Phosphoinositide 3-Kinase Signaling Mediates β-Catenin Activation in Intestinal Epithelial Stem and Progenitor Cells in Colitis

Abstract

Background & Aims Mechanisms responsible for crypt architectural distortion in chronic ulcerative colitis (CUC) are not well understood. Data indicate that Akt signaling cooperates with 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. Acute inflammation was induced in these mice (I-pik3r1KO) and their intestines were analyzed by biochemical and histological methods. The effects of chemically blocking PI3K in colitic IL-10−/− mice were examined. Biopsy samples from patients were examined. Results Compared to wild type mice, I-pik3r1KO mice had reduced T-cell–mediated Akt and β-catenin signaling in intestinal stem and progenitor cells and limited crypt epithelial proliferation. Biochemical analyses indicated that PI3K–Akt signaling increased nuclear total β-catenin and P-β-catenin552 levels and reduced phosphorylation of N-terminal β-catenin, which is associated with degradation. PI3K inhibition in IL-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-catenin552 throughout expanded crypts and increased mRNA expression of β-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 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.

Epithelial Phosphatidylinositol-3-Kinase Signaling Is Required for β-Catenin Activation and Host Defense against Citrobacter rodentium Infection

“…Our data for both human inflammatory bowel disease and experimental IL-10 Ϫ/Ϫ murine colitis (7,32) as well as data reported previously by Fang et al (18) suggest that Ser552 phosphorylation of ␤-catenin stimulates the transcriptional expression of Wnt/␤-catenin target genes. The c-Myc and cyclin D1 genes are Wnt/␤-catenin target genes involved in cell proliferation (23,59).…”

“…Histologic colitis scores were determined by measuring the severity of epithelial ulceration (0, none; 1, epithelial desquamation; 2, erosions with gaps of 1 to 10 IECs; 3, ulcers Ͼ10 IECs long), the extent of inflammatory cell infiltration (0, normal; 1, mild infiltration of the mucosa; 2, moderate to severe infiltration of the mucosa; 3, mild infiltration of the submucosa; 4, moderate to severe infiltration of the submucosa; 5, transmural infiltration into the serosa), and the extent of submucosal edema (0, none; 1, Ͻ200 m; 2, 200 to 450 m; 3, Ͼ450 m). BrdU, P-Akt, and P-␤-catenin 552 immunohistochemical (IHC) staining was performed as previously described (32).…”

Calcium Promotes Human Gastric Cancer via a Novel Coupling of Calcium-Sensing Receptor and TRPV4 Channel

“…Intracellular Ca 2þ can bind to calmodulin and stimulate PI3K/ AKT (33), resulting in subsequent nuclear accumulation of b-catenin, a process that plays a significant role in tumorigenesis (37,38). Targeted deletion of CaSR in intestinal epithelium of mice resulted in hyperplasia and enhanced b-catenin signaling (39), confirming negative effect of CaSR on normal gastrointestinal epithelial growth.…”

Sfrp5 mediates glucose-induced proliferation in rat pancreatic β-cells

“…However, further studies are required to establish the precise mechanisms by which transcriptional factors may be involved in the regulation. Furthermore, Wnt signaling could be modulated by the PI3K/AKT signaling pathway through the regulation of GSK3β phosphorylation and the direct inhibition of β-catenin nuclear localization (Fukumoto et al 2001, Lee et al 2010. Our results indicate another mechanism: in addition to phosphorylated GSK3β, the PI3K/AKT pathway can activate the Wnt pathway by downregulating the expression of the Wnt pathway inhibitor SFRP5.…”