KEGG   PATHWAY: ngi05218
ngi05218                    Pathway                                

Melanoma - Nannospalax galili (Upper Galilee mountains blind mole rat)
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
ngi05218  Melanoma

Nannospalax galili (Upper Galilee mountains blind mole rat) [GN:ngi]
103736084  Fgf1; fibroblast growth factor 1 [KO:K18496]
103746947  Fgf2; fibroblast growth factor 2 [KO:K18497]
103733041  Fgf7; fibroblast growth factor 7 [KO:K04358]
103734036  Fgf10; fibroblast growth factor 10 [KO:K04358]
103737833  Fgf16; fibroblast growth factor 16 [KO:K04358]
103737403  Fgf22; fibroblast growth factor 22 [KO:K04358]
103742625  Fgf5; fibroblast growth factor 5 [KO:K04358]
103743281  Fgf20; fibroblast growth factor 20 [KO:K04358]
103744005  Fgf8; fibroblast growth factor 8 [KO:K04358]
103748184  Fgf18; fibroblast growth factor 18 [KO:K04358]
103751508  Fgf3; fibroblast growth factor 3 [KO:K04358]
103751500  Fgf4; fibroblast growth factor 4 [KO:K04358]
103747727  Fgf17; fibroblast growth factor 17 [KO:K04358]
103727190  Fgf9; fibroblast growth factor 9 [KO:K04358]
103727544  Fgf6; fibroblast growth factor 6 [KO:K04358]
103751507  Fgf19; fibroblast growth factor 19 [KO:K22603]
103743629  Fgf21; fibroblast growth factor 21 [KO:K22429]
103727545  Fgf23; fibroblast growth factor 23 [KO:K22428]
103730723  Hgf; hepatocyte growth factor [KO:K05460]
103733723  Igf1; insulin like growth factor 1 [KO:K05459]
103748699  Pdgfa; platelet derived growth factor subunit A [KO:K04359]
103748570  Pdgfb; platelet derived growth factor subunit B [KO:K17386]
103731702  Pdgfd; platelet derived growth factor D [KO:K05450]
103751038  Pdgfc; platelet derived growth factor C [KO:K05450]
103742642  Egf; epidermal growth factor [KO:K04357]
103745770  Fgfr1; fibroblast growth factor receptor 1 [KO:K04362] [EC:]
103737431  Met; MET proto-oncogene, receptor tyrosine kinase [KO:K05099] [EC:]
103749467  Igf1r; insulin like growth factor 1 receptor [KO:K05087] [EC:]
103734393  Pdgfra; platelet derived growth factor receptor alpha [KO:K04363] [EC:]
103747076  Pdgfrb; platelet derived growth factor receptor beta [KO:K05089] [EC:]
103748852  epidermal growth factor receptor [KO:K04361] [EC:]
103751075  Hras; HRas proto-oncogene, GTPase [KO:K02833]
103736717  Kras; KRAS proto-oncogene, GTPase [KO:K07827]
103734938  Nras; neuroblastoma RAS viral oncogene homolog [KO:K07828]
103741627  Araf; A-Raf proto-oncogene, serine/threonine kinase [KO:K08845] [EC:]
103726107  Braf; B-Raf proto-oncogene, serine/threonine kinase [KO:K04365] [EC:]
103751450  Raf1; Raf-1 proto-oncogene, serine/threonine kinase [KO:K04366] [EC:]
103736801  Map2k1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:]
103737276  Map2k2; mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:]
103741442  Mapk1; mitogen-activated protein kinase 1 [KO:K04371] [EC:]
103726390  Mapk3; mitogen-activated protein kinase 3 [KO:K04371] [EC:]
103751498  Ccnd1; cyclin D1 [KO:K04503]
103742900  Cdk4; cyclin dependent kinase 4 [KO:K02089] [EC:]
103738596  Pik3ca; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:]
103733121  Pik3cd; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:]
103742946  Pik3cb; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:]
103738715  Pik3r1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649]
103726879  Pik3r2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649]
103730305  Pik3r3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649]
103746884  Akt3; AKT serine/threonine kinase 3 [KO:K04456] [EC:]
103750757  Akt2; AKT serine/threonine kinase 2 [KO:K04456] [EC:]
103752536  Akt1; AKT serine/threonine kinase 1 [KO:K04456] [EC:]
103738795  Bad; BCL2 associated agonist of cell death [KO:K02158]
103738044  Pten; phosphatase and tensin homolog [KO:K01110] [EC:]
103730663  cyclin-dependent kinase 4 inhibitor B-like [KO:K06621]
103745079  Mdm2; MDM2 proto-oncogene [KO:K06643] [EC:]
103752115  Tp53; tumor protein p53 [KO:K04451]
103739652  Cdkn1a; cyclin dependent kinase inhibitor 1A [KO:K06625]
103725210  Cdk6; cyclin dependent kinase 6 [KO:K02091] [EC:]
103726779  Rb1; RB transcriptional corepressor 1 [KO:K06618]
103751571  E2f1; E2F transcription factor 1 [KO:K17454]
103746411  E2f2; E2F transcription factor 2 [KO:K09389]
103745641  E2f3; E2F transcription factor 3 [KO:K06620]
103734864  Cdh1; cadherin 1 [KO:K05689]
103737285  Gadd45b; growth arrest and DNA damage inducible beta [KO:K04402]
103743354  Gadd45a; growth arrest and DNA damage inducible alpha [KO:K04402]
103751225  Gadd45g; growth arrest and DNA damage inducible gamma [KO:K04402]
103743639  Bax; BCL2 associated X, apoptosis regulator [KO:K02159]
103739733  Bak1; BCL2 antagonist/killer 1 [KO:K14021]
103742505  Ddb2; damage specific DNA binding protein 2 [KO:K10140]
103736569  Polk; DNA polymerase kappa [KO:K03511] [EC:]
103729150  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)
ngi04010  MAPK signaling pathway
ngi04110  Cell cycle
ngi04115  p53 signaling pathway
ngi04151  PI3K-Akt signaling pathway
ngi04520  Adherens junction
ngi04916  Melanogenesis
KO pathway

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