Phosphoinositide 3-kinase Signaling Mediates Beta-Catenin Activation in Intestinal Epithelial Stem and Progenitor Cells in Colitis

Gastroenterology. 2010 Sep;139(3):869-81, 881.e1-9. doi: 10.1053/j.gastro.2010.05.037. Epub 2010 May 24.

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 beta-catenin in intestinal stem and progenitor cells through phosphorylation at Ser552 (P-beta-catenin(552)). We investigated whether phosphoinositide 3-kinase (PI3K) is required for Akt-mediated activation of beta-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-cell-mediated Akt and beta-catenin signaling in intestinal stem and progenitor cells and limited crypt epithelial proliferation. Biochemical analyses indicated that PI3K-Akt signaling increased nuclear total beta-catenin and P-beta-catenin(552) levels and reduced N-terminal beta-catenin phosphorylation, which is associated with degradation. PI3K inhibition in interleukin-10(-/-) mice impaired colitis-induced epithelial Akt and beta-catenin activation, reduced progenitor cell expansion, and prevented dysplasia. Human samples had increased numbers of progenitor cells with P-beta-catenin(552) throughout expanded crypts and increased messenger RNA expression of beta-catenin target genes in CUC, colitis-associated cancer, tubular adenomas, and sporadic colorectal cancer, compared with control samples.

Conclusions: PI3K-Akt signaling cooperates with Wnt to increase beta-catenin signaling during inflammation. PI3K-induced and Akt-mediated beta-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.

Publication types

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

MeSH terms

  • Animals
  • Biopsy
  • Cell Proliferation
  • Colitis / complications
  • Colitis / enzymology*
  • Colitis / genetics
  • Colitis / immunology
  • Colitis / pathology
  • Colon / drug effects
  • Colon / enzymology*
  • Colon / immunology
  • Colon / pathology
  • Colonic Neoplasms / enzymology
  • Colonic Neoplasms / pathology
  • Colonoscopy
  • Disease Models, Animal
  • Humans
  • Interleukin-10 / deficiency
  • Interleukin-10 / genetics
  • Intestinal Mucosa / drug effects
  • Intestinal Mucosa / enzymology*
  • Intestinal Mucosa / immunology
  • Intestinal Mucosa / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phosphatidylinositol 3-Kinases / deficiency
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction* / drug effects
  • Stem Cells / drug effects
  • Stem Cells / enzymology*
  • Stem Cells / immunology
  • Stem Cells / pathology
  • T-Lymphocytes / enzymology
  • T-Lymphocytes / immunology
  • Time Factors
  • Wnt Proteins / metabolism
  • beta Catenin / metabolism*

Substances

  • CTNNB1 protein, human
  • CTNNB1 protein, mouse
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • Wnt Proteins
  • beta Catenin
  • Interleukin-10
  • Proto-Oncogene Proteins c-akt