Wnt/β-catenin signaling is required for crypt structure maintenance. We previously observed nuclear accumulation of Ser-552 phosphorylated β-catenin (pβ-CatSer-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 (p85ΔIEC) 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, p85ΔIEC 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.
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This work was supported by National Institutes of Health Grant 2R01DK095662-06A1 (to T. A. B.).
Tissue processing was supported by an Institutional Development Award (IDA) from the NIGMS of the National Institutes of Health under Grant 8 P20 GM103527-05.
Goretsky, Tatiana; Bradford, Emily M.; Ryu, Hyunji; Tahir, Maryam; Moyer, Mary Pat; Gao, Tianyan; Li, Linheng; and Barrett, Terrence A., "A Cytosolic Multiprotein Complex Containing p85α is Required for β-Catenin Activation in Colitis and Colitis-Associated Cancer" (2015). Internal Medicine Faculty Publications. 106.