Melanoma (Homo sapiens)

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Description

Melanoma, or malignant melanoma, is a highly aggressive cancer that develops in melanocytes. Many genes have been found to be mutated or amplified in melanoma, with the most commonly mutated genes being BRAF, CDKN2A, NRAS and TP53. MAPK and PI3K/Akt signaling are central to melanoma.

This pathway is a summary of information from figures 1 and 2 from [Kunz and Vera](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520749/) and supplemented with information from [KEGG](https://www.kegg.jp/dbget-bin/www_bget?pathway+hsa05218).

CDKN2A is frequently mutated in melanoma and germline mutations are associated with an increased susceptibility of developing skin cancer. The CDKN2A encodes two proteins, p16 (INK4A) and p14ARF, with different functions. p16 binds to CDK4, which prevents phosphorylation of Rb, thereby controlling the G1 to S transition. Without functioning p16, G1 to S transition can proceed. p14ARF is central to cell cycle regulation, inhibiting MDM2, which normally degrades p53, so loss of p14ARF has a similar effect to loss of p53.

Protein phosphorylation sites were added based on information from PhosphoSitePlus (R), www.phosphosite.org.

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Bibliography

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  1. Kunz M, Vera J; ''Modelling of Protein Kinase Signaling Pathways in Melanoma and Other Cancers.''; Cancers (Basel), 2019 PubMed Europe PMC Scholia
  2. Krauthammer M, Kong Y, Ha BH, Evans P, Bacchiocchi A, McCusker JP, Cheng E, Davis MJ, Goh G, Choi M, Ariyan S, Narayan D, Dutton-Regester K, Capatana A, Holman EC, Bosenberg M, Sznol M, Kluger HM, Brash DE, Stern DF, Materin MA, Lo RS, Mane S, Ma S, Kidd KK, Hayward NK, Lifton RP, Schlessinger J, Boggon TJ, Halaban R; ''Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma.''; Nat Genet, 2012 PubMed Europe PMC Scholia
  3. Cosci I, Salizzato V, Del Fiore P, Pigozzo J, Guarneri V, Mocellin S, Ferlin A, Mathlouthi S, Piccin L, Garofalo M; ''Molecular Basis of BRAF Inhibitor Resistance in Melanoma: A Systematic Review.''; Pharmaceuticals (Basel), 2025 PubMed Europe PMC Scholia
  4. Misek SA, Appleton KM, Dexheimer TS, Lisabeth EM, Lo RS, Larsen SD, Gallo KA, Neubig RR; ''Rho-mediated signaling promotes BRAF inhibitor resistance in de-differentiated melanoma cells.''; Oncogene, 2020 PubMed Europe PMC Scholia
  5. 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, 2005 PubMed Europe PMC Scholia
  6. Zhang RY, Yu ZH, Zeng L, Zhang S, Bai Y, Miao J, Chen L, Xie J, Zhang ZY; ''SHP2 phosphatase as a novel therapeutic target for melanoma treatment.''; Oncotarget, 2016 PubMed Europe PMC Scholia
  7. Hodis E, Watson IR, Kryukov GV, Arold ST, Imielinski M, Theurillat JP, Nickerson E, Auclair D, Li L, Place C, Dicara D, Ramos AH, Lawrence MS, Cibulskis K, Sivachenko A, Voet D, Saksena G, Stransky N, Onofrio RC, Winckler W, Ardlie K, Wagle N, Wargo J, Chong K, Morton DL, Stemke-Hale K, Chen G, Noble M, Meyerson M, Ladbury JE, Davies MA, Gershenwald JE, Wagner SN, Hoon DS, Schadendorf D, Lander ES, Gabriel SB, Getz G, Garraway LA, Chin L; ''A landscape of driver mutations in melanoma.''; Cell, 2012 PubMed Europe PMC Scholia
  8. ''Genomic Classification of Cutaneous Melanoma.''; Cell, 2015 PubMed Europe PMC Scholia
  9. Postow MA, Carvajal RD; ''Therapeutic implications of KIT in melanoma.''; Cancer J, 2012 PubMed Europe PMC Scholia
  10. ''''; https://www.kegg.jp/dbget-bin/www_bget?pathway+hsa05218,
  11. Berger MF, Hodis E, Heffernan TP, Deribe YL, Lawrence MS, Protopopov A, Ivanova E, Watson IR, Nickerson E, Ghosh P, Zhang H, Zeid R, Ren X, Cibulskis K, Sivachenko AY, Wagle N, Sucker A, Sougnez C, Onofrio R, Ambrogio L, Auclair D, Fennell T, Carter SL, Drier Y, Stojanov P, Singer MA, Voet D, Jing R, Saksena G, Barretina J, Ramos AH, Pugh TJ, Stransky N, Parkin M, Winckler W, Mahan S, Ardlie K, Baldwin J, Wargo J, Schadendorf D, Meyerson M, Gabriel SB, Golub TR, Wagner SN, Lander ES, Getz G, Chin L, Garraway LA; ''Melanoma genome sequencing reveals frequent PREX2 mutations.''; Nature, 2012 PubMed Europe PMC Scholia
  12. Ren J, Guo W; ''ERK1/2 regulate exocytosis through direct phosphorylation of the exocyst component Exo70.''; Dev Cell, 2012 PubMed Europe PMC Scholia
  13. Prickett TD, Wei X, Cardenas-Navia I, Teer JK, Lin JC, Walia V, Gartner J, Jiang J, Cherukuri PF, Molinolo A, Davies MA, Gershenwald JE, Stemke-Hale K, Rosenberg SA, Margulies EH, Samuels Y; ''Exon capture analysis of G protein-coupled receptors identifies activating mutations in GRM3 in melanoma.''; Nat Genet, 2011 PubMed Europe PMC Scholia
  14. Prickett TD, Agrawal NS, Wei X, Yates KE, Lin JC, Wunderlich JR, Cronin JC, Cruz P, Rosenberg SA, Samuels Y; ''Analysis of the tyrosine kinome in melanoma reveals recurrent mutations in ERBB4.''; Nat Genet, 2009 PubMed Europe PMC Scholia
  15. Zhang Y, Xiong Y, Yarbrough WG; ''ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways.''; Cell, 1998 PubMed Europe PMC Scholia
  16. Yelamos O, Merkel E, Meldi Sholl L, Zhang B, Amin S, Lee C, Guitart G, Yang J, Wenzel A, Bunick C, Yazdan P, Choi J, Gerami P; ''Non-overlapping Clinical and Mutational Patterns in Melanomas from the Female Genital Tract and Atypical Genital Nevi ''; Journal of Investigative Dermatology, 2016 PubMed Europe PMC Scholia

History

View all...
CompareRevisionActionTimeUserComment
142148view23:16, 5 December 2025Khanspersreferences
141870view18:22, 25 November 2025Khanspersremoved phosphosites from RAS
141821view01:01, 25 November 2025Khanspersupdate Ras phospho sites
141820view00:49, 25 November 2025Khanspersadded SHP2 and downstream phospho sites
141513view23:36, 17 November 2025Khanspersconnected P53/MDM2 network
141451view22:41, 14 November 2025Khanspersupdated RB1-E2F part, converted interactions to graphical lines (those ending in labels)
141291view00:37, 8 November 2025Khanspersfixed curation issues
141226view01:12, 7 November 2025KhanspersAdded trametinib, updated ptms
141223view00:20, 7 November 2025Khanspersadded ref for GRIN2A, improved spacing
141209view22:07, 6 November 2025Khanspersupdated ref forPDE5A/CTTN/EXOC7, added ptms for CTTN
141208view21:57, 6 November 2025Khansperscompleted PDE5A/CTTN/EXPO7/Rho section, updated layout, updated RB-E2F part to clarify, updated downstream from MAPK cascade to match KEGG pathway
141178view09:57, 6 November 2025DeSlAdded ID for Rho (family of proteins), 3 relevant proteins in this family (with UniProt annotations), and lit. ref supporting their link to melanoma
141170view00:43, 6 November 2025Khanspersconvert interactions to graphical lines, added Rho, CTTN, EXOC7, PDE5A
140458view18:53, 26 August 2025KhanspersModified description
140133view17:51, 31 July 2025Khanspersupdated ptms
139048view00:22, 13 May 2025Khansperslayout
137150view23:22, 27 February 2025KhanspersModified description
135116view11:58, 6 August 2024EweitzOntology Term : 'melanocyte' added !
135115view11:55, 6 August 2024EweitzRefine cell type label
135114view11:53, 6 August 2024EweitzEconomize layout
135113view11:52, 6 August 2024EweitzEconomize layout
129358view09:35, 27 March 2024MkutmonOntology Term : 'cancer pathway' added !
129357view09:35, 27 March 2024MkutmonOntology Term : 'disease pathway' added !
128513view00:48, 11 February 2024EweitzFix truncation in legend text, refine padding
128512view00:47, 11 February 2024EweitzFix membrane overlap, avoid truncation in special nodes
128511view00:44, 11 February 2024EweitzEconomize layout
128510view00:38, 11 February 2024EweitzFix order (z-index) of RTK
128509view00:36, 11 February 2024EweitzRefine legend
128508view00:26, 11 February 2024EweitzEconomize layout
128503view23:21, 10 February 2024EweitzRefine case
123437view04:37, 27 July 2022EgonwMade two pathways clickable
119240view19:10, 22 June 2021Finterlyadded KEGG biopax information
116638view11:26, 9 May 2021EweitzOntology Term : 'melanoma' added !
112160view18:23, 29 September 2020Khanspersfixed ptm state comments
106231view00:24, 17 August 2019KhanspersModified description
106230view00:08, 17 August 2019Khanspersadded final parts
106229view22:32, 16 August 2019Khanspersbetter defined CDKN2A content
106228view21:27, 16 August 2019Khanspersmore CDKN2A content
106227view21:23, 16 August 2019KhanspersAdding CDKN2A content
106226view21:06, 16 August 2019Khanspersupdated phospho sites
106225view21:00, 16 August 2019Khanspersadded legend, fixed interaction
106224view20:56, 16 August 2019KhanspersModified description
106189view12:08, 16 August 2019MaintBotHMDB identifier normalization
105702view05:07, 14 August 2019Khanspersadded KEGG reference
105701view00:05, 14 August 2019KhanspersNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
AKT1GeneProductENSG00000142208 (Ensembl) Homology Mapping from Mus musculus to Homo sapiens: Original ID = L:11651
AKT2GeneProductENSG00000105221 (Ensembl) Homology Mapping from Mus musculus to Homo sapiens: Original ID = L:11652
AKT3GeneProductENSG00000117020 (Ensembl) Homology Mapping from Mus musculus to Homo sapiens: Original ID = L:23797
ARAFGeneProductENSG00000078061 (Ensembl)
BADGeneProductENSG00000002330 (Ensembl)
  • SOS1; son of sevenless homolog 1 (Drosophila)
  • Homology Mapping from Mus musculus to Homo sapiens: Original ID = L:12015
BAK1GeneProductENSG00000030110 (Ensembl)
BAXGeneProductENSG00000087088 (Ensembl)
BRAFGeneProduct673 (Entrez Gene)
BinimetinibMetaboliteQ19903515 (Wikidata)
CALM1GeneProductENSG00000198668 (Ensembl)
CALM2GeneProductENSG00000143933 (Ensembl)
CALM3GeneProductENSG00000160014 (Ensembl)
CALML3GeneProductENSG00000178363 (Ensembl)
CALML4GeneProductENSG00000129007 (Ensembl)
CALML5GeneProductENSG00000178372 (Ensembl)
CALML6GeneProductENSG00000169885 (Ensembl)
CCND1GeneProductENSG00000110092 (Ensembl) CCND3; cyclin D3
CDH1GeneProductENSG00000039068 (Ensembl)
CDK4GeneProductENSG00000135446 (Ensembl) CDK4; cyclin-dependent kinase 4 [EC:2.7.1.-]
CDK6GeneProductENSG00000105810 (Ensembl) CDK6; cyclin-dependent kinase 6 [EC:2.7.1.-]
CDKN1AGeneProductENSG00000124762 (Ensembl)
CDKN2AGeneProductENSG00000147889 (Ensembl) p16 INK4a
CTTNGeneProductCTTN (HGNC)
Cell CyclePathwayWP179 (WikiPathways)
CobimetinibMetaboliteQ15708292 (Wikidata)
DDB2GeneProductENSG00000134574 (Ensembl)
DabrafenibMetaboliteCHEBI:75045 (ChEBI)
E2F1GeneProductENSG00000101412 (Ensembl) E2F1; E2F transcription factor 1
E2F2GeneProductENSG00000007968 (Ensembl) E2F2; E2F transcription factor 2
E2F3GeneProductENSG00000112242 (Ensembl) E2F3; E2F transcription factor 3
ERBB4GeneProductENSG00000178568 (Ensembl)
EXOC7GeneProductEXOC7 (HGNC)
GADD45AGeneProductENSG00000116717 (Ensembl)
GADD45BGeneProductENSG00000099860 (Ensembl)
GADD45GGeneProductENSG00000130222 (Ensembl)
GRB2GeneProduct2885 (Entrez Gene)
GRIN2AGeneProductENSG00000183454 (Ensembl)
GRM3GeneProductENSG00000198822 (Ensembl)
HRASGeneProductENSG00000174775 (Ensembl)
KDRGeneProductENSG00000128052 (Ensembl)
KITGeneProductENSG00000157404 (Ensembl)
KRASGeneProduct3845 (Entrez Gene)
MAP2K1GeneProduct5604 (Entrez Gene)
MAP2K2GeneProduct5605 (Entrez Gene)
MAPK1GeneProduct5594 (Entrez Gene)
MAPK3GeneProduct5595 (Entrez Gene)
MDM2GeneProductENSG00000135679 (Ensembl)
MITFGeneProductENSG00000187098 (Ensembl)
NF1GeneProductENSG00000196712 (Ensembl)
NRASGeneProduct4893 (Entrez Gene)
PAK1GeneProductENSG00000149269 (Ensembl)
PDE5AGeneProductPDE5A (HGNC)
PIK3CAGeneProductENSG00000121879 (Ensembl) Homology Mapping from Mus musculus to Homo sapiens: Original ID = L:18706
PIK3CBGeneProductENSG00000051382 (Ensembl) Homology Mapping from Mus musculus to Homo sapiens: Original ID = L:74769
PIK3CDGeneProductENSG00000171608 (Ensembl) Homology Mapping from Mus musculus to Homo sapiens: Original ID = L:18707
PIK3R1GeneProductENSG00000145675 (Ensembl) Homology Mapping from Mus musculus to Homo sapiens: Original ID = L:18708
PIK3R2GeneProductENSG00000105647 (Ensembl) Homology Mapping from Mus musculus to Homo sapiens: Original ID = L:18709
PIK3R3GeneProductENSG00000117461 (Ensembl) Homology Mapping from Mus musculus to Homo sapiens: Original ID = L:75669
PIP3MetaboliteHMDB0004249 (HMDB)
POLKGeneProductENSG00000122008 (Ensembl)
PREX2GeneProductENSG00000046889 (Ensembl)
PTENGeneProductENSG00000171862 (Ensembl) Homology Mapping from Mus musculus to Homo sapiens: Original ID = L:19211
RAC1GeneProductENSG00000136238 (Ensembl)
RAF1GeneProduct5894 (Entrez Gene)
RB1GeneProductENSG00000139687 (Ensembl)
RegorafenibMetaboliteCHEBI:68647 (ChEBI)
Regulation of actin cytoskeletonPathwayWP51 (WikiPathways)
RhoAGeneProductCD00157 (InterPro) "The RhoA subfamily (RhoA, RhoB, and RhoC) of GTPases [...] In melanoma the RhoA subfamily, especially RhoC, promotes invasion and metastasis 5, 22, 50, and inhibition of the RhoA isoform suppresses tumor growth" Source: https://doi.org/10.1038/s41388-019-1074-1
RhoAProteinP61586 (Uniprot-TrEMBL)
RhoBProteinP62745 (Uniprot-TrEMBL)
RhoCProteinP08134 (Uniprot-TrEMBL)
SHC2GeneProductENSG00000129946 (Ensembl)
SHP2GeneProductPTPN11 (HGNC)
SOS1GeneProductENSG00000115904 (Ensembl)
SOS2GeneProduct6655 (Entrez Gene)
STK19GeneProductENSG00000204344 (Ensembl)
SorafenibMetaboliteHMDB0014542 (HMDB)
TP53GeneProductENSG00000141510 (Ensembl)
VCLGeneProductENSG00000035403 (Ensembl)
VemurafenibMetaboliteCHEBI:63637 (ChEBI)
cGMPMetaboliteCHEBI:16356 (ChEBI)
p14 ARF (CDKN2A)GeneProductENSG00000147889 (Ensembl) Alternate reading frame product of CDKN2A
p38 MAPK signalingPathwayWP400 (WikiPathways)
trametinibMetaboliteCHEBI:75998 (ChEBI)

Annotated Interactions

No annotated interactions

Retrieved from "https://classic.wikipathways.org/index.php/Pathway:WP4685"
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