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. fab ca0 cb6 d7a b44 a2f b44 cb5 b44 b44 d64 afe "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 e15 a2f eab Homology Mapping from Mus musculus to Homo sapiens: Original ID = L:18706 Homology Mapping from Mus musculus to Homo sapiens: Original ID = L:18708 Homology Mapping from Mus musculus to Homo sapiens: Original ID = L:18709 Homology Mapping from Mus musculus to Homo sapiens: Original ID = L:74769 Homology Mapping from Mus musculus to Homo sapiens: Original ID = L:18707 Homology Mapping from Mus musculus to Homo sapiens: Original ID = L:75669 Homology Mapping from Mus musculus to Homo sapiens: Original ID = L:11651 Homology Mapping from Mus musculus to Homo sapiens: Original ID = L:23797 Homology Mapping from Mus musculus to Homo sapiens: Original ID = L:11652 SOS1; son of sevenless homolog 1 (Drosophila) Homology Mapping from Mus musculus to Homo sapiens: Original ID = L:12015 Homology Mapping from Mus musculus to Homo sapiens: Original ID = L:19211 fab CDK6; cyclin-dependent kinase 6 [EC:2.7.1.-] CDK4; cyclin-dependent kinase 4 [EC:2.7.1.-] CCND3; cyclin D3 E2F1; E2F transcription factor 1 E2F2; E2F transcription factor 2 E2F3; E2F transcription factor 3 Alternate reading frame product of CDKN2A p16 INK4a CDK4; cyclin-dependent kinase 4 [EC:2.7.1.-] CCND3; cyclin D3 E2F1; E2F transcription factor 1 E2F2; E2F transcription factor 2 E2F3; E2F transcription factor 3 e20 V600E parentid=P04049; parentsymbol=RAF1; site=IGDFGLAtVksRWsG; position=thr491; sitegrpid=447748; ptm=p; direction=u parentid=Q02750; parentsymbol=MAP2K1; site=LIDsMANsFVGTRSY; position=ser222; sitegrpid=448513; ptm=p; direction=u parentid=Q02750; parentsymbol=MAP2K1; site=VsGQLIDsMANsFVG; position=ser218; sitegrpid=448514; ptm=p; direction=u parentid=P28482; parentsymbol=MAPK1; site=HtGFLtEyVAtRWyR; position=tyr187; sitegrpid=447594; ptm=p; direction=u parentid=P28482; parentsymbol=MAPK1; site=HDHtGFLtEyVAtRW; position=thr185; sitegrpid=447593; ptm=p; direction=u parentid=P27361; parentsymbol=MAPK3; site=HDHtGFLtEyVAtRW; position=thr202; sitegrpid=447542; ptm=p; direction=u parentid=P27361; parentsymbol=MAPK3; site=HtGFLtEyVAtRWyR; position=tyr204; sitegrpid=447543; ptm=p; direction=u parentid=P36507; parentsymbol=MAP2K2; site=LIDsMANsFVGTRSY; position=ser226; sitegrpid=448074; ptm=p; direction=u parentid=P36507; parentsymbol=MAP2K2; site=VsGQLIDsMANsFVG; position=ser222; sitegrpid=448073; ptm=p; direction=u parentid=Q92934; parentsymbol=BAD; site=EIRsRHssyPAGtED; position=ser75; sitegrpid=447860; ptm=p; direction=d parentid=P24385; parentsymbol=CCND1; site=EEVDLACtPtDVRDV; position=thr286; sitegrpid=447839; ptm=p; direction=d parentid=Q14247; parentsymbol=CTTN; site=KtQtPPVsPAPQPtE; position=Ser405; sitegrpid=447700; ptm=p; direction=u parentid=Q14247; parentsymbol=CTTN; site=tEErLPssPVyEDAA; position=Ser418; sitegrpid=447701; ptm=p; direction=u parentid=Q9UPT5; parentsymbol=EXOC7; site=sSSGVPysPAIPNKR; position=Ser250; sitegrpid=483909; ptm=p; direction=u cb0 parentid=P06400; parentsymbol=RB1; site=AVIPINGsPRtPRRG; position=ser249; sitegrpid=447975; ptm=p; direction=d b05 d60 d60 d6d d60 21946352 PubMed Exon capture analysis of G protein-coupled receptors identifies activating mutations in GRM3 in melanoma. Nat Genet 2011 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 27650545 PubMed SHP2 phosphatase as a novel therapeutic target for melanoma treatment. Oncotarget 2016 Zhang RY Yu ZH Zeng L Zhang S Bai Y Miao J Chen L Xie J Zhang ZY 40872623 PubMed Molecular Basis of BRAF Inhibitor Resistance in Melanoma: A Systematic Review. Pharmaceuticals (Basel) 2025 Cosci I Salizzato V Del Fiore P Pigozzo J Guarneri V Mocellin S Ferlin A Mathlouthi S Piccin L Garofalo M hsa05218 KEGG Pathway https://www.kegg.jp/dbget-bin/www_bget?pathway+hsa05218 19718025 PubMed Analysis of the tyrosine kinome in melanoma reveals recurrent mutations in ERBB4. Nat Genet 2009 Prickett TD Agrawal NS Wei X Yates KE Lin JC Wunderlich JR Cronin JC Cruz P Rosenberg SA Samuels Y 26091043 PubMed Genomic Classification of Cutaneous Melanoma. Cell 2015 22595671 PubMed ERK1/2 regulate exocytosis through direct phosphorylation of the exocyst component Exo70. Dev Cell 2012 Ren J Guo W PMC5031419 PubMed Non-overlapping Clinical and Mutational Patterns in Melanomas from the Female Genital Tract and Atypical Genital Nevi Journal of Investigative Dermatology 2016 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 9529249 PubMed ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways. Cell 1998 Zhang Y Xiong Y Yarbrough WG cancer pathway PW:0000605 Pathway Ontology disease pathway PW:0000013 Pathway Ontology 22453014 PubMed Therapeutic implications of KIT in melanoma. Cancer J 2012 Postow MA Carvajal RD 22842228 PubMed Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma. Nat Genet 2012 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 melanocyte CL:0000148 Cell Type 16001072 PubMed Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma. Nature 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 31659259 PubMed Rho-mediated signaling promotes BRAF inhibitor resistance in de-differentiated melanoma cells. Oncogene 2020 Misek SA Appleton KM Dexheimer TS Lisabeth EM Lo RS Larsen SD Gallo KA Neubig RR 22817889 PubMed A landscape of driver mutations in melanoma. Cell 2012 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 melanoma DOID:1909 Disease 30987166 PubMed Modelling of Protein Kinase Signaling Pathways in Melanoma and Other Cancers. Cancers (Basel) 2019 Kunz M Vera J 22622578 PubMed Melanoma genome sequencing reveals frequent PREX2 mutations. Nature 2012 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