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J Biol Chem. 2016 Feb 19;291(8):4166-77. doi: 10.1074/jbc.M115.669416. Epub 2015 Nov 12.

A Cytosolic Multiprotein Complex Containing p85α Is Required for β-Catenin Activation in Colitis and Colitis-associated Cancer.

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From the Department of Internal Medicine, Division of Gastroenterology, University of Kentucky, Lexington, Kentucky 40536.
the Washington University School of Medicine, St. Louis, Missouri 63110.
INCELL Corporation, San Antonio, Texas 78249.
the Markey Cancer Center, University of Kentucky, Lexington, Kentucky 40536, and.
the Stowers Institute for Medical Research, Department of Pathology & Laboratory Medicine, The University of Kansas School of Medicine, Kansas City, Kansas 66160.
From the Department of Internal Medicine, Division of Gastroenterology, University of Kentucky, Lexington, Kentucky 40536,


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.


beta-catenin (B-catenin); colitis; colorectal cancer; phosphatidylinositide 3-kinase (PI 3-kinase); signal transduction; stem cells; β-catenin

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