KRAS and SKIL mutations synergistically promote pancreatic tumorigenesis through the ubiquitin-proteasome-mediated degradation of Smad4
HEK293T cells with engineered SKIL A512T and/or KRAS G12V mutations were analyzed for proliferation, tumorigenicity, and signaling. Transcriptomics, ubiquitination assays, and protein interaction studies (Co-IP, immunofluorescence) delineated the mechanism.Results: SKIL normally protects Smad4 by binding its MH2 domain; SKIL loss exposes this domain to ubiquitination, but degradation occurs only when KRAS mutation upregulates the E3 ligase SMURF2. Clinically, low SKIL expression is significantly correlated with poor prognosis in pancreatic cancer patients harboring KRAS mutations.