title: A Cytosolic Multiprotein Complex Containing p85α Is Required for β-Catenin Activation in Colitis and Colitis-associated Cancer.
abstract: Wnt/β-catenin signaling is required for crypt structure maintenance. We previously observed nuclear accumulation of Ser-552 phosphorylated β-catenin (pβ-Cat(Ser-552)) in intestinal epithelial cells (IEC) during colitis and colitis-associated cancer. Data here delineate a novel multiprotein cytosolic complex (MCC) involved in β-catenin signaling in the intestine. The MCC contains p85α, the class IA subunit of PI3K, along with β-catenin, 14-3-3ζ, Akt, and p110α. MCC levels in IEC increase in colitis and colitis-associated cancer patients. IEC-specific p85α-deficient (p85(ΔIEC)) mice develop more severe dextran sodium sulfate colitis due to delayed ulcer healing and reduced epithelial β-catenin activation. In colonic IEC, p85α deficiency did not alter PI3K signaling. In vitro shRNA depletion of individual complex members disrupts the MCC and reduces β-catenin signaling. Despite worse colitis, p85(ΔIEC) mice have reduced tumor burden after azoxymethane/dextran sodium sulfate treatment. Together the data indicate that the β-catenin MCC is needed for mucosal repair and carcinogenesis. This novel MCC may be an attractive therapeutic target in preventing cancer in colitis patients.
authors.affiliation: From the Department of Internal Medicine, Division of Gastroenterology, University of Kentucky, Lexington, Kentucky 40536.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Goretsky
authors.affiliation: From the Department of Internal Medicine, Division of Gastroenterology, University of Kentucky, Lexington, Kentucky 40536.
authors.forename: Emily M
authors.initials: EM
authors.lastname: Bradford
authors.affiliation: the Washington University School of Medicine, St. Louis, Missouri 63110.
authors.forename: Hyunji
authors.initials: H
authors.lastname: Ryu
authors.affiliation: From the Department of Internal Medicine, Division of Gastroenterology, University of Kentucky, Lexington, Kentucky 40536.
authors.forename: Maryam
authors.initials: M
authors.lastname: Tahir
authors.affiliation: INCELL Corporation, San Antonio, Texas 78249.
authors.forename: Mary Pat
authors.initials: MP
authors.lastname: Moyer
authors.affiliation: the Markey Cancer Center, University of Kentucky, Lexington, Kentucky 40536, and.
authors.forename: Tianyan
authors.initials: T
authors.lastname: Gao
authors.affiliation: the Stowers Institute for Medical Research, Department of Pathology & Laboratory Medicine, The University of Kansas School of Medicine, Kansas City, Kansas 66160.
authors.forename: Linheng
authors.initials: L
authors.lastname: Li
authors.affiliation: From the Department of Internal Medicine, Division of Gastroenterology, University of Kentucky, Lexington, Kentucky 40536, t.barrett@uky.edu.
authors.forename: Terrence A
authors.initials: TA
authors.lastname: Barrett
mesh_terms: D000818:Animals; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism*; D003092:Colitis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D046912:Multiprotein Complexes; D009363:Neoplasm Proteins; D051176:beta Catenin; D058543:Class Ia Phosphatidylinositol 3-Kinase
keywords: beta-catenin (B-catenin); colitis; colorectal cancer; phosphatidylinositide 3-kinase (PI 3-kinase); signal transduction; stem cells; β-catenin