KEGG   PATHWAY: umr05218
umr05218                    Pathway                                

Melanoma - Ursus maritimus (polar bear)
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
umr05218  Melanoma

Ursus maritimus (polar bear) [GN:umr]
103663709  FGF1; fibroblast growth factor 1 [KO:K18496]
103661850  FGF2; fibroblast growth factor 2 [KO:K18497]
103664645  FGF10; fibroblast growth factor 10 [KO:K04358]
103664292  FGF9; fibroblast growth factor 9 [KO:K04358]
103681372  FGF20; fibroblast growth factor 20 [KO:K04358]
103673325  FGF17; fibroblast growth factor 17 [KO:K04358]
103675746  FGF6; fibroblast growth factor 6 [KO:K04358]
103675826  FGF16; fibroblast growth factor 16 [KO:K04358]
103676724  FGF7; fibroblast growth factor 7 [KO:K04358]
103665349  FGF5; fibroblast growth factor 5 [KO:K04358]
103671137  FGF3; fibroblast growth factor 3 [KO:K04358]
103664781  FGF18; fibroblast growth factor 18 [KO:K04358]
103658995  FGF8; fibroblast growth factor 8 [KO:K04358]
103671138  FGF19; fibroblast growth factor 19 [KO:K22603]
103657101  FGF21; fibroblast growth factor 21 [KO:K22429]
103675745  FGF23; fibroblast growth factor 23 [KO:K22428]
103658669  HGF; hepatocyte growth factor [KO:K05460]
103676495  IGF1; insulin like growth factor 1 [KO:K05459]
103670054  PDGFA; platelet derived growth factor subunit A [KO:K04359]
103676520  PDGFB; platelet derived growth factor subunit B [KO:K17386]
103662543  PDGFD; platelet derived growth factor D [KO:K05450]
103658054  PDGFC; platelet derived growth factor C [KO:K05450]
103661742  EGF; epidermal growth factor [KO:K04357]
103659146  FGFR1; fibroblast growth factor receptor 1 [KO:K04362] [EC:]
103676585  MET; MET proto-oncogene, receptor tyrosine kinase [KO:K05099] [EC:]
103660044  insulin-like growth factor 1 receptor [KO:K05087] [EC:]
103672737  PDGFRA; platelet derived growth factor receptor alpha [KO:K04363] [EC:]
103664600  PDGFRB; platelet derived growth factor receptor beta [KO:K05089] [EC:]
103674660  EGFR; epidermal growth factor receptor [KO:K04361] [EC:]
103669173  GTPase HRas-like [KO:K02833]
103671035  HRAS; HRas proto-oncogene, GTPase [KO:K02833]
103665244  KRAS; KRAS proto-oncogene, GTPase [KO:K07827]
103669422  NRAS; neuroblastoma RAS viral oncogene homolog [KO:K07828]
103669103  BRAF; B-Raf proto-oncogene, serine/threonine kinase [KO:K04365] [EC:]
103669540  RAF1; Raf-1 proto-oncogene, serine/threonine kinase [KO:K04366] [EC:]
103679064  MAP2K1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:]
103681834  MAP2K2; mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:]
103669286  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:]
103657827  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:]
103671139  CCND1; cyclin D1 [KO:K04503]
103656694  CDK4; cyclin dependent kinase 4 [KO:K02089] [EC:]
103678592  PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:]
103666874  PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:]
103676125  PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:]
103675162  PIK3R2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649]
103663617  PIK3R1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649]
103670766  PIK3R3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649]
103666688  AKT3; AKT serine/threonine kinase 3 [KO:K04456] [EC:]
103661038  AKT2; AKT serine/threonine kinase 2 [KO:K04456] [EC:]
103676878  AKT1; AKT serine/threonine kinase 1 [KO:K04456] [EC:]
103679423  BAD; BCL2 associated agonist of cell death [KO:K02158]
103661921  PTEN; phosphatase and tensin homolog [KO:K01110] [EC:]
103656869  MDM2; MDM2 proto-oncogene [KO:K06643] [EC:]
103660368  TP53; tumor protein p53 [KO:K04451]
103665536  CDKN1A; cyclin dependent kinase inhibitor 1A [KO:K06625]
103658796  CDK6; cyclin dependent kinase 6 [KO:K02091] [EC:]
103677688  RB1; RB transcriptional corepressor 1 [KO:K06618]
103674455  E2F1; E2F transcription factor 1 [KO:K17454]
103666789  E2F2; E2F transcription factor 2 [KO:K09389]
103678383  E2F3; E2F transcription factor 3 [KO:K06620]
103673974  cadherin-1-like [KO:K05689]
103673623  CDH1; cadherin 1 [KO:K05689]
103681651  GADD45B; growth arrest and DNA damage inducible beta [KO:K04402]
103663135  GADD45A; growth arrest and DNA damage inducible alpha [KO:K04402]
103657107  BAX; BCL2 associated X, apoptosis regulator [KO:K02159]
103665481  putative Bcl-2 homologous antagonist/killer 2 [KO:K14021]
103672315  DDB2; damage specific DNA binding protein 2 [KO:K10140]
103663562  POLK; DNA polymerase kappa [KO:K03511] [EC:]
103674247  MITF; melanogenesis 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)
umr04010  MAPK signaling pathway
umr04110  Cell cycle
umr04115  p53 signaling pathway
umr04151  PI3K-Akt signaling pathway
umr04520  Adherens junction
umr04916  Melanogenesis
KO pathway

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