KEGG   PATHWAY: ecb05211
ecb05211                    Pathway                                

Renal cell carcinoma - Equus caballus (horse)
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.
Human Diseases; Cancer: specific types
Pathway map
ecb05211  Renal cell carcinoma

Equus caballus (horse) [GN:ecb]
100061166  HIF1A; hypoxia-inducible factor 1-alpha [KO:K08268]
100068622  EPAS1; endothelial PAS domain-containing protein 1 isoform X2 [KO:K09095]
100060551  EGLN1; egl nine homolog 1 [KO:K09592] [EC:]
100056635  EGLN3; egl nine homolog 3 [KO:K09592] [EC:]
100064859  EGLN2; egl nine homolog 2 [KO:K09592] [EC:]
100058139  VHL; von Hippel-Lindau disease tumor suppressor [KO:K03871]
100060902  ELOC; elongin-C [KO:K03872]
106781563  ELOB; elongin-B isoform X1 [KO:K03873]
100055581  RBX1; E3 ubiquitin-protein ligase RBX1 isoform X1 [KO:K03868] [EC:]
100054982  CUL2; cullin-2 [KO:K03870]
100059178  ARNT; aryl hydrocarbon receptor nuclear translocator isoform X1 [KO:K09097]
100067423  ARNT2; aryl hydrocarbon receptor nuclear translocator 2 isoform X1 [KO:K15589]
100055626  EP300; histone acetyltransferase p300 isoform X2 [KO:K04498] [EC:]
100069613  CREBBP; CREB-binding protein isoform X1 [KO:K04498] [EC:]
100034080  SLC2A1; solute carrier family 2, facilitated glucose transporter member 1 [KO:K07299]
100033839  VEGFA; vascular endothelial growth factor A precursor [KO:K05448]
100033900  TGFB1; transforming growth factor beta-1 precursor [KO:K13375]
100050377  TGFB2; transforming growth factor beta-2 isoform X2 [KO:K13376]
111771316  transforming growth factor beta-2-like isoform X1 [KO:K13376]
100051765  TGFB3; transforming growth factor beta-3 [KO:K13377]
100070283  PDGFB; platelet-derived growth factor subunit B isoform X1 [KO:K17386]
100060423  TGFA; protransforming growth factor alpha isoform X1 [KO:K08774]
100049848  HGF; hepatocyte growth factor isoform X1 [KO:K05460]
100056013  MET; hepatocyte growth factor receptor precursor [KO:K05099] [EC:]
100062924  GAB1; GRB2-associated-binding protein 1 isoform X2 [KO:K09593]
100051623  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:]
100058141  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform isoform X1 [KO:K00922] [EC:]
100051753  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:]
100052122  phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
100050227  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X3 [KO:K02649]
100146348  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
100064671  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:]
100054961  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:]
100061130  AKT1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:]
100055447  BAD; bcl2-associated agonist of cell death [KO:K02158]
100072356  CRK; adapter molecule crk isoform X1 [KO:K04438]
100050855  CRKL; crk-like protein [KO:K04438]
100069527  RAPGEF1; rap guanine nucleotide exchange factor 1 isoform X8 [KO:K06277]
100049912  ras-related protein Rap-1A [KO:K04353]
100058930  RAP1A; ras-related protein Rap-1A [KO:K04353]
100052025  RAP1B; ras-related protein Rap-1b [KO:K07836]
100056857  PTPN11; tyrosine-protein phosphatase non-receptor type 11 isoform X1 [KO:K07293] [EC:]
100146191  tyrosine-protein phosphatase non-receptor type 11 isoform X1 [KO:K07293] [EC:]
100051866  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
100053889  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
100066282  SOS2; son of sevenless homolog 2 isoform X1 [KO:K03099]
100055481  HRAS; GTPase HRas isoform X1 [KO:K02833]
100064473  KRAS; GTPase KRas isoform X1 [KO:K07827]
100051785  LOW QUALITY PROTEIN: GTPase KRas-like [KO:K07827]
100059469  NRAS; GTPase NRas [KO:K07828]
100061212  ARAF; serine/threonine-protein kinase A-Raf isoform X2 [KO:K08845] [EC:]
100065760  BRAF; serine/threonine-protein kinase B-raf isoform X2 [KO:K04365] [EC:]
100051110  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:]
100065996  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform X2 [KO:K04368] [EC:]
100063190  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:]
100057701  MAPK1; mitogen-activated protein kinase 1 isoform X2 [KO:K04371] [EC:]
100066173  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:]
100064559  ETS1; protein C-ets-1 isoform X2 [KO:K02678]
100067469  JUN; transcription factor AP-1 [KO:K04448]
100061732  RAC1; ras-related C3 botulinum toxin substrate 1 isoform X1 [KO:K04392]
100058188  CDC42; cell division control protein 42 homolog [KO:K04393]
100063217  PAK1; serine/threonine-protein kinase PAK 1 [KO:K04409] [EC:]
100060183  PAK2; serine/threonine-protein kinase PAK 2 [KO:K04410] [EC:]
100054315  PAK3; serine/threonine-protein kinase PAK 3 isoform X3 [KO:K05733] [EC:]
100067000  PAK4; serine/threonine-protein kinase PAK 4 isoform X1 [KO:K05734] [EC:]
100051415  PAK5; serine/threonine-protein kinase PAK 5 [KO:K05736] [EC:]
100071463  PAK6; serine/threonine-protein kinase PAK 6 [KO:K05735] [EC:]
100058204  PRCC; proline-rich protein PRCC isoform X1 [KO:K13105]
100051983  TFE3; transcription factor E3 isoform X1 [KO:K09105]
100064022  CDKN1A; cyclin-dependent kinase inhibitor 1 [KO:K06625]
100060381  FH; fumarate hydratase, mitochondrial [KO:K01679] [EC:]
100052790  FLCN; folliculin [KO:K09594]
C00007  Oxygen
C00122  Fumarate
C00149  (S)-Malate
Cohen HT, McGovern FJ.
Renal-cell carcinoma.
N Engl J Med 353:2477-90 (2005)
Pavlovich CP, Schmidt LS.
Searching for the hereditary causes of renal-cell carcinoma.
Nat Rev Cancer 4:381-93 (2004)
Linehan WM, Walther MM, Zbar B.
The genetic basis of cancer of the kidney.
J Urol 170:2163-72 (2003)
Kim WY, Kaelin WG.
Role of VHL gene mutation in human cancer.
J Clin Oncol 22:4991-5004 (2004)
Sudarshan S, Linehan WM, Neckers L.
HIF and fumarate hydratase in renal cancer.
Br J Cancer 96:403-7 (2007)
Sudarshan S, Pinto PA, Neckers L, Linehan WM.
Mechanisms of disease: hereditary leiomyomatosis and renal cell cancer--a distinct form of hereditary kidney cancer.
Nat Clin Pract Urol 4:104-10 (2007)
Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GF.
Met, metastasis, motility and more.
Nat Rev Mol Cell Biol 4:915-25 (2003)
Muller-Hocker J, Babaryka G, Schmid I, Jung A
Overexpression of cyclin D1, D3, and p21 in an infantile renal carcinoma with Xp11.2 TFE3-gene fusion.
Pathol Res Pract 204:589-97 (2008)
Bodmer D, van den Hurk W, van Groningen JJ, Eleveld MJ, Martens GJ, Weterman MA, van Kessel AG.
Understanding familial and non-familial renal cell cancer.
Hum Mol Genet 11:2489-98 (2002)
Kauffman EC, Ricketts CJ, Rais-Bahrami S, Yang Y, Merino MJ, Bottaro DP, Srinivasan R, Linehan WM
Molecular genetics and cellular features of TFE3 and TFEB fusion kidney cancers.
Nat Rev Urol 11:465-75 (2014)
Skalsky YM, Ajuh PM, Parker C, Lamond AI, Goodwin G, Cooper CS
PRCC, the commonest TFE3 fusion partner in papillary renal carcinoma is associated with pre-mRNA splicing factors.
Oncogene 20:178-87 (2001)
Medendorp K, van Groningen JJ, Vreede L, Hetterschijt L, Brugmans L, van den Hurk WH, van Kessel AG
The renal cell carcinoma-associated oncogenic fusion protein PRCCTFE3 provokes p21 WAF1/CIP1-mediated cell cycle delay.
Exp Cell Res 315:2399-409 (2009)
ecb00020  Citrate cycle (TCA cycle)
ecb04010  MAPK signaling pathway
ecb04066  HIF-1 signaling pathway
ecb04120  Ubiquitin mediated proteolysis
ecb04350  TGF-beta signaling pathway
ecb04370  VEGF signaling pathway
KO pathway

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