Phosphoinositide 3-kinase signaling mediates β-catenin activation in intestinal epithelial stem and progenitor cells in colitis

Goo Lee, Tatiana Goretsky, Elizabeth Managlia, Ramanarao Dirisina, Ajay Pal Singh, Jeffrey B. Brown, Randal May, Guangyu Yang, Josette William Ragheb, B. Mark Evers, Christopher R. Weber, Jerrold R. Turner, Xi C. He, Rebecca B. Katzman, Linheng Li, Terrence A. Barrett

Research output: Contribution to journalArticlepeer-review

112 Scopus citations

Abstract

Background & Aims: Mechanisms responsible for crypt architectural distortion in chronic ulcerative colitis (CUC) are not well understood. Data indicate that serine/threonine protein kinase Akt (Akt) signaling cooperates with Wingless (Wnt) to activate β-catenin in intestinal stem and progenitor cells through phosphorylation at Ser552 (P-β-catenin552). We investigated whether phosphoinositide 3-kinase (PI3K) is required for Akt-mediated activation of β-catenin during intestinal inflammation. Methods: The class IA subunit of PI3K was conditionally deleted from intestinal epithelial cells in mice named I-pik3r1KO. Acute inflammation was induced in mice and intestines were analyzed by biochemical and histologic methods. The effects of chemically blocking PI3K in colitic interleukin-10-/- mice were examined. Biopsy samples from patients were examined. Results: Compared with wild-type, I-pik3r1KO mice had reduced T-cellmediated Akt and β-catenin signaling in intestinal stem and progenitor cells and limited crypt epithelial proliferation. Biochemical analyses indicated that PI3KAkt signaling increased nuclear total β-catenin and P-β-catenin 552 levels and reduced N-terminal β-catenin phosphorylation, which is associated with degradation. PI3K inhibition in interleukin-10 -/- mice impaired colitis-induced epithelial Akt and β-catenin activation, reduced progenitor cell expansion, and prevented dysplasia. Human samples had increased numbers of progenitor cells with P-β-catenin 552 throughout expanded crypts and increased messenger RNA expression of β-catenin target genes in CUC, colitis-associated cancer, tubular adenomas, and sporadic colorectal cancer, compared with control samples. Conclusions: PI3KAkt signaling cooperates with Wnt to increase β-catenin signaling during inflammation. PI3K-induced and Akt-mediated β-catenin signaling are required for progenitor cell activation during the progression from CUC to CAC; these factors might be used as biomarkers of dysplastic transformation in the colon.

Original languageEnglish (US)
Pages (from-to)869-881.e9
JournalGastroenterology
Volume139
Issue number3
DOIs
StatePublished - Sep 2010

Keywords

  • Intestinal Progenitor Cells
  • Intestinal Stem Cells
  • PI3K
  • Pik3r1

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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