KEGG   PATHWAY: hsa05211
Entry
hsa05211                    Pathway                                
Name
Renal cell carcinoma - Homo sapiens (human)
Description
Renal cell cancer (RCC) accounts for ~3% of human malignancies and its incidence appears to be rising. Although most cases of RCC seem to occur sporadically, an inherited predisposition to renal cancer accounts for 1-4% of cases. RCC is not a single disease, it has several morphological subtypes. Conventional RCC (clear cell RCC) accounts for ~80% of cases, followed by papillary RCC (10-15%), chromophobe RCC (5%), and collecting duct RCC (<1%). Genes potentially involved in sporadic neoplasms of each particular type are VHL, MET, BHD, and FH respectively. In the absence of VHL, hypoxia-inducible factor alpha (HIF-alpha) accumulates, leading to production of several growth factors, including vascular endothelial growth factor and platelet-derived growth factor. Activated MET mediates a number of biological effects including motility, invasion of extracellular matrix, cellular transformation, prevention of apoptosis and metastasis formation. Loss of functional FH leads to accumulation of fumarate in the cell, triggering inhibition of HPH and preventing targeted pVHL-mediated degradation of HIF-alpha. BHD mutations cause the Birt-Hogg-Dube syndrome and its associated chromophobe, hybrid oncocytic, and conventional (clear cell) RCC.
Class
Human Diseases; Cancer: specific types
Pathway map
hsa05211  Renal cell carcinoma
hsa05211

Network
  Element
N00005  Mutation-activated MET to RAS-ERK signaling pathway
N00044  Mutation-activated MET to PI3K signaling pathway
N00080  Loss of VHL to HIF-1 signaling pathway
N00081  Mutation-inactivated VHL to HIF-1 signaling pathway
Disease
H00021  Renal cell carcinoma
Drug
D06272  Sorafenib tosylate (USAN)
D06409  Bevacizumab (USAN)
D08524  Sorafenib (USAN/INN)
D10095  Cabozantinib s-malate (USAN)
D11954  Belzutifan (JAN/USAN/INN)
Organism
Homo sapiens (human) [GN:hsa]
Gene
3091  HIF1A; hypoxia inducible factor 1 subunit alpha [KO:K08268]
2034  EPAS1; endothelial PAS domain protein 1 [KO:K09095]
54583  EGLN1; egl-9 family hypoxia inducible factor 1 [KO:K09592] [EC:1.14.11.29]
112399  EGLN3; egl-9 family hypoxia inducible factor 3 [KO:K09592] [EC:1.14.11.29]
112398  EGLN2; egl-9 family hypoxia inducible factor 2 [KO:K09592] [EC:1.14.11.29]
7428  VHL; von Hippel-Lindau tumor suppressor [KO:K03871]
6921  ELOC; elongin C [KO:K03872]
6923  ELOB; elongin B [KO:K03873]
9978  RBX1; ring-box 1 [KO:K03868] [EC:2.3.2.32]
8453  CUL2; cullin 2 [KO:K03870]
405  ARNT; aryl hydrocarbon receptor nuclear translocator [KO:K09097]
9915  ARNT2; aryl hydrocarbon receptor nuclear translocator 2 [KO:K15589]
1387  CREBBP; CREB binding protein [KO:K04498] [EC:2.3.1.48]
2033  EP300; E1A binding protein p300 [KO:K04498] [EC:2.3.1.48]
6513  SLC2A1; solute carrier family 2 member 1 [KO:K07299]
7422  VEGFA; vascular endothelial growth factor A [KO:K05448]
7040  TGFB1; transforming growth factor beta 1 [KO:K13375]
7042  TGFB2; transforming growth factor beta 2 [KO:K13376]
7043  TGFB3; transforming growth factor beta 3 [KO:K13377]
5155  PDGFB; platelet derived growth factor subunit B [KO:K17386]
7039  TGFA; transforming growth factor alpha [KO:K08774]
3082  HGF; hepatocyte growth factor [KO:K05460]
4233  MET; MET proto-oncogene, receptor tyrosine kinase [KO:K05099] [EC:2.7.10.1]
2549  GAB1; GRB2 associated binding protein 1 [KO:K09593]
5290  PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:2.7.1.153]
5293  PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:2.7.1.153]
5291  PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:2.7.1.153]
5295  PIK3R1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649]
5296  PIK3R2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649]
8503  PIK3R3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649]
207  AKT1; AKT serine/threonine kinase 1 [KO:K04456] [EC:2.7.11.1]
208  AKT2; AKT serine/threonine kinase 2 [KO:K04456] [EC:2.7.11.1]
10000  AKT3; AKT serine/threonine kinase 3 [KO:K04456] [EC:2.7.11.1]
572  BAD; BCL2 associated agonist of cell death [KO:K02158]
1398  CRK; CRK proto-oncogene, adaptor protein [KO:K04438]
1399  CRKL; CRK like proto-oncogene, adaptor protein [KO:K04438]
2889  RAPGEF1; Rap guanine nucleotide exchange factor 1 [KO:K06277]
5906  RAP1A; RAP1A, member of RAS oncogene family [KO:K04353]
5908  RAP1B; RAP1B, member of RAS oncogene family [KO:K07836]
5781  PTPN11; protein tyrosine phosphatase non-receptor type 11 [KO:K07293] [EC:3.1.3.48]
2885  GRB2; growth factor receptor bound protein 2 [KO:K04364]
6654  SOS1; SOS Ras/Rac guanine nucleotide exchange factor 1 [KO:K03099]
6655  SOS2; SOS Ras/Rho guanine nucleotide exchange factor 2 [KO:K03099]
3265  HRAS; HRas proto-oncogene, GTPase [KO:K02833]
3845  KRAS; KRAS proto-oncogene, GTPase [KO:K07827]
4893  NRAS; NRAS proto-oncogene, GTPase [KO:K07828]
369  ARAF; A-Raf proto-oncogene, serine/threonine kinase [KO:K08845] [EC:2.7.11.1]
673  BRAF; B-Raf proto-oncogene, serine/threonine kinase [KO:K04365] [EC:2.7.11.1]
5894  RAF1; Raf-1 proto-oncogene, serine/threonine kinase [KO:K04366] [EC:2.7.11.1]
5604  MAP2K1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
5605  MAP2K2; mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
5594  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
5595  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
2113  ETS1; ETS proto-oncogene 1, transcription factor [KO:K02678]
3725  JUN; Jun proto-oncogene, AP-1 transcription factor subunit [KO:K04448]
5879  RAC1; Rac family small GTPase 1 [KO:K04392]
998  CDC42; cell division cycle 42 [KO:K04393]
5058  PAK1; p21 (RAC1) activated kinase 1 [KO:K04409] [EC:2.7.11.1]
5062  PAK2; p21 (RAC1) activated kinase 2 [KO:K04410] [EC:2.7.11.1]
5063  PAK3; p21 (RAC1) activated kinase 3 [KO:K05733] [EC:2.7.11.1]
10298  PAK4; p21 (RAC1) activated kinase 4 [KO:K05734] [EC:2.7.11.1]
57144  PAK5; p21 (RAC1) activated kinase 5 [KO:K05736] [EC:2.7.11.1]
56924  PAK6; p21 (RAC1) activated kinase 6 [KO:K05735] [EC:2.7.11.1]
106821730  BUB1B-PAK6; BUB1B-PAK6 readthrough [KO:K05735] [EC:2.7.11.1]
5546  PRCC; proline rich mitotic checkpoint control factor [KO:K13105]
7030  TFE3; transcription factor binding to IGHM enhancer 3 [KO:K09105]
1026  CDKN1A; cyclin dependent kinase inhibitor 1A [KO:K06625]
2271  FH; fumarate hydratase [KO:K01679] [EC:4.2.1.2]
201163  FLCN; folliculin [KO:K09594]
Compound
C00007  Oxygen
C00122  Fumarate
C00149  (S)-Malate
Reference
PMID:16339096
  Authors
Cohen HT, McGovern FJ.
  Title
Renal-cell carcinoma.
  Journal
N Engl J Med 353:2477-90 (2005)
DOI:10.1056/NEJMra043172
Reference
PMID:15122209
  Authors
Pavlovich CP, Schmidt LS.
  Title
Searching for the hereditary causes of renal-cell carcinoma.
  Journal
Nat Rev Cancer 4:381-93 (2004)
DOI:10.1038/nrc1364
Reference
PMID:14634372
  Authors
Linehan WM, Walther MM, Zbar B.
  Title
The genetic basis of cancer of the kidney.
  Journal
J Urol 170:2163-72 (2003)
DOI:10.1097/01.ju.0000096060.92397.ed
Reference
PMID:15611513
  Authors
Kim WY, Kaelin WG.
  Title
Role of VHL gene mutation in human cancer.
  Journal
J Clin Oncol 22:4991-5004 (2004)
DOI:10.1200/JCO.2004.05.061
Reference
PMID:17211469
  Authors
Sudarshan S, Linehan WM, Neckers L.
  Title
HIF and fumarate hydratase in renal cancer.
  Journal
Br J Cancer 96:403-7 (2007)
DOI:10.1038/sj.bjc.6603547
Reference
PMID:17287871
  Authors
Sudarshan S, Pinto PA, Neckers L, Linehan WM.
  Title
Mechanisms of disease: hereditary leiomyomatosis and renal cell cancer--a distinct form of hereditary kidney cancer.
  Journal
Nat Clin Pract Urol 4:104-10 (2007)
DOI:10.1038/ncpuro0711
Reference
PMID:14685170
  Authors
Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GF.
  Title
Met, metastasis, motility and more.
  Journal
Nat Rev Mol Cell Biol 4:915-25 (2003)
DOI:10.1038/nrm1261
Reference
PMID:18358634
  Authors
Muller-Hocker J, Babaryka G, Schmid I, Jung A
  Title
Overexpression of cyclin D1, D3, and p21 in an infantile renal carcinoma with Xp11.2 TFE3-gene fusion.
  Journal
Pathol Res Pract 204:589-97 (2008)
DOI:10.1016/j.prp.2008.01.010
Reference
PMID:12351585
  Authors
Bodmer D, van den Hurk W, van Groningen JJ, Eleveld MJ, Martens GJ, Weterman MA, van Kessel AG.
  Title
Understanding familial and non-familial renal cell cancer.
  Journal
Hum Mol Genet 11:2489-98 (2002)
DOI:10.1093/hmg/11.20.2489
Reference
PMID:25048860
  Authors
Kauffman EC, Ricketts CJ, Rais-Bahrami S, Yang Y, Merino MJ, Bottaro DP, Srinivasan R, Linehan WM
  Title
Molecular genetics and cellular features of TFE3 and TFEB fusion kidney cancers.
  Journal
Nat Rev Urol 11:465-75 (2014)
DOI:10.1038/nrurol.2014.162
Reference
PMID:11313942
  Authors
Skalsky YM, Ajuh PM, Parker C, Lamond AI, Goodwin G, Cooper CS
  Title
PRCC, the commonest TFE3 fusion partner in papillary renal carcinoma is associated with pre-mRNA splicing factors.
  Journal
Oncogene 20:178-87 (2001)
DOI:10.1038/sj.onc.1204056
Reference
PMID:19422821
  Authors
Medendorp K, van Groningen JJ, Vreede L, Hetterschijt L, Brugmans L, van den Hurk WH, van Kessel AG
  Title
The renal cell carcinoma-associated oncogenic fusion protein PRCCTFE3 provokes p21 WAF1/CIP1-mediated cell cycle delay.
  Journal
Exp Cell Res 315:2399-409 (2009)
DOI:10.1016/j.yexcr.2009.04.022
Related
pathway
hsa00020  Citrate cycle (TCA cycle)
hsa04010  MAPK signaling pathway
hsa04066  HIF-1 signaling pathway
hsa04120  Ubiquitin mediated proteolysis
hsa04350  TGF-beta signaling pathway
hsa04370  VEGF signaling pathway
KO pathway
ko05211   
LinkDB

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