Phosphoinositide 3-kinase signaling mediates beta-catenin activation in intestinal epithelial stem and progenitor cells in colitis.
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.
Lee
Goo
G
Department of Internal Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Goretsky
Tatiana
T
Managlia
Elizabeth
E
Dirisina
Ramanarao
R
Singh
Ajay Pal
AP
Brown
Jeffrey B
JB
May
Randal
R
Yang
Guang-Yu
GY
Ragheb
Josette William
JW
Evers
B Mark
BM
Weber
Christopher R
CR
Turner
Jerrold R
JR
He
Xi C
XC
Katzman
Rebecca B
RB
Li
Linheng
L
Barrett
Terrence A
TA
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*
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