KEGG   PATHWAY: ray05218
ray05218                    Pathway                                

Melanoma - Rousettus aegyptiacus (Egyptian rousette)
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
ray05218  Melanoma

Rousettus aegyptiacus (Egyptian rousette) [GN:ray]
107500865  FGF1; fibroblast growth factor 1 [KO:K18496]
107518501  FGF2; LOW QUALITY PROTEIN: fibroblast growth factor 2 [KO:K18497]
107507115  FGF16; fibroblast growth factor 16 [KO:K04358]
107503931  FGF3; fibroblast growth factor 3 [KO:K04358]
107503977  FGF4; LOW QUALITY PROTEIN: fibroblast growth factor 4 [KO:K04358]
107511020  FGF18; fibroblast growth factor 18 [KO:K04358]
107514447  FGF9; fibroblast growth factor 9 [KO:K04358]
107502706  FGF20; fibroblast growth factor 20 [KO:K04358]
107513447  FGF6; fibroblast growth factor 6 [KO:K04358]
107516440  FGF5; fibroblast growth factor 5 isoform X1 [KO:K04358]
107509200  FGF17; fibroblast growth factor 17 isoform X1 [KO:K04358]
107518965  FGF10; fibroblast growth factor 10 [KO:K04358]
107500922  FGF22; fibroblast growth factor 22 isoform X1 [KO:K04358]
107497786  FGF8; fibroblast growth factor 8 isoform X1 [KO:K04358]
107501960  FGF7; LOW QUALITY PROTEIN: fibroblast growth factor 7 [KO:K04358]
107498854  FGF21; fibroblast growth factor 21 [KO:K22429]
107513448  FGF23; fibroblast growth factor 23 [KO:K22428]
107501285  HGF; hepatocyte growth factor isoform X1 [KO:K05460]
107501166  IGF1; insulin-like growth factor I isoform X1 [KO:K05459]
107497394  PDGFA; platelet-derived growth factor subunit A isoform X1 [KO:K04359]
107502078  PDGFB; platelet-derived growth factor subunit B isoform X1 [KO:K17386]
107507553  PDGFC; platelet-derived growth factor C isoform X1 [KO:K05450]
107520204  PDGFD; platelet-derived growth factor D isoform X1 [KO:K05450]
107508819  EGF; pro-epidermal growth factor isoform X1 [KO:K04357]
107515961  FGFR1; fibroblast growth factor receptor 1 isoform X1 [KO:K04362] [EC:]
107497465  MET; hepatocyte growth factor receptor isoform X1 [KO:K05099] [EC:]
107509347  insulin-like growth factor 1 receptor [KO:K05087] [EC:]
107499793  PDGFRA; platelet-derived growth factor receptor alpha isoform X1 [KO:K04363] [EC:]
107497163  PDGFRB; platelet-derived growth factor receptor beta [KO:K05089] [EC:]
107498193  EGFR; epidermal growth factor receptor [KO:K04361] [EC:]
107507127  HRAS; GTPase HRas isoform X1 [KO:K02833]
107497434  KRAS; GTPase KRas isoform X1 [KO:K07827]
107499847  NRAS; LOW QUALITY PROTEIN: GTPase NRas [KO:K07828]
107509353  ARAF; serine/threonine-protein kinase A-Raf isoform X1 [KO:K08845] [EC:]
107504052  BRAF; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:]
107519729  RAF1; RAF proto-oncogene serine/threonine-protein kinase [KO:K04366] [EC:]
107508942  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform X1 [KO:K04368] [EC:]
107510634  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 isoform X1 [KO:K04369] [EC:]
107515836  MAPK3; mitogen-activated protein kinase 3 isoform X1 [KO:K04371] [EC:]
107497830  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:]
107503391  CCND1; G1/S-specific cyclin-D1 [KO:K04503]
107501504  CDK4; cyclin-dependent kinase 4 [KO:K02089] [EC:]
107520152  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:]
107517828  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:]
107513958  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:]
107521668  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta isoform X1 [KO:K02649]
107517899  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
107498704  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
107513978  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:]
107521783  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:]
107498395  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:]
107497091  BAD; bcl2-associated agonist of cell death [KO:K02158]
107501760  PTEN; phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN [KO:K01110] [EC:]
107506789  cyclin-dependent kinase inhibitor 2A-like [KO:K06621]
107512674  MDM2; E3 ubiquitin-protein ligase Mdm2 [KO:K06643] [EC:]
107515689  TP53; cellular tumor antigen p53 isoform X1 [KO:K04451]
107514682  CDKN1A; cyclin-dependent kinase inhibitor 1 isoform X1 [KO:K06625]
107519055  CDK6; cyclin-dependent kinase 6 [KO:K02091] [EC:]
107520925  RB1; retinoblastoma-associated protein [KO:K06618]
107519491  E2F1; transcription factor E2F1 [KO:K17454]
107501037  E2F2; transcription factor E2F2 isoform X1 [KO:K09389]
107501692  E2F3; transcription factor E2F3 isoform X1 [KO:K06620]
107520648  CDH1; LOW QUALITY PROTEIN: cadherin-1 [KO:K05689]
107520573  GADD45A; growth arrest and DNA damage-inducible protein GADD45 alpha [KO:K04402]
107520147  GADD45B; growth arrest and DNA damage-inducible protein GADD45 beta [KO:K04402]
107499083  GADD45G; growth arrest and DNA damage-inducible protein GADD45 gamma [KO:K04402]
107498831  BAX; apoptosis regulator BAX isoform X1 [KO:K02159]
107511968  BAK1; bcl-2 homologous antagonist/killer isoform X1 [KO:K14021]
107511851  DDB2; DNA damage-binding protein 2 isoform X1 [KO:K10140]
107506450  POLK; DNA polymerase kappa [KO:K03511] [EC:]
107509178  MITF; microphthalmia-associated transcription factor isoform X1 [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)
ray04010  MAPK signaling pathway
ray04110  Cell cycle
ray04115  p53 signaling pathway
ray04151  PI3K-Akt signaling pathway
ray04520  Adherens junction
ray04916  Melanogenesis
KO pathway

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