KEGG   PATHWAY: ko05218Help
Entry
ko05218                     Pathway                                

Name
Melanoma
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
ko05218

All organismsOrtholog table
Disease
H00038  
Malignant melanoma
Orthology
K04358  
fibroblast growth factor
K05460  
hepatocyte growth factor
K05459  
insulin-like growth factor 1
K04359  
platelet-derived growth factor subunit A
K17386  
platelet-derived growth factor subunit B
K05450  
platelet derived growth factor C/D
K04357  
epidermal growth factor
K04362  
fibroblast growth factor receptor 1 [EC:2.7.10.1]
K05099  
proto-oncogene tyrosine-protein kinase Met [EC:2.7.10.1]
K05087  
insulin-like growth factor 1 receptor [EC:2.7.10.1]
K04363  
platelet-derived growth factor receptor alpha [EC:2.7.10.1]
K05089  
platelet-derived growth factor receptor beta [EC:2.7.10.1]
K04361  
epidermal growth factor receptor [EC:2.7.10.1]
K02833  
GTPase HRas
K07827  
GTPase KRas
K07828  
GTPase NRas
K08845  
A-Raf proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]
K04365  
B-Raf proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]
K04366  
RAF proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]
K04368  
mitogen-activated protein kinase kinase 1 [EC:2.7.12.2]
K04369  
mitogen-activated protein kinase kinase 2 [EC:2.7.12.2]
K04371  
mitogen-activated protein kinase 1/3 [EC:2.7.11.24]
K02089  
cyclin-dependent kinase 4 [EC:2.7.11.22]
K00922  
phosphatidylinositol-4,5-bisphosphate 3-kinase [EC:2.7.1.153]
K02649  
phosphoinositide-3-kinase, regulatory subunit
K04456  
RAC serine/threonine-protein kinase [EC:2.7.11.1]
K02158  
BCL2-antagonist of cell death
K01110  
phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN [EC:3.1.3.67 3.1.3.48 3.1.3.16]
K06621  
cyclin-dependent kinase inhibitor 2A
K06643  
E3 ubiquitin-protein ligase Mdm2 [EC:6.3.2.19]
K04451  
tumor protein p53
K06625  
cyclin-dependent kinase inhibitor 1A
K04503  
cyclin D1
K02091  
cyclin-dependent kinase 6 [EC:2.7.11.22]
K06618  
retinoblastoma-associated protein
K17454  
transcription factor E2F1
K09389  
transcription factor E2F2
K06620  
transcription factor E2F3
K05689  
cadherin 1, type 1, E-cadherin
K09455  
microphthalmia-associated transcription factor
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)

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