KEGG PATHWAY: ko05218

PATHWAY: ko05218

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; Cancer: specific types

Pathway map

ko05218

Melanoma

Disease

H00038

Melanoma

Orthology

K18496

fibroblast growth factor 1

K18497

fibroblast growth factor 2

K04358

fibroblast growth factor

K22603

fibroblast growth factor 19

K22429

fibroblast growth factor 21

K22428

fibroblast growth factor 23

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]

K04503

G1/S-specific cyclin-D1

K02089

cyclin-dependent kinase 4 [EC:2.7.11.22]

K00922

phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha/beta/delta [EC:2.7.1.153]

K02649

phosphoinositide-3-kinase regulatory subunit alpha/beta/delta

K04456

RAC serine/threonine-protein kinase [EC:2.7.11.1]

K02158

Bcl-2-antagonist of cell death

K01110

phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN [EC:3.1.3.16 3.1.3.48 3.1.3.67]

K06621

cyclin-dependent kinase inhibitor 2A

K06643

E3 ubiquitin-protein ligase Mdm2 [EC:2.3.2.27]

K04451

tumor protein p53

K06625

cyclin-dependent kinase inhibitor 1A

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

K04402

growth arrest and DNA-damage-inducible protein

K02159

apoptosis regulator BAX

K14021

Bcl-2 homologous antagonist/killer

K10140

DNA damage-binding protein 2

K03511

DNA polymerase kappa [EC:2.7.7.7]

K09455

microphthalmia-associated transcription factor

Compound

C05981

Phosphatidylinositol-3,4,5-trisphosphate

Reference

PMID:16822996

Authors

Miller AJ, Mihm MC Jr.

Title

Melanoma.

Journal

N Engl J Med 355:51-65 (2006)
DOI:10.1056/NEJMra052166

Reference

PMID:12894244

Authors

Chin L.

Title

The genetics of malignant melanoma: lessons from mouse and man.

Journal

Nat Rev Cancer 3:559-70 (2003)
DOI:10.1038/nrc1145

Reference

PMID:16750612

Authors

Takata M, Saida T.

Title

Genetic alterations in melanocytic tumors.

Journal

J Dermatol Sci 43:1-10 (2006)
DOI:10.1016/j.jdermsci.2006.05.002

Reference

PMID:15841168

Authors

Chudnovsky Y, Khavari PA, Adams AE.

Title

Melanoma genetics and the development of rational therapeutics.

Journal

J Clin Invest 115:813-24 (2005)
DOI:10.1172/JCI24808

Reference

PMID:16001050

Authors

Merlino G.

Title

Cancer biology: the weakest link?

Journal

Nature 436:33-5 (2005)
DOI:10.1038/436033a

Reference

PMID:16001072

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)
DOI:10.1038/nature03664

Reference

PMID:16899407

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)
DOI:10.1016/j.molmed.2006.07.008