KEGG   PATHWAY: hsa05218Help
Entry
hsa05218                    Pathway                                

Name
Melanoma - Homo sapiens (human)
Description
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.
Class
Human Diseases; Cancers
BRITE hierarchy
Pathway map
Melanoma
hsa05218

All organismsOrtholog table
Disease
H00038  
Malignant melanoma
Drug
D09996  
Vemurafenib (JAN/USAN/INN)
D10064  
Dabrafenib (USAN)
D10104  
Dabrafenib mesylate (USAN)
D10405  
Cobimetinib (USAN/INN)
D10615  
Cobimetinib fumarate (USAN)
Organism
Homo sapiens (human) [GN:hsa]
Gene
2246  
FGF1; fibroblast growth factor 1 [KO:K18496]
2247  
FGF2; fibroblast growth factor 2 [KO:K18497]
2248  
FGF3; fibroblast growth factor 3 [KO:K04358]
2249  
FGF4; fibroblast growth factor 4 [KO:K04358]
8822  
FGF17; fibroblast growth factor 17 [KO:K04358]
2251  
FGF6; fibroblast growth factor 6 [KO:K04358]
2252  
FGF7; fibroblast growth factor 7 [KO:K04358]
2253  
FGF8; fibroblast growth factor 8 [KO:K04358]
2254  
FGF9; fibroblast growth factor 9 [KO:K04358]
2255  
FGF10; fibroblast growth factor 10 [KO:K04358]
2256  
FGF11; fibroblast growth factor 11 [KO:K04358]
2257  
FGF12; fibroblast growth factor 12 [KO:K04358]
2258  
FGF13; fibroblast growth factor 13 [KO:K04358]
2259  
FGF14; fibroblast growth factor 14 [KO:K04358]
8823  
FGF16; fibroblast growth factor 16 [KO:K04358]
2250  
FGF5; fibroblast growth factor 5 [KO:K04358]
8817  
FGF18; fibroblast growth factor 18 [KO:K04358]
9965  
FGF19; fibroblast growth factor 19 [KO:K04358]
26281  
FGF20; fibroblast growth factor 20 [KO:K04358]
26291  
FGF21; fibroblast growth factor 21 [KO:K04358]
27006  
FGF22; fibroblast growth factor 22 [KO:K04358]
8074  
FGF23; fibroblast growth factor 23 [KO:K04358]
3082  
HGF; hepatocyte growth factor [KO:K05460]
3479  
IGF1; insulin like growth factor 1 [KO:K05459]
5154  
PDGFA; platelet derived growth factor subunit A [KO:K04359]
5155  
PDGFB; platelet derived growth factor subunit B [KO:K17386]
56034  
PDGFC; platelet derived growth factor C [KO:K05450]
80310  
PDGFD; platelet derived growth factor D [KO:K05450]
1950  
EGF; epidermal growth factor [KO:K04357]
2260  
FGFR1; fibroblast growth factor receptor 1 [KO:K04362] [EC:2.7.10.1]
4233  
MET; MET proto-oncogene, receptor tyrosine kinase [KO:K05099] [EC:2.7.10.1]
3480  
IGF1R; insulin like growth factor 1 receptor [KO:K05087] [EC:2.7.10.1]
5156  
PDGFRA; platelet derived growth factor receptor alpha [KO:K04363] [EC:2.7.10.1]
5159  
PDGFRB; platelet derived growth factor receptor beta [KO:K05089] [EC:2.7.10.1]
1956  
EGFR; epidermal growth factor receptor [KO:K04361] [EC:2.7.10.1]
3265  
HRAS; HRas proto-oncogene, GTPase [KO:K02833]
3845  
KRAS; KRAS proto-oncogene, GTPase [KO:K07827]
4893  
NRAS; neuroblastoma RAS viral oncogene homolog [KO:K07828]
369  
ARAF; A-Raf proto-oncogene, serine/threonine kinase [KO:K08845] [EC:2.7.11.1]
673  
BRAF; B-Raf proto-oncogene, serine/threonine kinase [KO:K04365] [EC:2.7.11.1]
5894  
RAF1; Raf-1 proto-oncogene, serine/threonine kinase [KO:K04366] [EC:2.7.11.1]
5604  
MAP2K1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
5605  
MAP2K2; mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
5594  
MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
5595  
MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
1019  
CDK4; cyclin dependent kinase 4 [KO:K02089] [EC:2.7.11.22]
5290  
PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:2.7.1.153]
5293  
PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:2.7.1.153]
5291  
PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:2.7.1.153]
5294  
PIK3CG; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma [KO:K00922] [EC:2.7.1.153]
5295  
PIK3R1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649]
23533  
PIK3R5; phosphoinositide-3-kinase regulatory subunit 5 [KO:K02649]
5296  
PIK3R2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649]
8503  
PIK3R3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649]
207  
AKT1; AKT serine/threonine kinase 1 [KO:K04456] [EC:2.7.11.1]
208  
AKT2; AKT serine/threonine kinase 2 [KO:K04456] [EC:2.7.11.1]
10000  
AKT3; AKT serine/threonine kinase 3 [KO:K04456] [EC:2.7.11.1]
572  
BAD; BCL2 associated agonist of cell death [KO:K02158]
5728  
PTEN; phosphatase and tensin homolog [KO:K01110] [EC:3.1.3.67 3.1.3.48 3.1.3.16]
1029  
CDKN2A; cyclin dependent kinase inhibitor 2A [KO:K06621]
4193  
MDM2; MDM2 proto-oncogene [KO:K06643] [EC:2.3.2.27]
7157  
TP53; tumor protein p53 [KO:K04451]
1026  
CDKN1A; cyclin dependent kinase inhibitor 1A [KO:K06625]
595  
CCND1; cyclin D1 [KO:K04503]
1021  
CDK6; cyclin dependent kinase 6 [KO:K02091] [EC:2.7.11.22]
5925  
RB1; RB transcriptional corepressor 1 [KO:K06618]
1869  
E2F1; E2F transcription factor 1 [KO:K17454]
1870  
E2F2; E2F transcription factor 2 [KO:K09389]
1871  
E2F3; E2F transcription factor 3 [KO:K06620]
999  
CDH1; cadherin 1 [KO:K05689]
4286  
MITF; melanogenesis associated transcription factor [KO:K09455]
Compound
C05981  
Phosphatidylinositol-3,4,5-trisphosphate
Reference
  Authors
Miller AJ, Mihm MC Jr.
  Title
Melanoma.
  Journal
N Engl J Med 355:51-65 (2006)
Reference
  Authors
Chin L.
  Title
The genetics of malignant melanoma: lessons from mouse and man.
  Journal
Nat Rev Cancer 3:559-70 (2003)
Reference
  Authors
Takata M, Saida T.
  Title
Genetic alterations in melanocytic tumors.
  Journal
J Dermatol Sci 43:1-10 (2006)
Reference
  Authors
Chudnovsky Y, Khavari PA, Adams AE.
  Title
Melanoma genetics and the development of rational therapeutics.
  Journal
J Clin Invest 115:813-24 (2005)
Reference
  Authors
Merlino G.
  Title
Cancer biology: the weakest link?
  Journal
Nature 436:33-5 (2005)
Reference
  Authors
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.
  Title
Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma.
  Journal
Nature 436:117-22 (2005)
Reference
  Authors
Levy C, Khaled M, Fisher DE.
  Title
MITF: master regulator of melanocyte development and melanoma oncogene.
  Journal
Trends Mol Med 12:406-14 (2006)
Reference
  Authors
Tsao H, Goel V, Wu H, Yang G, Haluska FG.
  Title
Genetic interaction between NRAS and BRAF mutations and PTEN/MMAC1 inactivation in melanoma.
  Journal
J Invest Dermatol 122:337-41 (2004)
Reference
  Authors
Gruss C, Herlyn M.
  Title
Role of cadherins and matrixins in melanoma.
  Journal
Curr Opin Oncol 13:117-23 (2001)
Reference
  Authors
Thompson JF, Scolyer RA, Kefford RF.
  Title
Cutaneous melanoma.
  Journal
Lancet 365:687-701 (2005)
Reference
  Authors
Omholt K, Platz A, Kanter L, Ringborg U, Hansson J.
  Title
NRAS and BRAF mutations arise early during melanoma pathogenesis and are preserved throughout tumor progression.
  Journal
Clin Cancer Res 9:6483-8 (2003)
Reference
  Authors
Hussein MR.
  Title
The TP53 tumor suppressor gene and melanoma tumorigenesis: is there a relationship?
  Journal
Tumour Biol 25:200-7 (2004)
Reference
  Authors
Lazar-Molnar E, Hegyesi H, Toth S, Falus A.
  Title
Autocrine and paracrine regulation by cytokines and growth factors in melanoma.
  Journal
Cytokine 12:547-54 (2000)
KO pathway
 

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