A Cytosolic Multiprotein Complex Containing p85α is Required for β-Catenin Activation in Colitis and Colitis-Associated Cancer

Authors

Tatiana Goretsky, University of KentuckyFollow
Emily M. Bradford, University of KentuckyFollow
Hyunji Ryu, Washington University
Maryam Tahir, University of Kentucky
Mary Pat Moyer, INCELL Corporation
Tianyan Gao, University of KentuckyFollow
Linheng Li, The University of Kansas
Terrence A. Barrett, University of KentuckyFollow

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.

Document Type

Article

Publication Date

11-12-2015

Notes/Citation Information

Published in Journal of Biological Chemistry, v. 291, no. 8, p. 4166-4177.

This research was originally published in the Journal of Biological Chemistry. Goretsky, T., Bradford, E., Ryu, H., Tahir, M., Moyer, M., Gao, T., Li, L., and Barrett, T. A Cytosolic Multiprotein Complex Containing p85α Is Required for β-Catenin Activation in Colitis and Colitis-associated Cancer. J. Biol. Chem. 2015; 291: 4166-4177. © 2016 by the American Society for Biochemistry and Molecular Biology, Inc.

The copyright holder has granted the permission for posting the article here.

Digital Object Identifier (DOI)

https://doi.org/10.1074/jbc.M115.669416

Funding Information

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.

Repository Citation

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.
https://uknowledge.uky.edu/internalmedicine_facpub/106