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 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520749/ Kunz and Vera] and supplemented with information from [https://www.kegg.jp/dbget-bin/www_bget?pathway+hsa05218 KEGG].
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. fabca0d7ab44a2fb44cb5b44b44d64afee15a2fHomology Mapping from Mus musculus to Homo sapiens: Original ID = L:18706Homology Mapping from Mus musculus to Homo sapiens: Original ID = L:18708Homology Mapping from Mus musculus to Homo sapiens: Original ID = L:18709Homology Mapping from Mus musculus to Homo sapiens: Original ID = L:74769Homology Mapping from Mus musculus to Homo sapiens: Original ID = L:18707Homology Mapping from Mus musculus to Homo sapiens: Original ID = L:75669Homology Mapping from Mus musculus to Homo sapiens: Original ID = L:11651Homology Mapping from Mus musculus to Homo sapiens: Original ID = L:23797Homology Mapping from Mus musculus to Homo sapiens: Original ID = L:11652SOS1; son of sevenless homolog 1 (Drosophila)Homology Mapping from Mus musculus to Homo sapiens: Original ID = L:12015Homology Mapping from Mus musculus to Homo sapiens: Original ID = L:19211CDK6; cyclin-dependent kinase 6 [EC:2.7.1.-]CDK4; cyclin-dependent kinase 4 [EC:2.7.1.-]CCND3; cyclin D3E2F1; E2F transcription factor 1E2F2; E2F transcription factor 2E2F3; E2F transcription factor 3V600Eparentid=P04049; parentsymbol=RAF1; site=IGDFGLAtVksRWsG; position=thr491; sitegrpid=447748; ptm=p; direction=uparentid=Q02750; parentsymbol=MAP2K1; site=LIDsMANsFVGTRSY; position=ser222; sitegrpid=448513; ptm=p; direction=uparentid=Q02750; parentsymbol=MAP2K1; site=VsGQLIDsMANsFVG; position=ser218; sitegrpid=448514; ptm=p; direction=uparentid=P28482; parentsymbol=MAPK1; site=HtGFLtEyVAtRWyR; position=tyr187; sitegrpid=447594; ptm=p; direction=uparentid=P28482; parentsymbol=MAPK1; site=HDHtGFLtEyVAtRW; position=thr185; sitegrpid=447593; ptm=p; direction=uparentid=P27361; parentsymbol=MAPK3; site=HDHtGFLtEyVAtRW; position=thr202; sitegrpid=447542; ptm=p; direction=uparentid=P27361; parentsymbol=MAPK3; site=HtGFLtEyVAtRWyR; position=tyr204; sitegrpid=447543; ptm=p; direction=uparentid=P36507; parentsymbol=MAP2K2; site=LIDsMANsFVGTRSY; position=ser226; sitegrpid=448074; ptm=p; direction=uparentid=P36507; parentsymbol=MAP2K2; site=VsGQLIDsMANsFVG; position=ser222; sitegrpid=448073; ptm=p; direction=uparentid=P19419; parentsymbol=ELK1; site=RDLELPLsPsLLGGP; position=ser324; sitegrpid=471887; ptm=p; direction=uparentid=P19419; parentsymbol=ELK1; site=LsPIAPRsPAKLSFQ; position=ser389; sitegrpid=449757; ptm=p; direction=uparentid=Q92934; parentsymbol=BAD; site=EIRsRHssyPAGtED; position=ser75; sitegrpid=447860; ptm=p; direction=dparentid=P06400; position=ser249; ptm=p; direction=dparentid=P24385; position=thr286; ptm=p; direction=d26091043PubMedGenomic Classification of Cutaneous Melanoma.Cell2015hsa05218KEGG Pathwayhttps://www.kegg.jp/dbget-bin/www_bget?pathway+hsa0521822453014PubMedTherapeutic implications of KIT in melanoma.Cancer J2012Postow MACarvajal RD19718025PubMedAnalysis of the tyrosine kinome in melanoma reveals recurrent mutations in ERBB4.Nat Genet2009Prickett TDAgrawal NSWei XYates KELin JCWunderlich JRCronin JCCruz PRosenberg SASamuels Y22622578PubMedMelanoma genome sequencing reveals frequent PREX2 mutations.Nature2012Berger MFHodis EHeffernan TPDeribe YLLawrence MSProtopopov AIvanova EWatson IRNickerson EGhosh PZhang HZeid RRen XCibulskis KSivachenko AYWagle NSucker ASougnez COnofrio RAmbrogio LAuclair DFennell TCarter SLDrier YStojanov PSinger MAVoet DJing RSaksena GBarretina JRamos AHPugh TJStransky NParkin MWinckler WMahan SArdlie KBaldwin JWargo JSchadendorf DMeyerson MGabriel SBGolub TRWagner SNLander ESGetz GChin LGarraway LA22817889PubMedA landscape of driver mutations in melanoma.Cell2012Hodis EWatson IRKryukov GVArold STImielinski MTheurillat JPNickerson EAuclair DLi LPlace CDicara DRamos AHLawrence MSCibulskis KSivachenko AVoet DSaksena GStransky NOnofrio RCWinckler WArdlie KWagle NWargo JChong KMorton DLStemke-Hale KChen GNoble MMeyerson MLadbury JEDavies MAGershenwald JEWagner SNHoon DSSchadendorf DLander ESGabriel SBGetz GGarraway LAChin L21946352PubMedExon capture analysis of G protein-coupled receptors identifies activating mutations in GRM3 in melanoma.Nat Genet2011Prickett TDWei XCardenas-Navia ITeer JKLin JCWalia VGartner JJiang JCherukuri PFMolinolo ADavies MAGershenwald JEStemke-Hale KRosenberg SAMargulies EHSamuels YmelanomaDOID:1909Diseasecancer pathwayPW:0000605Pathway Ontology30987166PubMedModelling of Protein Kinase Signaling Pathways in Melanoma and Other Cancers.Cancers (Basel)2019Kunz MVera J22842228PubMedExome sequencing identifies recurrent somatic RAC1 mutations in melanoma.Nat Genet2012Krauthammer MKong YHa BHEvans PBacchiocchi AMcCusker JPCheng EDavis MJGoh GChoi MAriyan SNarayan DDutton-Regester KCapatana AHolman ECBosenberg MSznol MKluger HMBrash DEStern DFMaterin MALo RSMane SMa SKidd KKHayward NKLifton RPSchlessinger JBoggon TJHalaban Rdisease pathwayPW:0000013Pathway Ontology