title: Phosphoinositide 3-kinase signaling mediates beta-catenin activation in intestinal epithelial stem and progenitor cells in colitis.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Internal Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Goo
authors.initials: G
authors.lastname: Lee
authors.forename: Tatiana
authors.initials: T
authors.lastname: Goretsky
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Managlia
authors.forename: Ramanarao
authors.initials: R
authors.lastname: Dirisina
authors.forename: Ajay Pal
authors.initials: AP
authors.lastname: Singh
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Brown
authors.forename: Randal
authors.initials: R
authors.lastname: May
authors.forename: Guang-Yu
authors.initials: GY
authors.lastname: Yang
authors.forename: Josette William
authors.initials: JW
authors.lastname: Ragheb
authors.forename: B Mark
authors.initials: BM
authors.lastname: Evers
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Weber
authors.forename: Jerrold R
authors.initials: JR
authors.lastname: Turner
authors.forename: Xi C
authors.initials: XC
authors.lastname: He
authors.forename: Rebecca B
authors.initials: RB
authors.lastname: Katzman
authors.forename: Linheng
authors.initials: L
authors.lastname: Li
authors.forename: Terrence A
authors.initials: TA
authors.lastname: Barrett
mesh_terms: D000818:Animals; D001706:Biopsy; D049109:Cell Proliferation; D003092:Colitis / Q000150:complications / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D003106:Colon / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D003110:Colonic Neoplasms / Q000201:enzymology / Q000473:pathology; D003113:Colonoscopy; D004195:Disease Models, Animal; D006801:Humans; D016753:Interleukin-10 / Q000172:deficiency / Q000235:genetics; D007413:Intestinal Mucosa / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013234:Stem Cells / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology; D013997:Time Factors; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D016753:Interleukin-10; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D051153:Wnt Proteins; D051176:beta Catenin; C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse