaboliteCHEBI:16155 (ChEBI)
I(3,4,5,6)P4MetaboliteCHEBI:15844 (ChEBI)
IFN alpha/beta (IFNA/B)ProteinREACT_26595 (Reactome)
IRF1 [nucleoplasm]ProteinP10914 (Uniprot-TrEMBL)
IRF1:Promotors of IFN alpha, IFN betaComplexREACT_26239 (Reactome)
IRF1ProteinP10914 (Uniprot-TrEMBL)
IRF2 [nucleoplasm]ProteinP14316 (Uniprot-TrEMBL)
IRF2:promoters of INF alpha, INF betaComplexREACT_26555 (Reactome)
IRF2ProteinP14316 (Uniprot-TrEMBL)
ITPK1ProteinQ13572 (Uniprot-TrEMBL)
JMJD1CProteinQ15652 (Uniprot-TrEMBL)
KDM1A [nucleoplasm]ProteinO60341 (Uniprot-TrEMBL)
KinesinsPathwayWP1842 (WikiPathways) Kinesins are a superfamily of microtubule-based motor proteins that have diverse functions in transport of vesicles, organelles and chromosomes, and regulate microtubule dynamics. There are 14 families of kinesins, all reprsented in humans. A standardized nomenclature was published in 2004 (Lawrence et al.).
LRRC16A [cytosol]ProteinQ5VZK9 (Uniprot-TrEMBL)
LRRC16A:F-actin capping proteinComplexREACT_26939 (Reactome)
LRRC16AProteinQ5VZK9 (Uniprot-TrEMBL)
MAFF [nucleoplasm]ProteinQ9ULX9 (Uniprot-TrEMBL)
MAFG [nucleoplasm]ProteinO15525 (Uniprot-TrEMBL)
MAFK [nucleoplasm]ProteinO60675 (Uniprot-TrEMBL)
MYB [nucleoplasm]ProteinP10242 (Uniprot-TrEMBL)
MYBProteinP10242 (Uniprot-TrEMBL)
MeK-H3F3A [nucleoplasm]ProteinP84243 (Uniprot-TrEMBL)
MeK-HIST1H3A [nucleoplasm]ProteinP68431 (Uniprot-TrEMBL)
MeK-HIST2H3A [nucleoplasm]ProteinQ71DI3 (Uniprot-TrEMBL)
Mitofusin complexComplexREACT_25928 (Reactome)
MitofusinsProteinREACT_26095 (Reactome)
NF-E2:Promoter

region of

beta-globin		ComplexREACT_27022 (Reactome)
NF-E2ComplexREACT_26613 (Reactome)
NFE2 [nucleoplasm]ProteinQ16621 (Uniprot-TrEMBL)
NFE2ProteinQ16621 (Uniprot-TrEMBL)
PHF21A [nucleoplasm]ProteinQ96BD5 (Uniprot-TrEMBL)
PKA tetramerComplexREACT_5749 (Reactome)
PRKACA [cytosol]ProteinP17612 (Uniprot-TrEMBL)
PRKACB [cytosol]ProteinP22694 (Uniprot-TrEMBL)
PRKACG [cytosol]ProteinP22612 (Uniprot-TrEMBL)
PRKAR1A(1-381) [cytosol]ProteinP10644 (Uniprot-TrEMBL)
PRKAR1B [cytosol]ProteinP31321 (Uniprot-TrEMBL)
PRKAR2A [cytosol]ProteinP13861 (Uniprot-TrEMBL)
PRKAR2B [cytosol]ProteinP31323 (Uniprot-TrEMBL)
Promotor region of beta-globinREACT_25634 (Reactome)
Promotor region of interferon alphaREACT_26381 (Reactome)
Promotor region of interferon betaREACT_25836 (Reactome)
RAB5A(2-215) [endosome membrane]ProteinP20339 (Uniprot-TrEMBL)
RAB5A(2-215)ProteinP20339 (Uniprot-TrEMBL)
RAC1 [cytosol]ProteinP63000 (Uniprot-TrEMBL)
RAC1, CDC42ProteinREACT_25943 (Reactome)
RAD51B [nucleoplasm]ProteinO15315 (Uniprot-TrEMBL)
RAD51B:RAD51C:Single-stranded DNAComplexREACT_25469 (Reactome)
RAD51B:RAD51CComplexREACT_26032 (Reactome)
RAD51BProteinO15315 (Uniprot-TrEMBL)
RAD51C [nucleoplasm]ProteinO43502 (Uniprot-TrEMBL)
RAD51CProteinO43502 (Uniprot-TrEMBL)
RCOR1 [nucleoplasm]ProteinQ9UKL0 (Uniprot-TrEMBL)
REST:REST DNA binding sitesComplexREACT_25691 (Reactome)
Rabenosyn-5:VPS-45ComplexREACT_26968 (Reactome)
SH2B family:p(Y813)-JAK2ComplexREACT_26825 (Reactome)
SH2B familyProteinREACT_26906 (Reactome)
SH2B1 [cytosol]ProteinQ9NRF2 (Uniprot-TrEMBL)
SH2B2 [cytosol]ProteinO14492 (Uniprot-TrEMBL)
SH2B3 [cytosol]ProteinQ9UQQ2 (Uniprot-TrEMBL)
SIN3A [nucleoplasm]ProteinQ96ST3 (Uniprot-TrEMBL)
SIN3AProteinQ96ST3 (Uniprot-TrEMBL)
Single-stranded DNA [nucleoplasm]MetaboliteCHEBI:9160 (ChEBI)
Single-stranded DNACHEBI:9160 (ChEBI)
Small Maf family membersProteinREACT_25969 (Reactome)
TP53 [nucleoplasm]ProteinP04637 (Uniprot-TrEMBL)
TP53ProteinP04637 (Uniprot-TrEMBL)
VAF/pIRF7:CBP/p300

bound to type I IFN

gene promoter		ComplexREACT_26244 (Reactome)
VPS45 [endosome membrane]ProteinQ9NRW7 (Uniprot-TrEMBL)
VPS45ProteinQ9NRW7 (Uniprot-TrEMBL)
WEE1 [nucleoplasm]ProteinP30291 (Uniprot-TrEMBL)
WEE1ProteinP30291 (Uniprot-TrEMBL)
ZFPM proteins:GATA proteinsComplexREACT_25675 (Reactome)
ZFPM1 [nucleoplasm]ProteinQ8IX07 (Uniprot-TrEMBL)
ZFPM1, ZFPM2ProteinREACT_25560 (Reactome)
ZFPM2 [nucleoplasm]ProteinQ8WW38 (Uniprot-TrEMBL)
ZFYVE20(2-784) [endosome membrane]ProteinQ9H1K0 (Uniprot-TrEMBL)
ZFYVE20(2-784)ProteinQ9H1K0 (Uniprot-TrEMBL)
f-actinREACT_25435 (Reactome)
p-4S,T404-IRF3 [nucleoplasm]ProteinQ14653 (Uniprot-TrEMBL)
p-S477,S479-IRF7 [nucleoplasm]ProteinQ92985 (Uniprot-TrEMBL)
p-Y813-JAK2 [cytosol]ProteinO60674 (Uniprot-TrEMBL)
p-Y813-JAK2ProteinO60674 (Uniprot-TrEMBL)
p53:MYB:SIN3AComplexREACT_26185 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ABL1REACT_25197 (Reactome)
ADPArrowREACT_120737 (Reactome)
ADPArrowREACT_25076 (Reactome)
ADPArrowREACT_25214 (Reactome)
ADPArrowREACT_25345 (Reactome)
AK3mim-catalysisREACT_25345 (Reactome)
AMPREACT_25345 (Reactome)
ATPREACT_120737 (Reactome)
ATPREACT_25076 (Reactome)
ATPREACT_25214 (Reactome)
BHC

complex:REST:REST

DNA binding sites		ArrowREACT_25101 (Reactome)
BHC complexREACT_25101 (Reactome)
C-terminal EH domain

containing

proteins:Rabenosyn-5		ArrowREACT_25249 (Reactome)
C-terminal EH domain containing proteinsREACT_25249 (Reactome)
CABLES1REACT_25027 (Reactome)
CABLESREACT_25197 (Reactome)
CAPZBREACT_25363 (Reactome)
CBX5REACT_25059 (Reactome)
CDK2:CABLES1:Wee-1ArrowREACT_25027 (Reactome)
CDK2REACT_25027 (Reactome)
CDK5:CABLES:ABLArrowREACT_25197 (Reactome)
CDK5REACT_25197 (Reactome)
DOCK-GEFs:RAC1, CDC42ArrowREACT_25140 (Reactome)
DOCK-GEFsREACT_25140 (Reactome)
Dual-specific AKAPs:PKA tetramerArrowREACT_24992 (Reactome)
Dual-specific AKAPsREACT_24992 (Reactome)
F-actin capping

protein alpha

subunit		REACT_25363 (Reactome)
F-actin capping protein:f-actinArrowREACT_25135 (Reactome)
F-actin capping proteinArrowREACT_25363 (Reactome)
F-actin capping proteinREACT_25135 (Reactome)
F-actin capping proteinREACT_25319 (Reactome)
GATA proteinsREACT_25215 (Reactome)
GDPArrowREACT_25345 (Reactome)
GTPREACT_25345 (Reactome)
HBBArrowREACT_25336 (Reactome)
HBDArrowREACT_25336 (Reactome)
HBE1ArrowREACT_25336 (Reactome)
HBG1ArrowREACT_25336 (Reactome)
HBG2ArrowREACT_25336 (Reactome)
HP1alpha:Histone H3 methylated at K9ArrowREACT_25059 (Reactome)
Histone H3

methylated at

lysine-9		REACT_25059 (Reactome)
Histone H3 mono or di-methylated at K9REACT_25371 (Reactome)
Histone H3 mono- or unmethylated at K9ArrowREACT_25371 (Reactome)
I(1,3,4)P3REACT_120737 (Reactome)
I(1,3,4)P3REACT_25214 (Reactome)
I(1,3,4,5)P4ArrowREACT_25214 (Reactome)
I(1,3,4,5,6)P5ArrowREACT_25076 (Reactome)
I(1,3,4,6)P4ArrowREACT_120737 (Reactome)
I(3,4,5,6)P4REACT_25076 (Reactome)
IFN alpha/beta (IFNA/B)ArrowREACT_25209 (Reactome)
IRF1:Promotors of IFN alpha, IFN betaArrowREACT_25209 (Reactome)
IRF1:Promotors of IFN alpha, IFN betaArrowREACT_25334 (Reactome)
IRF1REACT_25334 (Reactome)
IRF2:promoters of INF alpha, INF betaArrowREACT_25232 (Reactome)
IRF2:promoters of INF alpha, INF betaTBarREACT_25209 (Reactome)
IRF2REACT_25232 (Reactome)
ITPK1mim-catalysisREACT_120737 (Reactome)
ITPK1mim-catalysisREACT_25076 (Reactome)
ITPK1mim-catalysisREACT_25214 (Reactome)
JMJD1Cmim-catalysisREACT_25371 (Reactome)
LRRC16A:F-actin capping proteinArrowREACT_25319 (Reactome)
LRRC16AREACT_25319 (Reactome)
MYBREACT_25138 (Reactome)
Mitofusin complexArrowREACT_25188 (Reactome)
MitofusinsREACT_25188 (Reactome)
NF-E2:Promoter

region of

beta-globin		ArrowREACT_25336 (Reactome)
NF-E2:Promoter

region of

beta-globin		ArrowREACT_25340 (Reactome)
NF-E2ArrowREACT_25294 (Reactome)
NF-E2REACT_25340 (Reactome)
NFE2REACT_25294 (Reactome)
PKA tetramerREACT_24992 (Reactome)
Promotor region of beta-globinREACT_25340 (Reactome)
Promotor region of interferon alphaREACT_25232 (Reactome)
Promotor region of interferon alphaREACT_25334 (Reactome)
Promotor region of interferon betaREACT_25232 (Reactome)
Promotor region of interferon betaREACT_25334 (Reactome)
RAB5A(2-215)REACT_24949 (Reactome)
RAC1, CDC42REACT_25140 (Reactome)
RAD51B:RAD51C:Single-stranded DNAArrowREACT_25328 (Reactome)
RAD51B:RAD51CArrowREACT_24936 (Reactome)
RAD51B:RAD51CREACT_25328 (Reactome)
RAD51BREACT_24936 (Reactome)
RAD51CREACT_24936 (Reactome)
REACT_120737 (Reactome) Inositol-tetrakisphosphate 1-kinase (ITPK1) phosphorylates Ins(1,3,4)P3 on O-6 to form Ins(1,3,4,6)P4, an essential molecule in the hexakisphosphate (InsP6) pathway.
REACT_24936 (Reactome) The Rad51-like proteins Rad51B and Rad51C form a highly stable complex. This complex assists Rad51 in the early stages of homologous recombination.
REACT_24949 (Reactome) The small GTPase Rab5 regulates membrane traffic into and between early endosomes by specifically recruiting cytosolic effector proteins to their site of action on early endosomal membranes. Rab5 occupies a restricted membrane subdomain on endosomes that has distinct biochemical features when compared with neighboring subcompartments (Sonnichsen et al. 2000). Rab5 is believed to form this subdomain by recruiting the specific PI3 kinase VPS-45, causing localized production of PI-3-phosphate (PI-3P) (Christoforidis et al. 1999). Rabenosyn-5 is a Rab5 effector, recruited in a phosphatidylinositol-3-kinase dependent fashion to early endosomes where it serves as a molecular link between VPS-45 and Rab5.
REACT_24992 (Reactome) Protein kinase A (PKA) refers to a family of multimeric enzyme complexes whose activity is dependent on the level of cyclic AMP (cAMP), hence PKA is also known as cAMP-dependent protein kinase (EC 2.7.11.11). PKA has several functions in the cell, including regulation of glycogen, sugar, and lipid metabolism. PKA is a holoenzyme complex consisting of two regulatory and two catalytic subunits. When cAMP levela are low the holoenzyme remains intact and is inactive. When the concentration of cAMP rises (e.g. as a result of adenylate cyclase activation by G protein-coupled receptors coupled to Gs, or inhibition of phosphodiesterases that degrade cAMP) cAMP binds to two binding sites on the regulatory subunits, leading to the release and activation of the catalytic subunits. The regulatory subunits of PKA are also important for localizing the kinase inside the cell. A-kinase anchor proteins (AKAPs) bind to the regulatory subunits and to cytoskeletal structures or membranes, anchoring the enzyme complex to a particular subcellular compartment. Dual-specificity A kinase-anchoring proteins (AKAP1/D-AKAP1) and (AKAP10/D-AKAP2) interact with the type I and type II regulatory subunits of PKA (Huang et al. 1997). AKAP10 additionally has two regulator of G-protein signaling (RGS) domains, giving it the potential to coordinate a signaling complex that links cAMP signaling with G-protein-coupled receptor (GPCR) signaling (Burns-Hamuro et al. 2004).
REACT_25027 (Reactome) CDK5 and ABL1 enzyme substrate 1 (Cables1) is a negative regulator of cell proliferation. Loss of Cables1 function can lead to uncontrolled growth in vivo, observed in many human cancers, such as colon, lung and gynecological malignancies including ovarian and endometrial cancers (Sakamoto et al. 2008). Cables1 is up-regulated by progesterone and down-regulated by estrogen (Zukerberg et al. 2004). Cables1 is predominantly located in the nucleus of proliferating cells (Zukerberg et al. 2000, Wu et al. 2001) but some fully differentiated cells such as mature neurons have a significant proportion in the cytoplasm. Cables1 interacts with cyclin-dependent kinases (Cdk) 2, 3 and 5 (Wu et al. 2001, Matsuoka et al. 2000, Zukerberg et al. 2000). In proliferating cells, Cables1 links Cdk2 and Wee1, a dual specificity kinase. Phosphorylation of Cdk2 on tyrosine-15 by Wee-1 leads to decreased Cdk2 activity; Cables1 enhances this inhibitory phosphorylation (Wu et al. 2001). Cables1 has also been shown to interact with two regulators of apoptosis, p53 and p73. The physiological relevance of this interaction is not fully understood, but Cables1 augments p53-induced apoptosis in human osteosarcoma cells (Tsuji et al. 2002). Cables2 interacts with Cdk3, Cdk5 and c-Abl (Sato et al. 2002).
REACT_25059 (Reactome) Chromobox (CBX) genes encode members of the Heterochromatin Protein (HP) family. HP1 was discovered in Drosophila as a dominant suppressor of position-effect variegation and a major component of heterochromatin. The HP1 family is evolutionarily conserved, with members in fungi, plants and animals. Most animal species have several HP1 isoforms; humans have HP alpha, beta and gamme encoded by the genes CBX5, CBX1 and CBX3 respectively.
The HP1 amino-terminal chromodomain binds methylated lysine-9 of histone H3, causing transcriptional repression (Lachner et al. 2001). A crystal structure of human HP1 alpha in complex with H3K9(me)3 peptide is available (Amaya et al. 2008). The highly-conserved carboxy-terminal chromoshadow domain enables dimerization and also serves as a docking site for proteins involved in a wide variety of nuclear functions, from transcription to nuclear architecture.

REACT_25076 (Reactome) Inositol-tetrakisphosphate 1-kinase (ITPK1) can phosphorylate inositol polyphosphates Ins(3,4,5,6)P4 at position 1 to form Ins(1,3,4,5,6)P5. This reaction is thought to have regulatory importance, since Ins(3,4,5,6)P4 is an inhibitor of plasma membrane Ca2+-activated Cl- channels.
REACT_25101 (Reactome) The BHC (BRAF-HDAC) complex is involved in the repression of neuronal-specific genes during development. It is recruited by RE1-silencing transcription factor (REST) to mediate the repression of REST-responsive genes. The BHC complex includes histone deacetylases (HDACs) 1 and 2, and the histone demethylase KDM1A (also knowns as BHC110, LSD1 or AOF2). KDM1A demethylates both Lys-4 (H3K4me) and Lys-9 (H3K9me) of histone H3, acting as a coactivator or a corepressor, depending on the context. Corepressor for element-1-silencing transcription factor (CoREST) is an essential component of the BHC complex, enhancing the association with nucleosomes (Lee et al. 2005).

REST is a modular transcriptional regulator that recruits CoREST and other regulatory cofactors to activate or repress transcription through dynamic epigenetic mechanisms (Ballas & Mandel 2005).
REACT_25135 (Reactome) Actin capping protein (CP) was named for its ability to bind the barbed ends of actin filaments. CP inhibits the addition and loss of actin subunits at the barbed end and is important for the dynamics of actin filament assembly, and therefore important for the control of cell shape and movement. CP was called beta-actinin when first characterized and purified from muscle (Maruyama 1966). Actin polymerization is controlled by a large cellular excess of capping proteins which bind to the barbed end of actin filaments preventing elongation.
REACT_25138 (Reactome) The DNA-binding domain of c-Myb binds the co-repressor protein SIN3A (Nomura et al. 2004). The tumor repressor p53 also binds MYB directly (Tanikawa et al. 2004), promoting formation of a trimeric SIN3A:c-Myb:p53 complex. This does not affect the ability of c-Myb to bind to DNA, but may represent the mechanism that allows p53 to to regulate specific Myb target genes.
c-Myb (gene symbol MYB) is highly conserved in all vertebrates and some invertebrate species (Lipsick 1996). It plays an important role in the control of proliferation and differentiation of hematopoietic progenitor cells (Duprey & Boettiger 1985); Down-regulation of c-Myb is believed to be critical for the commitment of cells to terminal differentiation (Oh & Reddy, 1999). c-Myb interacts with many other transcription factors including CBP, several CCAAT binding protein (c/EBP) family members, and Ets family proteins such as Ets-2 (Oh & Reddy, 1999).
Loss of c-Myb function results in embryonic lethality due to failure of fetal hepatic hematopoiesis (Mucenski et al. 1991).
REACT_25140 (Reactome) Members of the Dedicator of cytokinesis (DOCK) family, also known as the Dock180 superfamily, are Rho GTPase guanine nucleotide exchange factors (GEFs), modulating Rho GTPase activity (Cote & Vuori 2002). All eleven human members share the presence of two evolutionarily conserved protein domains, termed DHR-1 and DHR-2 (Cote & Vuori 2007). The DHR-2 domains of several DOCKs interact with the nucleotide-free forms of Rho GTPases, intermediates in the catalytic reaction leading to the exchange of GDP for GTP. DHR-2 domains have been shown necessary and sufficient to promote specific guanine nucleotide exchange on various Rho GTPases, both in vitro and in vivo. Inactivation of the DHR-2 domain in DOCK1 (Dock180) has been shown to block Rac activation, cell migration and phagocytosis (Brugnera et al. 2002, Grimsley et al. 2004, Cote & Vuori 2002). The DHR-1 domain of DOCK1 was shown to mediate a specific interaction with PIP2 and PIP3 signaling lipids in vitro and in cells (Cote et al. 2005). Mutations of the DOCK1 DHR-1 domain blocked Rac-dependent cell elongation and cell migration suggesting that the role of DHR-1 is to position DOCK1 at sites of PIP3 production by PI3-kinase, coupling this to Rac signaling (Cote & Vuori 2007).
REACT_25188 (Reactome) Mitochondria frequently fuse and divide (Bereiter-Hahn & Voth 1994); these processes affect morphology and are important for normal mitochondrial functions such as respiration, development and apoptosis. Mitofusins (MFNs) are mitochondrial GTPases that mediate mitochondrial outer membrane fusion. Mammals have two mitofusins; Mfn1-null or Mfn2-null mouse embryonic fibroblast cells show predominantly fragmented mitochondria and have greatly reduced mitochondrial fusion in vivo (Chen et al. 2003, 2005). MFNs acts in trans to bring mitochondria into close proximity prior to fusion (Koshiba et al. 2004). They also tether the endoplasmic reticulum (ER) to mitochondria, cross-linking MFNs expressed on the mitochondrial outer membrane and ER membrane (de Brito & Scorrano 2008).
REACT_25197 (Reactome) CDK5 and ABL1 enzyme substrate 1 (Cables1) is a negative regulator of cell proliferation. Loss of Cables1 function can lead to uncontrolled growth in vivo, observed in many human cancers, such as colon, lung and gynecological malignancies including ovarian and endometrial cancers (Sakamoto et al. 2008). Cables1 is up-regulated by progesterone and down-regulated by estrogen (Zukerberg et al. 2004). Cables1 is predominantly located in the nucleus of proliferating cells (Zukerberg et al. 2000, Wu et al. 2001) but some fully differentiated cells such as mature neurons have a significant proportion in the cytoplasm. Cables1 interacts with cyclin-dependent kinases (Cdk) 2, 3 and 5 (Wu et al. 2001, Matsuoka et al. 2000, Zukerberg et al. 2000). In neurons, Cables1 links Cdk5 and c-Abl, enhancing Cdk5 tyrosine-15 phosphorylation which results in increased Cdk5 activity, important in neurite outgrowth (Zukerberg et al. 2000). In proliferating cells, Cables1 links Cdk2 and Wee1, a dual specificity kinase. Phosphorylation of Cdk2 on tyrosine-15 by Wee-1 leads to decreased Cdk2 activity, Cables1 enhances this inhibitory phosphorylation (Wu et al. 2001). Cables1 has also been shown to interact with two regulators of apoptosis, p53 and p73. The physiological relevance of this interaction is not fully understood, but Cables1 augments p53-induced apoptosis in human osteosarcoma cells (Tsuji et al. 2002). Cables2 interacts with Cdk3, Cdk5 and c-Abl (Sato et al. 2002).
REACT_25209 (Reactome) The Interferon alpha and beta genes are transcribed and translated yielding IFNA and IFNB which are secreted. This process is positively regulated by Interferon Regulatory Factor 1 and negatively regulated by Interferon Regulatory Factor 2, which compete for binding to the same regulatory element (Harada et al. 1989).
REACT_25214 (Reactome) Inositol-tetrakisphosphate 1-kinase (ITPK1) phosphorylates Ins(1,3,4)P3 on O-5 to form Ins(1,3,4,5)P4.
REACT_25215 (Reactome) The Friend of GATA (FOG) family of proteins are a highly-conserved family of large multitype zinc finger cofactors that bind to the amino zinc finger of GATA transcription factors, modulating their activity. GATA proteins are named for the DNA consensus sequence they recognize, (T/A)GATA(A/G). FOG/GATA protein interactions are essential for the development of many tissues. All six GATA family members are capable of interacting with both FOG-1 and FOG-2 (Tsang et al. 1997, Tevosian et al. 1999). Mutations that disrupt binding of GATA-1 to FOG-1 are associated with a syndrome of severe X-linked macrothrombocytopenia (Cantor & Orkin 2005) and in some cases dyserythropoietic anemia (Nichols et al. 2000). In addition to binding GAG proteins, FOGs interact with complexes containing the co-repressor C-terminal binding protein (CtBP) that are thought to coordinate histone modifications leading to a transcriptionally repressed state (Shi et al. 2003).
REACT_25232 (Reactome) Interferon regulatory factor 2 (IRF-2) represses the action of IRF-1 on type I interferon genes (Harada et al, 1989, 1990; Palombella & Maniatis, 1992) by competing with IRF-1 for binding at the PRDI site.
REACT_25249 (Reactome) The four human EH domain-containing proteins (EHD1-4) are a distinct highly-homologous subfamily of the Eps15-homology (EH) domain family. They are distinct from most other EH family members in having the EH-domain at the C-terminus (Naslavsky & Caplan 2005). EH domains interact with other proteins; peptides containing Asp-Pro-Phe (NPF) motifs are major targets for EH-domain binding (Salcini et al. 1997).

EH domain family proteins have regulatory roles in endocytic membrane transport events (Naslavsky & Caplan 2005); the EHD subfamily is believed to regulate endocytic recycling (George et al. 2007). All four human EHD proteins can rescue the vacuolated intestinal phenotype observed when the C. elegans orthologue rme-1 is mutated (George et al. 2007).

Over 20 interaction partners have been reported for the C-terminal EHD proteins including clathirin, syndaptins and Arp2/3 (see Naslavsky & Caplan 2005). EHD1-3 all interact with Rabenosyn-5 (Rab5), a Rab5 effector (Naslavsky et al. 2004).
REACT_25294 (Reactome) NF-E2 is a heterodimer consisting of a hematopoietic-specific subunit NFE2-p45, a member of the cap and collar (CNC) family, and a more widely expressed small subunit which can be any of the three small members of the Maf protein family MafF, MafG OR MafK (Motohashi et al. 1997). MafG and MafK are the predominant small Maf molecules in erythroid cells and megakaryocytes (Shavit et al. 1998).

NF-E2 binds to an extended AP-1-like element, TGCTGA(G/C)TCA, which is found in the locus control regions (LCRs) of the alpha- and beta-globin genes and in the promoters of several heme biosynthetic enzyme genes (see Motohashi et al. 1997). NF-E2 binding sites in the DNase I hypersensitive site 2 (HS2) of the beta-globin LCR are essential for its enhancer activity (Ney et al. 1990, Talbot & Grosveld 1991).

NFE2-p45 null mice have a mild defect in globin gene expression, suggesting that other members of the CNC protein family can substitute for function in vivo (Shivdasani & Orkin 1995).
REACT_25319 (Reactome) Leucine rich repeat-containing protein 16A (CARMIL homolog) binds F-actin capping protein (CP) with high affinity, significantly decreasing the affinity of CP for actin barbed ends. Actin polymerization occurs at the barbed end; proteins like CP that cap the barbed end inhibit elongation. Inhibition of CP therefore enhances the rate of barbed-end actin polymerization. In cells, GFP-LRRC16A was seen to be concentrated in lamellipodia and increased the fraction of cells with large lamellipodia. Decreasing LRRC16A levels with siRNA lowered F-actin levels, decreased lamellipodia protrusion and slowed cell migration.
REACT_25328 (Reactome) The complex of Rad51B and Rad51C binds single-stranded DNA and hydrolyses ATP (Sigurdsson et al. 2001). Rad51B and Rad51C are both required for recombination and DNA double-strand break repair in vivo. The complex cannot substitute for RPA but enhances Rad51/RPA mediated repair. The proposed mechanism for this is that Rad51b:Rad51C partially overcomes the suppressive effect of RPA on Rad51-catalyzed DNA pairing and strand exchange; RPA is an important accessory factor for Rad51-mediated homologous DNA pairing and strand exchange, but it can also compete with Rad51 for binding sites on the ssDNA template, which, when allowed to occur, suppresses pairing and strand exchange efficiency markedly (Sung et al. 2000).
REACT_25334 (Reactome) Interferon regulatory factor-1 (IRF-1) is a positive transcription factor for genes involved in immune response, cell growth regulation and apoptosis in mammalian cells. Many agents such as viruses, interferon (IFN), double-stranded RNA (dsRNA), and proinflammatory cytokines induce IRF-1 transcription. IRF-1 transcriptionally activates many IRF-1-regulated genes during normal physiological and pathological conditions, including interferon-beta and alpha (Escalante et al. 1998, Harada et al. 1990), iNOS, COX-2, VCAM-1, IL-12, IL-15, CIITA, Caspase-1 and Caspase-7 (Upreti & Rath 2005).
REACT_25336 (Reactome) The human beta-globin locus consists of five genes encoding the beta globin gene but also delta, gamma-A, gamma-G and epsilon globin. All of these genes are controlled by the beta globin locus control region.
REACT_25338 (Reactome) The SH2B family has 3 members sharing a common domain structure, including a dimerization domain, a pleckstrin homology (PH) region, and a SH2 domain. The SH2 domain binds phosphotyrosines of various signal-transducing proteins such as c-Kit, MPL, EpoR. All are able to bind JAK2 phosphorylated at Tyr-813 (Bersenev et al. 2008, Kurzer et al. 2004, 2006), inhibiting JAK2 proliferative signaling (Gery et al. 2009).
REACT_25340 (Reactome) The human beta-globin locus control region (LCR) controls expression of the beta-globin gene family. It consists of four erythroid-cell-specific DNase I hypersensitive sites, HS1-4. DNAse I HS sites are thought to represent nucleosome-free regions of DNA which are available to trans-acting factors. NF-E2 binds two tandem AP1-like sites in HS2 which form the core of its enhancer activity. Interaction of NF-E2 with HS2 allows a second erythroid factor, GATA-1, to bind its nearby sites.
REACT_25345 (Reactome) GTP-AMP phosphotransferase, also called Adenylate kinase 3 catalyzes phosphate transfer from GTP to AMP (EC 2.7.4.10). A crystal structure is available (Choe et al. 2005).
REACT_25363 (Reactome) F-actin-capping protein binds in a Ca2+-independent manner to the fast growing ends of actin filaments (barbed end) thereby blocking the exchange of subunits. Unlike other capping proteins (such as gelsolin and severin), they do not sever actin filaments.
REACT_25371 (Reactome) JMJD1C specifically demethylates histone H3K9 mono- and di-methylation, thereby mediating transcriptional activation.
REST:REST DNA binding sitesREACT_25101 (Reactome)
Rabenosyn-5:VPS-45ArrowREACT_24949 (Reactome)
SH2B family:p(Y813)-JAK2ArrowREACT_25338 (Reactome)
SH2B familyREACT_25338 (Reactome)
SIN3AREACT_25138 (Reactome)
Single-stranded DNAREACT_25328 (Reactome)
Small Maf family membersREACT_25294 (Reactome)
TP53REACT_25138 (Reactome)
VAF/pIRF7:CBP/p300

bound to type I IFN

gene promoter		ArrowREACT_25209 (Reactome)
VPS45REACT_24949 (Reactome)
WEE1REACT_25027 (Reactome)
ZFPM proteins:GATA proteinsArrowREACT_25215 (Reactome)
ZFPM1, ZFPM2REACT_25215 (Reactome)
ZFYVE20(2-784)REACT_24949 (Reactome)
ZFYVE20(2-784)REACT_25249 (Reactome)
f-actinREACT_25135 (Reactome)
p-Y813-JAK2REACT_25338 (Reactome)
p53:MYB:SIN3AArrowREACT_25138 (Reactome)
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