Pathways in clear cell renal cell carcinoma (Homo sapiens)

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DEPTOR MLST8 MTOR RPTOR AKT1S1 Malfunction of epigenetic machinery Legend glucose AMPK P STAT3 HK3 Glycolysis HK1 HK2 GPI PFKL PFKP PFKM ALDOA ALDOB ALDOC TPI1 GAPDH PGK1 PGK2 PGM1 PGM2 ENO1 ENO2 ENO3 PHGDH PSAT1 PSPH SHMT1 SHMT2 SDS SDSL PKLR LDHA LDHB LDHD LDHC PKM FASN Fatty Acid Synthesis ACLY MDH1 ME1 ACACA ACACB EGFR GLUT1 VEGFA PDGFB TGFB1 TGFB2 TGFB3 PKM2 PDGFRA FLT1 Angiogenesis PDGFRB KDR Protein Translation Cell migration and invasion KCNJ2 EFCAB3 ENPP3 Cell proliferation CAMK1 BHLHE41 CDH13 CEP290 KSR1 PGBD5 PLOD2 SSPN RAPGEF5 ZEB1 TOX2 AKT1 SQSTM1 TSC1 TSC2 p300 CBP Me GRB10 PI3K Me MIR21 RTKs PTEN RHEB VHL HIF1A HIF1B p300 CBP PBRM1 BAP1 SETD2 KDM5C Ub H2 H3 Me Me H3 H2 Activation of PI3K-mTOR pathway HIF1B HIF1A HIF1A HIF1B Ub HIF1A HIF1A Activating mutation Inactivating mutation Proteasome degradation Nucleus Name: Pathways in clear cell renal cell carcinoma Organism: Homo sapiens


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 upregulation of downstream genes promotes cell proliferation, glucose uptake, glycolysis, and angiogenesis.

Mutations in chromatin remodellers 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 signalling promotes cell proliferation and tumour aggression, and increases translation of HIF-α, leading to enhanced HIF-α-mediated gene expression. The proposed development pattern of ccRCC is based on tumour 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 (

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Ontology Terms



  1. Riazalhosseini Y, Lathrop M; ''Precision medicine from the renal cancer genome.''; Nat Rev Nephrol, 2016 PubMed
  2. 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
  3. 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
  4. 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
  5. Demaria M, Poli V; ''PKM2, STAT3 and HIF-1α: The Warburg's vicious circle.''; JAKSTAT, 2012 PubMed
  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
  7. ''Comprehensive molecular characterization of clear cell renal cell carcinoma.''; Nature, 2013 PubMed
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97121view 09:25, 30 April 2018Khanspersremoved unused anchor
97120view 09:23, 30 April 2018Khanspersmutations
93145view 13:21, 31 July 2017KhanspersModified description
93144view 13:13, 31 July 2017Khanspersremoved extraneous comments on nodes
93143view 13:05, 31 July 2017Khanspersupdated lit refs, updated details of PBRM1-STAT3 interaction
93142view 12:00, 31 July 2017Khanspersadded lit refs
93141view 11:28, 31 July 2017KhanspersModified title
93140view 11:27, 31 July 2017KhanspersModified description
93139view 11:12, 31 July 2017Khanspersupdated mutations, added legend, updated interactions
93109view 11:39, 28 July 2017AlexanderPicoOntology Term : 'DOID:4451' removed !
93108view 11:39, 28 July 2017AlexanderPicoOntology Term : 'renal clear cell carcinoma' added !
93107view 11:38, 28 July 2017AlexanderPicoOntology Term : 'kidney proximal convoluted tubule epithelial cell' added !
93106view 11:37, 28 July 2017AlexanderPicoOntology Term : 'kidney cell' added !
93105view 11:23, 28 July 2017AlexanderPicoTesting new mutation glyphs
93104view 11:16, 28 July 2017AlexanderPicoTesting mutation state glyphs
92883view 15:30, 13 July 2017AlexanderPicoOntology Term : 'signaling pathway' added !
92882view 15:30, 13 July 2017AlexanderPicoOntology Term : 'renal carcinoma' added !
92881view 15:29, 13 July 2017AlexanderPicoModified title
92880view 15:29, 13 July 2017AlexanderPicoNew pathway

External references


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NameTypeDatabase referenceComment
ACACAGeneProductENSG00000278540 (Ensembl)
ACACBGeneProductENSG00000076555 (Ensembl)
ACLYGeneProductENSG00000131473 (Ensembl)
AKT1GeneProductENSG00000142208 (Ensembl)
AKT1S1GeneProductENSG00000204673 (Ensembl)
ALDOAGeneProductENSG00000149925 (Ensembl)
ALDOBGeneProductENSG00000136872 (Ensembl)
ALDOCGeneProductENSG00000109107 (Ensembl)
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)
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)
MIR21RnaENSG00000199004 (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)
PKLRGeneProductENSG00000143627 (Ensembl)
PKM2GeneProductENSG00000067225 (Ensembl)
PKMGeneProductENSG00000067225 (Ensembl)
PLOD2GeneProductENSG00000152952 (Ensembl)
PSAT1GeneProductENSG00000135069 (Ensembl)
PSPHGeneProductENSG00000146733 (Ensembl)
PTENGeneProductENSG00000171862 (Ensembl)
Protein TranslationPathwayWP107 (WikiPathways)
RAPGEF5GeneProductENSG00000136237 (Ensembl)
RHEBGeneProductENSG00000106615 (Ensembl)
RPTORGeneProductENSG00000141564 (Ensembl)
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

<cite>No annotated interactions</cite>