KEGG   PATHWAY: mpah05218
mpah05218                   Pathway                                

Melanoma - Mus pahari (shrew mouse)
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
mpah05218  Melanoma

Mus pahari (shrew mouse) [GN:mpah]
110333309  Fgf1; fibroblast growth factor 1 isoform X1 [KO:K18496]
110320512  Fgf2; fibroblast growth factor 2 isoform X1 [KO:K18497]
110314005  Fgf16; fibroblast growth factor 16 [KO:K04358]
110325648  Fgf17; fibroblast growth factor 17 isoform X1 [KO:K04358]
110318603  Fgf7; fibroblast growth factor 7 [KO:K04358]
110326486  Fgf8; fibroblast growth factor 8 isoform X1 [KO:K04358]
110325518  Fgf9; fibroblast growth factor 9 [KO:K04358]
110337766  Fgf3; fibroblast growth factor 3 [KO:K04358]
110332000  Fgf18; fibroblast growth factor 18 [KO:K04358]
110336807  Fgf20; fibroblast growth factor 20 [KO:K04358]
110317154  Fgf6; fibroblast growth factor 6 [KO:K04358]
110327081  Fgf22; fibroblast growth factor 22 isoform X1 [KO:K04358]
110330786  Fgf5; fibroblast growth factor 5 isoform X1 [KO:K04358]
110336606  Fgf4; fibroblast growth factor 4 [KO:K04358]
110329060  Fgf10; fibroblast growth factor 10 [KO:K04358]
110334904  Fgf19; fibroblast growth factor 19 [KO:K22603]
110338839  Fgf21; fibroblast growth factor 21 [KO:K22429]
110317286  Fgf23; fibroblast growth factor 23 [KO:K22428]
110316234  Hgf; hepatocyte growth factor isoform X1 [KO:K05460]
110326668  Igf1; insulin-like growth factor I isoform X1 [KO:K05459]
110312881  Pdgfa; platelet-derived growth factor subunit A isoform X1 [KO:K04359]
110334927  Pdgfb; platelet-derived growth factor subunit B [KO:K17386]
110327924  Pdgfd; platelet-derived growth factor D isoform X1 [KO:K05450]
110319957  Pdgfc; platelet-derived growth factor C isoform X1 [KO:K05450]
110320006  Egf; pro-epidermal growth factor isoform X1 [KO:K04357]
110336809  Fgfr1; fibroblast growth factor receptor 1 [KO:K04362] [EC:]
110316104  Met; hepatocyte growth factor receptor [KO:K05099] [EC:]
110324292  Igf1r; insulin-like growth factor 1 receptor isoform X1 [KO:K05087] [EC:]
110331028  Pdgfra; platelet-derived growth factor receptor alpha isoform X1 [KO:K04363] [EC:]
110333065  Pdgfrb; platelet-derived growth factor receptor beta isoform X1 [KO:K05089] [EC:]
110330480  Egfr; epidermal growth factor receptor isoform X1 [KO:K04361] [EC:]
110318967  GTPase HRas-like isoform X1 [KO:K02833]
110319567  Hras; GTPase HRas [KO:K02833]
110338480  GTPase HRas-like [KO:K02833]
110333346  GTPase HRas-like [KO:K02833]
110316221  Kras; GTPase KRas isoform X1 [KO:K07827]
110320340  Nras; GTPase NRas [KO:K07828]
110314283  Araf; serine/threonine-protein kinase A-Raf [KO:K08845] [EC:]
110316269  Braf; serine/threonine-protein kinase B-raf [KO:K04365] [EC:]
110314893  Raf1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:]
110327244  Map2k1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:]
110326321  Map2k2; dual specificity mitogen-activated protein kinase kinase 2 isoform X1 [KO:K04369] [EC:]
110329343  Mapk1; mitogen-activated protein kinase 1 isoform X1 [KO:K04371] [EC:]
110320020  Mapk3; mitogen-activated protein kinase 3 isoform X1 [KO:K04371] [EC:]
110322378  Ccnd1; G1/S-specific cyclin-D1 [KO:K04503]
110326196  Cdk4; cyclin-dependent kinase 4 [KO:K02089] [EC:]
110323448  Pik3cd; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:]
110319750  Pik3ca; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform isoform X1 [KO:K00922] [EC:]
110327251  Pik3cb; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:]
110328811  Pik3r1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
110336420  Pik3r2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
110322865  Pik3r3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
110317258  Akt2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:]
110324386  Akt1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:]
110322284  Akt3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:]
110326250  Bad; bcl2-associated agonist of cell death isoform X1 [KO:K02158]
110312812  Pten; phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN [KO:K01110] [EC:]
110323545  cyclin-dependent kinase inhibitor 2A [KO:K06621]
110326473  Mdm2; E3 ubiquitin-protein ligase Mdm2 isoform X1 [KO:K06643] [EC:]
110331731  Tp53; cellular tumor antigen p53 isoform X1 [KO:K04451]
110338236  Cdkn1a; cyclin-dependent kinase inhibitor 1 [KO:K06625]
110316496  Cdk6; cyclin-dependent kinase 6 [KO:K02091] [EC:]
110325233  Rb1; retinoblastoma-associated protein [KO:K06618]
110318578  E2f1; transcription factor E2F1 [KO:K17454]
110323461  E2f2; transcription factor E2F2 [KO:K09389]
110333784  E2f3; transcription factor E2F3 isoform X1 [KO:K06620]
110337432  Cdh1; cadherin-1 isoform X1 [KO:K05689]
110316550  Gadd45a; growth arrest and DNA damage-inducible protein GADD45 alpha isoform X1 [KO:K04402]
110326839  Gadd45b; growth arrest and DNA damage-inducible protein GADD45 beta [KO:K04402]
110333844  Gadd45g; growth arrest and DNA damage-inducible protein GADD45 gamma [KO:K04402]
110320030  Bax; apoptosis regulator BAX isoform X1 [KO:K02159]
110338169  Bak1; bcl-2 homologous antagonist/killer isoform X1 [KO:K14021]
110319597  Ddb2; DNA damage-binding protein 2 isoform X1 [KO:K10140]
110329143  Polk; DNA polymerase kappa isoform X1 [KO:K03511] [EC:]
110316879  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)
mpah04010  MAPK signaling pathway
mpah04110  Cell cycle
mpah04115  p53 signaling pathway
mpah04151  PI3K-Akt signaling pathway
mpah04520  Adherens junction
mpah04916  Melanogenesis
KO pathway

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