KEGG   PATHWAY: ecb05218
ecb05218                    Pathway                                

Melanoma - Equus caballus (horse)
Melanoma is a form of skin cancer that has a poor prognosis and which is on the rise in Western populations. Melanoma arises from the malignant transformation of pigment-producing cells, melanocytes. The only known environmental risk factor is exposure to ultraviolet (UV) light and in people with fair skin the risk is greatly increased. Melanoma pathogenesis is also driven by genetic factors. Oncogenic NRAS mutations activate both effector pathways Raf-MEK-ERK and PI3K-Akt. The Raf-MEK-ERK pathway may also be activated via mutations in the BRAF gene. The PI3K-Akt pathway may be activated through loss or mutation of the inhibitory tumor suppressor gene PTEN. These mutations arise early during melanoma pathogenesis and are preserved throughout tumor progression. Melanoma development has been shown to be strongly associated with inactivation of the p16INK4a/cyclin dependent kinases 4 and 6/retinoblastoma protein (p16INK4a/CDK4,6/pRb) and p14ARF/human double minute 2/p53 (p14ARF/HMD2/p53) tumor suppressor pathways. MITF and TP53 are implicated in further melanoma progression.
Human Diseases; Cancer: specific types
Pathway map
ecb05218  Melanoma

Equus caballus (horse) [GN:ecb]
100033960  FGF1; fibroblast growth factor 1 [KO:K18496]
100033955  FGF2; fibroblast growth factor 2 [KO:K18497]
100033961  FGF7; fibroblast growth factor 7 [KO:K04358]
100056444  FGF17; fibroblast growth factor 17 isoform X3 [KO:K04358]
100071790  FGF16; fibroblast growth factor 16 [KO:K04358]
100050353  FGF9; fibroblast growth factor 9 [KO:K04358]
100060219  FGF5; fibroblast growth factor 5 isoform X1 [KO:K04358]
100052655  FGF10; fibroblast growth factor 10 [KO:K04358]
100050037  FGF20; fibroblast growth factor 20 [KO:K04358]
100060309  FGF8; fibroblast growth factor 8 [KO:K04358]
100051221  FGF6; fibroblast growth factor 6 [KO:K04358]
100629648  FGF18; fibroblast growth factor 18 [KO:K04358]
100072461  FGF22; fibroblast growth factor 22 [KO:K04358]
100146649  FGF3; fibroblast growth factor 3 [KO:K04358]
100060525  FGF4; fibroblast growth factor 4 [KO:K04358]
100060488  FGF19; fibroblast growth factor 19 [KO:K22603]
100054542  FGF21; fibroblast growth factor 21 [KO:K22429]
100058460  FGF23; fibroblast growth factor 23 [KO:K22428]
100049848  HGF; hepatocyte growth factor isoform X1 [KO:K05460]
100034198  IGF1; insulin-like growth factor I precursor [KO:K05459]
100055086  PDGFA; platelet-derived growth factor subunit A isoform X1 [KO:K04359]
100070283  PDGFB; platelet-derived growth factor subunit B isoform X1 [KO:K17386]
100062015  PDGFC; platelet-derived growth factor C isoform X2 [KO:K05450]
100061488  PDGFD; platelet-derived growth factor D isoform X1 [KO:K05450]
106782874  EGF; pro-epidermal growth factor isoform X1 [KO:K04357]
100057614  FGFR1; fibroblast growth factor receptor 1 isoform X1 [KO:K04362] [EC:]
100056013  MET; hepatocyte growth factor receptor precursor [KO:K05099] [EC:]
100055698  IGF1R; insulin-like growth factor 1 receptor [KO:K05087] [EC:]
100059815  PDGFRA; platelet-derived growth factor receptor alpha [KO:K04363] [EC:]
100071665  PDGFRB; platelet-derived growth factor receptor beta isoform X2 [KO:K05089] [EC:]
100067755  EGFR; epidermal growth factor receptor isoform X1 [KO:K04361] [EC:]
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:]
102149114  CCND1; G1/S-specific cyclin-D1 [KO:K04503]
100051005  CDK4; cyclin-dependent kinase 4 isoform X2 [KO:K02089] [EC:]
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]
100062388  PTEN; phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN [KO:K01110] [EC:]
100146270  cyclin-dependent kinase 4 inhibitor B [KO:K06621]
100052084  MDM2; E3 ubiquitin-protein ligase Mdm2 isoform X1 [KO:K06643] [EC:]
100062044  TP53; cellular tumor antigen p53 [KO:K04451]
100064022  CDKN1A; cyclin-dependent kinase inhibitor 1 [KO:K06625]
100061625  CDK6; cyclin-dependent kinase 6 isoform X1 [KO:K02091] [EC:]
100057080  RB1; retinoblastoma-associated protein isoform X1 [KO:K06618]
100069192  E2F1; transcription factor E2F1 [KO:K17454]
100057866  E2F2; transcription factor E2F2 isoform X2 [KO:K09389]
100052248  E2F3; transcription factor E2F3 isoform X1 [KO:K06620]
100066844  CDH1; cadherin-1 [KO:K05689]
100054996  GADD45G; growth arrest and DNA damage-inducible protein GADD45 gamma [KO:K04402]
100059768  GADD45B; growth arrest and DNA damage-inducible protein GADD45 beta [KO:K04402]
100630299  GADD45A; growth arrest and DNA damage-inducible protein GADD45 alpha [KO:K04402]
100054674  BAX; apoptosis regulator BAX isoform X1 [KO:K02159]
100061755  BAK1; bcl-2 homologous antagonist/killer [KO:K14021]
100051180  DDB2; DNA damage-binding protein 2 isoform X1 [KO:K10140]
100065534  POLK; DNA polymerase kappa [KO:K03511] [EC:]
100033918  MITF; microphthalmia-associated transcription factor [KO:K09455]
C05981  Phosphatidylinositol-3,4,5-trisphosphate
Miller AJ, Mihm MC Jr.
N Engl J Med 355:51-65 (2006)
Chin L.
The genetics of malignant melanoma: lessons from mouse and man.
Nat Rev Cancer 3:559-70 (2003)
Takata M, Saida T.
Genetic alterations in melanocytic tumors.
J Dermatol Sci 43:1-10 (2006)
Chudnovsky Y, Khavari PA, Adams AE.
Melanoma genetics and the development of rational therapeutics.
J Clin Invest 115:813-24 (2005)
Merlino G.
Cancer biology: the weakest link?
Nature 436:33-5 (2005)
Garraway LA, Widlund HR, Rubin MA, Getz G, Berger AJ, Ramaswamy S, Beroukhim R, Milner DA, Granter SR, Du J, Lee C, Wagner SN, Li C, Golub TR, Rimm DL, Meyerson ML, Fisher DE, Sellers WR.
Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma.
Nature 436:117-22 (2005)
Levy C, Khaled M, Fisher DE.
MITF: master regulator of melanocyte development and melanoma oncogene.
Trends Mol Med 12:406-14 (2006)
Tsao H, Goel V, Wu H, Yang G, Haluska FG.
Genetic interaction between NRAS and BRAF mutations and PTEN/MMAC1 inactivation in melanoma.
J Invest Dermatol 122:337-41 (2004)
Gruss C, Herlyn M.
Role of cadherins and matrixins in melanoma.
Curr Opin Oncol 13:117-23 (2001)
Thompson JF, Scolyer RA, Kefford RF.
Cutaneous melanoma.
Lancet 365:687-701 (2005)
Omholt K, Platz A, Kanter L, Ringborg U, Hansson J.
NRAS and BRAF mutations arise early during melanoma pathogenesis and are preserved throughout tumor progression.
Clin Cancer Res 9:6483-8 (2003)
Hussein MR.
The TP53 tumor suppressor gene and melanoma tumorigenesis: is there a relationship?
Tumour Biol 25:200-7 (2004)
Lazar-Molnar E, Hegyesi H, Toth S, Falus A.
Autocrine and paracrine regulation by cytokines and growth factors in melanoma.
Cytokine 12:547-54 (2000)
ecb04010  MAPK signaling pathway
ecb04110  Cell cycle
ecb04115  p53 signaling pathway
ecb04151  PI3K-Akt signaling pathway
ecb04520  Adherens junction
ecb04916  Melanogenesis
KO pathway

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