title: GSK-3α promotes oncogenic KRAS function in pancreatic cancer via TAK1-TAB stabilization and regulation of noncanonical NF-κB.
abstract: Mutations in KRAS drive the oncogenic phenotype in a variety of tumors of epithelial origin. The NF-κB transcription factor pathway is important for oncogenic RAS to transform cells and to drive tumorigenesis in animal models. Recently, TGF-β-activated kinase 1 (TAK1), an upstream regulator of IκB kinase (IKK), which controls canonical NF-κB signaling, was shown to be important for chemoresistance in pancreatic cancer and for regulating KRAS-mutant colorectal cancer cell growth and survival. Here, we show that mutant KRAS upregulates glycogen synthase kinase 3α (GSK-3α), leading to its interaction with TAK1 to stabilize the TAK1-TAB complex to promote IKK activity. In addition, GSK-3α is required for promoting critical noncanonical NF-κB signaling in pancreatic cancer cells. Pharmacologic inhibition of GSK-3 suppresses growth of human pancreatic tumor explants, consistent with the loss of expression of oncogenic genes such as c-myc and TERT. These data identify GSK-3α as a key downstream effector of oncogenic KRAS via its ability to coordinately regulate distinct NF-κB signaling pathways.
authors.affiliation: Department of Cell and Developmental Biology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
authors.forename: Deepali
authors.initials: D
authors.lastname: Bang
authors.forename: Willie
authors.initials: W
authors.lastname: Wilson
authors.forename: Meagan
authors.initials: M
authors.lastname: Ryan
authors.forename: Jen Jen
authors.initials: JJ
authors.lastname: Yeh
authors.forename: Albert S
authors.initials: AS
authors.lastname: Baldwin
mesh_terms: D000818:Animals; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D015536:Down-Regulation; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras); D015398:Signal Transduction; D014157:Transcription Factors; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D038362:Glycogen Synthase Kinase 3; D047908:Intracellular Signaling Peptides and Proteins; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D014157:Transcription Factors; D018631:ras Proteins; D000099151:MAP Kinase Kinase Kinase 7; C117307:KRAS protein, human; C099510:TAB1 protein, MAPKKK activator, vertebrate; C448021:glycogen synthase kinase 3 alpha
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