Clear cell renal cell carcinoma pathways (Homo sapiens)

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4, 87DEPTOR536212333333Malfunction of epigenetic machineryLegendFASNProtein TranslationFLT1HK3KCNJ2CAMK1ENPP3EGFRSTAT3ACACAFatty Acid SynthesisPDGFRAAMPKCell proliferationglucoseGlycolysisEFCAB3PAngiogenesisAKT1MLST8SQSTM1MTORRPTORTSC1p300GRB10MePI3KMIR21MeRTKsPTENGLUT1VEGFARHEBVHLHIF1AHIF1BPBRM1SETD2BAP1KDM5CH2UbH3H3MeMeH2Activation of PI3K-mTOR pathwayTSC2HIF1BHIF1ACell migrationand invasionHIF1AHIF1BHIF1AUbPDGFBTGFB1TGFB2TGFB3CBPp300CBPAKT1S1ACACBACLYMDH1ME1HK1HK2GPIPFKLPFKPPFKMALDOAALDOBALDOCTPI1GAPDHPGK1PGK2PGM1PGM2ENO1ENO2ENO3PHGDHPSAT1PSPHSHMT1SHMT2SDSSDSLPKLRLDHALDHBLDHDLDHCPKMHIF1APKM2PDGFRBKDRBHLHE41CDH13CEP290KSR1PGBD5PLOD2SSPNRAPGEF5ZEB1TOX2Activating mutationInactivating mutationProteasome degradationNucleus


Description

Inactivation of VHL due to mutation or DNA methylation is an early event in ccRCC that leads to accumulation of the transcription factor HIF-α, which dimerizes with HIF-β and translocates to the nucleus. The resulting HIF-α–HIF-β-induced up-regulation of downstream genes promotes cell proliferation, glucose uptake, glycolysis, and angiogenesis.

Mutations in chromatin remodelers and histone modifiers including PBRM1, SETD2, BAP1 and KDM5C lead to global abnormal gene expression patterns, and deficiency in DNA repair, which contributes to genomic instability.

Activation of PI3K–mTOR signaling promotes cell proliferation and tumor aggression, and increases translation of HIF-α, leading to enhanced HIF-α-mediated gene expression. The proposed development pattern of ccRCC is based on tumor evolution analyses and current understanding of genomic variation.

Description adapted from "Precision medicine from the renal cancer genome", Riazalhosseini and Lathrop.

Additional sources of information: mTORC1 complex is based on Wikipedia. PDGFB and TGFB as targets of HIF1A based on KEGG.

Phosphorylation sites were added based on information from PhosphoSitePlus (R), www.phosphosite.org.

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Bibliography

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  1. Dey N, Das F, Mariappan MM, Mandal CC, Ghosh-Choudhury N, Kasinath BS, Choudhury GG; ''MicroRNA-21 orchestrates high glucose-induced signals to TOR complex 1, resulting in renal cell pathology in diabetes.''; J Biol Chem, 2011 PubMed Europe PMC Scholia
  2. Demaria M, Poli V; ''PKM2, STAT3 and HIF-1α: The Warburg's vicious circle.''; JAKSTAT, 2012 PubMed Europe PMC Scholia
  3. ''Comprehensive molecular characterization of clear cell renal cell carcinoma.''; Nature, 2013 PubMed Europe PMC Scholia
  4. Riazalhosseini Y, Lathrop M; ''Precision medicine from the renal cancer genome.''; Nat Rev Nephrol, 2016 PubMed Europe PMC Scholia
  5. Nargund AM, Pham CG, Dong Y, Wang PI, Osmangeyoglu HU, Xie Y, Aras O, Han S, Oyama T, Takeda S, Ray CE, Dong Z, Berge M, Hakimi AA, Monette S, Lekaye CL, Koutcher JA, Leslie CS, Creighton CJ, Weinhold N, Lee W, Tickoo SK, Wang Z, Cheng EH, Hsieh JJ; ''The SWI/SNF Protein PBRM1 Restrains VHL-Loss-Driven Clear Cell Renal Cell Carcinoma.''; Cell Rep, 2017 PubMed Europe PMC Scholia
  6. Gao X, Wang H, Yang JJ, Liu X, Liu ZR; ''Pyruvate kinase M2 regulates gene transcription by acting as a protein kinase.''; Mol Cell, 2012 PubMed Europe PMC Scholia
  7. Von Roemeling CA, Marlow LA, Radisky DC, Rohl A, Larsen HE, Wei J, Sasinowska H, Zhu H, Drake R, Sasinowski M, Tun HW, Copland JA; ''Functional genomics identifies novel genes essential for clear cell renal cell carcinoma tumor cell proliferation and migration.''; Oncotarget, 2014 PubMed Europe PMC Scholia
  8. Hornbeck PV, Zhang B, Murray B, Kornhauser JM, Latham V, Skrzypek E; ''PhosphoSitePlus, 2014: mutations, PTMs and recalibrations.''; Nucleic Acids Res, 2015 PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
127315view23:09, 12 September 2023KhanspersUpdated phospho site
123404view06:42, 23 July 2022EgonwMade four pathways clickable
117168view09:52, 18 May 2021EweitzModified title
111011view23:07, 29 June 2020KhanspersModified description
110874view16:34, 16 June 2020KhanspersModified description
106515view21:04, 5 September 2019KhanspersModified description
105485view05:41, 8 August 2019KhanspersModified description
105457view05:07, 8 August 2019KhanspersModified description
98359view06:12, 24 August 2018EgonwUpdated the MIR21 identifier.
97121view16:25, 30 April 2018Khanspersremoved unused anchor
97120view16:23, 30 April 2018Khanspersmutations
93145view20:21, 31 July 2017KhanspersModified description
93144view20:13, 31 July 2017Khanspersremoved extraneous comments on nodes
93143view20:05, 31 July 2017Khanspersupdated lit refs, updated details of PBRM1-STAT3 interaction
93142view19:00, 31 July 2017Khanspersadded lit refs
93141view18:28, 31 July 2017KhanspersModified title
93140view18:27, 31 July 2017KhanspersModified description
93139view18:12, 31 July 2017Khanspersupdated mutations, added legend, updated interactions
93109view18:39, 28 July 2017AlexanderPicoOntology Term : 'DOID:4451' removed !
93108view18:39, 28 July 2017AlexanderPicoOntology Term : 'renal clear cell carcinoma' added !
93107view18:38, 28 July 2017AlexanderPicoOntology Term : 'kidney proximal convoluted tubule epithelial cell' added !
93106view18:37, 28 July 2017AlexanderPicoOntology Term : 'kidney cell' added !
93105view18:23, 28 July 2017AlexanderPicoTesting new mutation glyphs
93104view18:16, 28 July 2017AlexanderPicoTesting mutation state glyphs
92883view22:30, 13 July 2017AlexanderPicoOntology Term : 'signaling pathway' added !
92882view22:30, 13 July 2017AlexanderPicoOntology Term : 'renal carcinoma' added !
92881view22:29, 13 July 2017AlexanderPicoModified title
92880view22:29, 13 July 2017AlexanderPicoNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ACACAGeneProductENSG00000278540 (Ensembl)
ACACBGeneProductENSG00000076555 (Ensembl)
ACLYGeneProductENSG00000131473 (Ensembl)
AKT1GeneProductENSG00000142208 (Ensembl)
AKT1S1GeneProductENSG00000204673 (Ensembl)
ALDOAGeneProductENSG00000149925 (Ensembl)
ALDOBGeneProductENSG00000136872 (Ensembl)
ALDOCGeneProductENSG00000109107 (Ensembl)
AMPKGeneProduct
AngiogenesisPathwayWP1539 (WikiPathways)
BAP1GeneProductENSG00000163930 (Ensembl)
BHLHE41GeneProductENSG00000123095 (Ensembl)
CAMK1GeneProductENSG00000134072 (Ensembl)
CBPGeneProductENSG00000005339 (Ensembl)
CDH13GeneProductENSG00000140945 (Ensembl)
CEP290GeneProductENSG00000198707 (Ensembl)
Cell proliferationPathway
DEPTORGeneProductENSG00000155792 (Ensembl)
EFCAB3GeneProductENSG00000172421 (Ensembl)
EGFRGeneProductENSG00000146648 (Ensembl)
ENO1GeneProductENSG00000074800 (Ensembl)
ENO2GeneProductENSG00000111674 (Ensembl)
ENO3GeneProductENSG00000108515 (Ensembl)
ENPP3GeneProductENSG00000154269 (Ensembl)
FASNGeneProductENSG00000169710 (Ensembl)
FLT1GeneProductENSG00000102755 (Ensembl)
Fatty Acid SynthesisPathwayWP357 (WikiPathways)
GAPDHGeneProductENSG00000111640 (Ensembl)
GLUT1GeneProductENSG00000117394 (Ensembl)
GPIGeneProductENSG00000105220 (Ensembl)
GRB10GeneProductENSG00000106070 (Ensembl)
GlycolysisPathwayWP534 (WikiPathways)
H2GeneProduct
H3GeneProduct
HIF1AGeneProductENSG00000100644 (Ensembl)
HIF1BGeneProductENSG00000143437 (Ensembl)
HK1GeneProductENSG00000156515 (Ensembl)
HK2GeneProductENSG00000159399 (Ensembl)
HK3GeneProductENSG00000160883 (Ensembl)
KCNJ2GeneProductENSG00000123700 (Ensembl)
KDM5CGeneProductENSG00000126012 (Ensembl)
KDRGeneProductENSG00000128052 (Ensembl)
KSR1GeneProductENSG00000141068 (Ensembl)
LDHAGeneProductENSG00000134333 (Ensembl)
LDHBGeneProductENSG00000111716 (Ensembl)
LDHCGeneProductENSG00000166796 (Ensembl)
LDHDGeneProductENSG00000166816 (Ensembl)
MDH1GeneProductENSG00000014641 (Ensembl)
ME1GeneProductENSG00000065833 (Ensembl)
MIR21RnaENSG00000284190 (Ensembl)
MLST8GeneProductENSG00000167965 (Ensembl)
MTORGeneProductENSG00000198793 (Ensembl)
PBRM1GeneProductENSG00000163939 (Ensembl)
PDGFBGeneProductENSG00000100311 (Ensembl)
PDGFRAGeneProductENSG00000134853 (Ensembl)
PDGFRBGeneProductENSG00000113721 (Ensembl)
PFKLGeneProductENSG00000141959 (Ensembl)
PFKMGeneProductENSG00000152556 (Ensembl)
PFKPGeneProductENSG00000067057 (Ensembl)
PGBD5GeneProductENSG00000177614 (Ensembl)
PGK1GeneProductENSG00000102144 (Ensembl)
PGK2GeneProductENSG00000170950 (Ensembl)
PGM1GeneProductENSG00000079739 (Ensembl)
PGM2GeneProductENSG00000169299 (Ensembl)
PHGDHGeneProductENSG00000092621 (Ensembl)
PI3KGeneProduct
PKLRGeneProductENSG00000143627 (Ensembl)
PKM2GeneProductENSG00000067225 (Ensembl)
PKMGeneProductENSG00000067225 (Ensembl)
PLOD2GeneProductENSG00000152952 (Ensembl)
PSAT1GeneProductENSG00000135069 (Ensembl)
PSPHGeneProductENSG00000146733 (Ensembl)
PTENGeneProductENSG00000171862 (Ensembl)
Protein TranslationPathwayWP107 (WikiPathways)
RAPGEF5GeneProductENSG00000136237 (Ensembl)
RHEBGeneProductENSG00000106615 (Ensembl)
RPTORGeneProductENSG00000141564 (Ensembl)
RTKsGeneProduct
SDSGeneProductENSG00000135094 (Ensembl)
SDSLGeneProductENSG00000139410 (Ensembl)
SETD2GeneProductENSG00000181555 (Ensembl)
SHMT1GeneProductENSG00000176974 (Ensembl)
SHMT2GeneProductENSG00000182199 (Ensembl)
SQSTM1GeneProductENSG00000161011 (Ensembl)
SSPNGeneProductENSG00000123096 (Ensembl)
STAT3GeneProductENSG00000168610 (Ensembl)
TGFB1GeneProductENSG00000105329 (Ensembl)
TGFB2GeneProductENSG00000092969 (Ensembl)
TGFB3GeneProductENSG00000119699 (Ensembl)
TOX2GeneProductENSG00000124191 (Ensembl)
TPI1GeneProductENSG00000111669 (Ensembl)
TSC1GeneProductENSG00000165699 (Ensembl)
TSC2GeneProductENSG00000103197 (Ensembl)
VEGFAGeneProductENSG00000112715 (Ensembl)
VHLGeneProductENSG00000134086 (Ensembl)
ZEB1GeneProductENSG00000148516 (Ensembl)
glucoseMetaboliteCHEBI:17234 (ChEBI)
p300GeneProductENSG00000100393 (Ensembl)

Annotated Interactions

No annotated interactions

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