KEGG   PATHWAY: mcc05218
mcc05218                    Pathway                                
Melanoma - Macaca mulatta (rhesus monkey)
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
mcc05218  Melanoma

Macaca mulatta (rhesus monkey) [GN:mcc]
705970  FGF1; fibroblast growth factor 1 [KO:K18496]
574136  FGF2; fibroblast growth factor 2 [KO:K18497]
710739  FGF6; fibroblast growth factor 6 [KO:K04358]
574345  FGF7; fibroblast growth factor 7 precursor [KO:K04358]
701584  FGF10; fibroblast growth factor 10 precursor [KO:K04358]
705612  FGF16; fibroblast growth factor 16 [KO:K04358]
702727  FGF22; fibroblast growth factor 22 precursor [KO:K04358]
701847  FGF20; fibroblast growth factor 20 [KO:K04358]
708918  FGF3; fibroblast growth factor 3 precursor [KO:K04358]
709016  FGF4; fibroblast growth factor 4 [KO:K04358]
706659  FGF17; fibroblast growth factor 17 precursor [KO:K04358]
721324  FGF9; fibroblast growth factor 9 [KO:K04358]
695896  FGF5; fibroblast growth factor 5 isoform X1 [KO:K04358]
702072  FGF18; fibroblast growth factor 18 [KO:K04358]
722394  FGF8; fibroblast growth factor 8 [KO:K04358]
709109  FGF19; fibroblast growth factor 19 [KO:K22603]
718288  FGF21; fibroblast growth factor 21 [KO:K22429]
710643  FGF23; fibroblast growth factor 23 precursor [KO:K22428]
708316  HGF; hepatocyte growth factor isoform X3 [KO:K05460]
698444  IGF1; insulin-like growth factor I precursor [KO:K05459]
707725  PDGFA; platelet-derived growth factor subunit A isoform X1 [KO:K04359]
703173  PDGFB; platelet-derived growth factor subunit B [KO:K17386]
704310  PDGFD; platelet-derived growth factor D isoform X2 [KO:K05450]
700236  PDGFC; platelet-derived growth factor C [KO:K05450]
698619  EGF; pro-epidermal growth factor isoform X2 [KO:K04357]
700126  FGFR1; fibroblast growth factor receptor 1 precursor [KO:K04362] [EC:]
704562  MET; hepatocyte growth factor receptor precursor [KO:K05099] [EC:]
708227  IGF1R; insulin-like growth factor 1 receptor precursor [KO:K05087] [EC:]
697002  PDGFRA; platelet-derived growth factor receptor alpha [KO:K04363] [EC:]
711353  PDGFRB; platelet-derived growth factor receptor beta [KO:K05089] [EC:]
613027  EGFR; epidermal growth factor receptor isoform X1 [KO:K04361] [EC:]
698830  HRAS; GTPase HRas [KO:K02833]
707977  KRAS; GTPase KRas [KO:K07827]
709089  NRAS; GTPase NRas [KO:K07828]
707169  ARAF; serine/threonine-protein kinase A-Raf [KO:K08845] [EC:]
693554  BRAF; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:]
694725  RAF1; RAF proto-oncogene serine/threonine-protein kinase [KO:K04366] [EC:]
710415  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:]
721821  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 isoform X1 [KO:K04369] [EC:]
708938  MAPK3; mitogen-activated protein kinase 3 isoform X1 [KO:K04371] [EC:]
698569  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:]
574320  CCND1; G1/S-specific cyclin-D1 [KO:K04503]
715650  CDK4; cyclin-dependent kinase 4 [KO:K02089] [EC:]
716098  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:]
709959  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:]
710552  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:]
707310  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
719367  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
698996  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha [KO:K02649]
714717  AKT3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:]
697747  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:]
700591  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:]
717740  BAD; bcl2-associated agonist of cell death [KO:K02158]
705121  PTEN; phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN [KO:K01110] [EC:]
709988  cyclin-dependent kinase inhibitor 2A [KO:K06621]
718284  MDM2; E3 ubiquitin-protein ligase Mdm2 [KO:K06643] [EC:]
716170  TP53; cellular tumor antigen p53 [KO:K04451]
719199  CDKN1A; cyclin-dependent kinase inhibitor 1 [KO:K06625]
701822  CDK6; cyclin-dependent kinase 6 [KO:K02091] [EC:]
704871  RB1; retinoblastoma-associated protein [KO:K06618]
714126  E2F1; transcription factor E2F1 [KO:K17454]
710200  E2F2; transcription factor E2F2 [KO:K09389]
713904  E2F3; transcription factor E2F3 isoform X1 [KO:K06620]
704387  CDH1; cadherin-1 [KO:K05689]
697835  GADD45G; growth arrest and DNA damage-inducible protein GADD45 gamma [KO:K04402]
701054  GADD45A; growth arrest and DNA damage-inducible protein GADD45 alpha [KO:K04402]
711257  GADD45B; growth arrest and DNA damage-inducible protein GADD45 beta [KO:K04402]
718948  BAX; apoptosis regulator BAX [KO:K02159]
706534  BAK1; bcl-2 homologous antagonist/killer [KO:K14021]
114675515  bcl-2 homologous antagonist/killer-like [KO:K14021]
713813  DDB2; DNA damage-binding protein 2 [KO:K10140]
114672263  LOW QUALITY PROTEIN: DNA damage-binding protein 2-like [KO:K10140]
705713  POLK; DNA polymerase kappa isoform X1 [KO:K03511] [EC:]
695537  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)
mcc04010  MAPK signaling pathway
mcc04110  Cell cycle
mcc04115  p53 signaling pathway
mcc04151  PI3K-Akt signaling pathway
mcc04520  Adherens junction
mcc04916  Melanogenesis
KO pathway

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