A Cytosolic Multiprotein Complex Containing p85α Is Required for β-Catenin Activation in Colitis and Colitis-associated Cancer

Abstract

Wnt/␤-catenin signaling is required for crypt structure maintenance. We previously observed nuclear accumulation of Ser-552 phosphorylated ␤-catenin (p␤-Cat Ser-552 ) in intestinal epithelial cells (IEC) during colitis and colitis-associated cancer. Data here delineate a novel multiprotein cytosolic complex (MCC) involved in ␤-catenin signaling in the intestine. The MCC contains p85␣, the class IA subunit of PI3K, along with ␤-catenin, 14-3-3, Akt, and p110␣. MCC levels in IEC increase in colitis and colitis-associated cancer patients. IEC-specific p85␣-deficient (p85 ⌬IEC ) mice develop more severe dextran sodium sulfate colitis due to delayed ulcer healing and reduced epithelial ␤-catenin activation. In colonic IEC, p85␣ deficiency did not alter PI3K signaling. In vitro shRNA depletion of individual complex members disrupts the MCC and reduces ␤-catenin signaling. Despite worse colitis, p85 ⌬IEC mice have reduced tumor burden after azoxymethane/dextran sodium sulfate treatment. Together the data indicate that the ␤-catenin MCC is needed for mucosal repair and carcinogenesis. This novel MCC may be an attractive therapeutic target in preventing cancer in colitis patients.

Upregulated claudin-1 expression promotes colitis-associated cancer by promoting β-catenin phosphorylation and activation in Notch/p-AKT-dependent manner

“…The dysregulation of β-Catenin homeostasis is a key indicator of the hyperactive Wnt signaling (15), and β-Catenin is a mutational target in colitis-associated carcinogenesis, based on its increased expression and altered subcellular distribution (11). We have previously demonstrated a cross talk between Cld-1 and the Wnt-signaling (6).…”

“…It was however interesting that it was β-Catenin ser552-phosphorylation that was impacted in Cld-1Tg mice when subjected to colitis. Of note, recent studies have highlighted the essential role of this signaling mechanism in colitis-associated injury/repair and colon carcinogenesis (11, 26). Our findings that the Wnt/β-Catenin Ser552 signaling was upregulated even in colon cancer cells overexpressing Cld-1 suggests an epithelial cell intrinsic effect of the upregulated Cld-1 levels upon Wnt/β-catenin signaling.…”

“…Accordingly, deregulated β-catenin signaling promotes colon cancer (9, 10). In colitis-associated regeneration and/or CAC, upregulated expression and nuclear accumulation of Ser-552 phosphorylated β-Catenin (p-β-Cat S552 ) has been found to be of prime importance (11). A cross-talk between Cld-1 and β-Catenin has been reported previously by our lab and of others (5, 12, 13).…”

Transducin (β)-like 1 X-linked receptor 1 promotes gastric cancer progression via the ERK1/2 pathway

“…34, 35, 36 Recent findings indicated that TBL1XR1 and β-catenin can recruit each other to Wnt target gene promoters to facilitate transcriptional activation and oncogenesis. 10 TBL1XR1 can promote the EMT of tumour cells via activating β-catenin signalling.…”

Cherry Polyphenol Extract Ameliorated Dextran Sodium Sulfate-Induced Ulcerative Colitis in Mice by Suppressing Wnt/β-Catenin Signaling Pathway

“…When the active Wnt ligand was absent, β-catenin would bind to Axin (the scaffold proteins axis inhibition protein) and APC (adenomatosis polyposis coli), and interact with GSK-3β leading to the phosphorylation of four n-terminal residues of β-catenin ( Figure 10 ). The phosphorylated β-catenin controlled by APC, GSK-3β, Axin2, and CK1 (casein kinase 1) was a target for ubiquitination and proteosomal degradation [ 65 ]. When the Wnt ligand was present, β-catenin would bind to membrane receptor frizzled (FZD) and the low-density lipoprotein receptor-related protein (LRP), leading to the cytoplasmic LRP phosphorylation by GSK-3β, which further caused the aggregation of cytoplasmic proteins, Dishevelled (Dvl) and Axin, and then the β-catenin phosphorylation and protein degradation were inhibited [ 64 ].…”