J Biol Chem. 2016 Feb 19;291(8):4166-77. doi: 10.1074/jbc.M115.669416.
A Cytosolic Multiprotein Complex Containing p85α Is Required for β-Catenin Activation in Colitis and Colitis-associated Cancer.
- 1From the Department of Internal Medicine, Division of Gastroenterology, University of Kentucky, Lexington, Kentucky 40536.
- 2the Washington University School of Medicine, St. Louis, Missouri 63110.
- 3INCELL Corporation, San Antonio, Texas 78249.
- 4the Markey Cancer Center, University of Kentucky, Lexington, Kentucky 40536, and.
- 5the Stowers Institute for Medical Research, Department of Pathology & Laboratory Medicine, The University of Kansas School of Medicine, Kansas City, Kansas 66160.
- 6From the Department of Internal Medicine, Division of Gastroenterology, University of Kentucky, Lexington, Kentucky 40536, email@example.com.
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.
KEYWORDS: beta-catenin (B-catenin); colitis; colorectal cancer; phosphatidylinositide 3-kinase (PI 3-kinase); signal transduction; stem cells; β-catenin