Infiltrating ductal adenocarcinoma is the most common malignancy of the pancreas. When most investigators use the term 'pancreatic cancer' they are referring to pancreatic ductal adenocarcinoma (PDA). Normal duct epithelium progresses to infiltrating cancer through a series of histologically defined precursors, Pancreatic Intraepithelial Neoplasia (PanINs: https://pathology.jhu.edu/pancreas/professionals/DuctLesions.php). The overexpression of HER-2/neu (ERBB2) and activating point mutations in the K-ras gene occur early, inactivation of the p16 gene (CDKN2A) at an intermediate stage, and the inactivation of p53, SMAD4, and BRCA2 occur relatively late. Activated K-ras engages multiple effector pathways. Although EGF receptors are conventionally regarded as upstream activators of RAS proteins, they can also act as RAS signal transducers via RAS-induced autocrine activation of the EGFR family ligands. Moreover, PDA shows extensive genomic instability and aneuploidy. Telomere attrition and mutations in p53 and BRCA2 are likely to contribute to these phenotypes. Inactivation of the SMAD4 tumor suppressor gene leads to loss of the inhibitory influence of the transforming growth factor-beta signaling pathway.
The progression of disease and associated mutations is defined based on the arrow at the top, from left to right.
Phosphorylation sites were added based on information from PhosphoSitePlus (R), www.phosphosite.org.d15parentid=O15111; parentsymbol=CHUK; site=AKDVDQGsLCtsFVG; position=ser176; sitegrpid=447778; ptm=p; direction=uparentid=O14920; parentsymbol=IKBKB; site=DQGsLCtsFVGTLQy; position=ser181; sitegrpid=447489; ptm=p; direction=uparentid=Q92934; parentsymbol=BAD; site=PFrGrsRsAPPNLWA; position=ser99; sitegrpid=447862; ptm=p; direction=dparentid=Q92934; parentsymbol=BAD; site=KGLPRPKsAGtAtQM; position=ser134; sitegrpid=447864; ptm=p; direction=dparentid=P55211; parentsymbol=CASP9; site=kLRRRFssLHFMVEV; position=ser196; sitegrpid=448454; ptm=p; direction=dparentid=Q02750; parentsymbol=MAP2K1; site=VsGQLIDsMANsFVG; position=ser218; sitegrpid=448514; ptm=p; direction=uparentid=Q02750; parentsymbol=MAP2K1; site=LIDsMANsFVGtRSY; position=ser222; sitegrpid=448513; ptm=p; direction=uparentid=P36507; parentsymbol=MAP2K2; site=VsGQLIDsMANsFVG; position=ser222; sitegrpid=448073; ptm=p; direction=uparentid=P36507; parentsymbol=MAP2K2; site=LIDsMANsFVGtRSY; position=ser226; sitegrpid=448074; 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=HtGFLtEyVAtRWyr; position=tyr204; sitegrpid=447543; ptm=p; direction=uparentid=P27361; parentsymbol=MAPK3; site=HDHtGFLtEyVAtRW; position=thr202; sitegrpid=447542; ptm=p; direction=uparentid=P42345; parentsymbol=MTOR; site=PTPAILEsLIsINNK; position=ser1415; sitegrpid=25745815; ptm=p; direction=uparentid=P42345; parentsymbol=MTOR; site=RsRtRtDsysAGQsV; position=ser2448; sitegrpid=447578; ptm=p; direction=uparentid=P42224; parentsymbol=STAT1; site=DGPkGtGyIktELIs; position=tyr701; sitegrpid=447754; ptm=p; direction=uparentid=P42224; parentsymbol=STAT1; site=TDNLLPMsPEEFDEV; position=ser727; sitegrpid=447753; ptm=p; direction=ufe1ffb25514926PubMedPhosphoSitePlus, 2014: mutations, PTMs and recalibrations.Nucleic Acids Res2015Hornbeck PVZhang BMurray BKornhauser JMLatham VSkrzypek Epancreatic ductal cellCL:0002079Cell Typepancreatic adenocarcinomaDOID:4074DiseaseJak-Stat signaling pathwayPW:0000209Pathway Ontologydisease pathwayPW:0000013Pathway Ontology12759238PubMedPotential tumor suppressive pathway involving DUSP6/MKP-3 in pancreatic cancer.Am J Pathol2003Furukawa TSunamura MMotoi FMatsuno SHorii A29436617PubMedRIPK4/PEBP1 axis promotes pancreatic cancer cell migration and invasion by activating RAF1/MEK/ERK signaling.Int J Oncol2018Qi ZHXu HXZhang SRXu JZLi SGao HLJin WWang WQWu CTNi QXYu XJLiu Lcancer pathwayPW:0000605Pathway Ontologyphosphatidylinositol 3-kinase-Akt signaling pathwayPW:0000232Pathway Ontology