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

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


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Class Ia Phosphatidylinositol 3-Kinase / genetics
  • Class Ia Phosphatidylinositol 3-Kinase / metabolism*
  • Colitis / genetics
  • Colitis / metabolism*
  • Colitis / pathology
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / metabolism*
  • Colonic Neoplasms / pathology
  • Humans
  • Mice
  • Mice, Transgenic
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism*
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Signal Transduction*
  • beta Catenin / genetics
  • beta Catenin / metabolism*


  • Multiprotein Complexes
  • Neoplasm Proteins
  • beta Catenin
  • Class Ia Phosphatidylinositol 3-Kinase