KEGG   PATHWAY: mcal05218
mcal05218                   Pathway                                

Melanoma - Mus caroli (Ryukyu 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
mcal05218  Melanoma

Mus caroli (Ryukyu mouse) [GN:mcal]
110284837  Fgf1; fibroblast growth factor 1 isoform X1 [KO:K18496]
110291557  Fgf2; fibroblast growth factor 2 isoform X1 [KO:K18497]
110300580  Fgf20; fibroblast growth factor 20 [KO:K04358]
110295342  Fgf5; fibroblast growth factor 5 isoform X1 [KO:K04358]
110285629  Fgf8; fibroblast growth factor 8 isoform X1 [KO:K04358]
110287226  Fgf16; fibroblast growth factor 16 [KO:K04358]
110305760  Fgf18; fibroblast growth factor 18 [KO:K04358]
110308847  Fgf17; fibroblast growth factor 17 isoform X1 [KO:K04358]
110303818  Fgf22; fibroblast growth factor 22 isoform X1 [KO:K04358]
110309422  Fgf9; fibroblast growth factor 9 [KO:K04358]
110289950  Fgf7; fibroblast growth factor 7 [KO:K04358]
110296943  Fgf6; fibroblast growth factor 6 [KO:K04358]
110299316  Fgf4; fibroblast growth factor 4 [KO:K04358]
110299386  Fgf3; fibroblast growth factor 3 [KO:K04358]
110308330  Fgf10; fibroblast growth factor 10 [KO:K04358]
110299450  Fgf19; fibroblast growth factor 19 [KO:K22603]
110299358  Fgf21; fibroblast growth factor 21 [KO:K22429]
110297028  Fgf23; fibroblast growth factor 23 [KO:K22428]
110294216  Hgf; hepatocyte growth factor isoform X1 [KO:K05460]
110304009  Igf1; insulin-like growth factor I isoform X1 [KO:K05459]
110294651  Pdgfa; platelet-derived growth factor subunit A isoform X1 [KO:K04359]
110310626  Pdgfb; platelet-derived growth factor subunit B [KO:K17386]
110290924  Pdgfc; platelet-derived growth factor C [KO:K05450]
110301590  Pdgfd; platelet-derived growth factor D isoform X1 [KO:K05450]
110291005  Egf; pro-epidermal growth factor isoform X1 [KO:K04357]
110299550  Fgfr1; fibroblast growth factor receptor 1 isoform X1 [KO:K04362] [EC:]
110295947  Met; hepatocyte growth factor receptor isoform X1 [KO:K05099] [EC:]
110297825  Igf1r; insulin-like growth factor 1 receptor [KO:K05087] [EC:]
110295292  Pdgfra; platelet-derived growth factor receptor alpha isoform X1 [KO:K04363] [EC:]
110284880  Pdgfrb; platelet-derived growth factor receptor beta [KO:K05089] [EC:]
110304228  Egfr; epidermal growth factor receptor [KO:K04361] [EC:]
110297313  Hras; GTPase HRas isoform X1 [KO:K02833]
110296194  Kras; GTPase KRas isoform X1 [KO:K07827]
110290873  Nras; GTPase NRas [KO:K07828]
110287540  Araf; serine/threonine-protein kinase A-Raf isoform X1 [KO:K08845] [EC:]
110295945  Braf; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:]
110296919  Raf1; RAF proto-oncogene serine/threonine-protein kinase [KO:K04366] [EC:]
110301502  Map2k1; dual specificity mitogen-activated protein kinase kinase 1 isoform X1 [KO:K04368] [EC:]
110303196  Map2k2; dual specificity mitogen-activated protein kinase kinase 2 isoform X1 [KO:K04369] [EC:]
110297836  Mapk3; mitogen-activated protein kinase 3 [KO:K04371] [EC:]
110311382  Mapk1; mitogen-activated protein kinase 1 [KO:K04371] [EC:]
110298189  Ccnd1; G1/S-specific cyclin-D1 isoform X1 [KO:K04503]
110303132  Cdk4; cyclin-dependent kinase 4 [KO:K02089] [EC:]
110290798  Pik3ca; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:]
110292183  Pik3cd; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:]
110301355  Pik3cb; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:]
110308009  Pik3r1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
110299855  Pik3r2; phosphatidylinositol 3-kinase regulatory subunit beta isoform X1 [KO:K02649]
110292624  phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
110297609  Akt2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:]
110294471  Akt3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:]
110307022  Akt1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:]
110285481  Bad; bcl2-associated agonist of cell death isoform X1 [KO:K02158]
110285202  Pten; phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN [KO:K01110] [EC:]
110293174  cyclin-dependent kinase inhibitor 2A [KO:K06621]
110303712  Mdm2; E3 ubiquitin-protein ligase Mdm2 [KO:K06643] [EC:]
110305297  Tp53; cellular tumor antigen p53 isoform X1 [KO:K04451]
110283679  Cdkn1a; cyclin-dependent kinase inhibitor 1 [KO:K06625]
110294345  Cdk6; cyclin-dependent kinase 6 [KO:K02091] [EC:]
110309179  Rb1; retinoblastoma-associated protein [KO:K06618]
110289983  E2f1; transcription factor E2F1 isoform X1 [KO:K17454]
110293508  E2f2; transcription factor E2F2 [KO:K09389]
110308034  E2f3; transcription factor E2F3 isoform X1 [KO:K06620]
110300286  Cdh1; cadherin-1 [KO:K05689]
110303739  Gadd45b; growth arrest and DNA damage-inducible protein GADD45 beta [KO:K04402]
110296344  Gadd45a; growth arrest and DNA damage-inducible protein GADD45 alpha [KO:K04402]
110308191  Gadd45g; growth arrest and DNA damage-inducible protein GADD45 gamma [KO:K04402]
110297919  Bax; apoptosis regulator BAX isoform X1 [KO:K02159]
110283660  Bak1; bcl-2 homologous antagonist/killer [KO:K14021]
110290093  Ddb2; DNA damage-binding protein 2 [KO:K10140]
110308520  Polk; DNA polymerase kappa isoform X1 [KO:K03511] [EC:]
110296033  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)
mcal04010  MAPK signaling pathway
mcal04110  Cell cycle
mcal04115  p53 signaling pathway
mcal04151  PI3K-Akt signaling pathway
mcal04520  Adherens junction
mcal04916  Melanogenesis
KO pathway

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