Overexpression of CD97 in Intestinal Epithelial Cells of Transgenic Mice Attenuates Colitis by Strengthening Adherens Junctions

Abstract

The adhesion G-protein-coupled receptor CD97 is present in normal colonic enterocytes but overexpressed in colorectal carcinoma. To investigate the function of CD97 in colorectal carcinogenesis, transgenic Tg(villin-CD97) mice overexpressing CD97 in enterocytes were generated and subjected to azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colitis-associated tumorigenesis. Unexpectedly, we found a CD97 cDNA copy number-dependent reduction of DSS-induced colitis in Tg compared to wild-type (WT) mice that was confirmed by applying a simple DSS protocol. Ultrastructural analysis revealed that overexpression of CD97 strengthened lateral cell-cell contacts between enterocytes, which, in contrast, were weakened in CD97 knockout (Ko) mice. Transepithelial resistance was not altered in Tg and Ko mice, indicating that tight junctions were not affected. In Tg murine and normal human colonic enterocytes as well as in colorectal cell lines CD97 was localized preferentially in E-cadherin-based adherens junctions. CD97 overexpression upregulated membrane-bound but not cytoplasmic or nuclear β-catenin and reduced phospho-β-catenin, labeled for degradation. This was associated with inactivation of glycogen synthase kinase-3β (GSK-3β) and activation of Akt. In summary, CD97 increases the structural integrity of enterocytic adherens junctions by increasing and stabilizing junctional β-catenin, thereby regulating intestinal epithelial strength and attenuating experimental colitis.

Shear Stress–Dependent Downregulation of the Adhesion-G Protein–Coupled Receptor CD97 on Circulating Leukocytes upon Contact with Its Ligand CD55

“…Recent in vitro and in vivo studies with epithelial cells overexpressing CD97 have started to shed light on the signaling properties of the receptor. First, Becker et al (22) and coworkers demonstrated an increase in membraneassociated b-catenin owing to PKB/Akt-GSK-3b signaling in transgenic Villin-Cd97 mice that overexpress CD97 in intestinal epithelial cells. Second, Kelly et al (24) showed that in prostate cancer cells, CD97 signals through ERK, PKB/Akt, and RhoA activation.…”

“…Recent studies demonstrated that ectopic overexpression of CD97 in fibroblasts and epithelial cells, and constitutive expression of CD97 in prostate cancer cells stimulates ERK, protein kinase B (PKB)/Akt, and RhoA activation (22,24). To explore the possibility that interaction with its ligand CD55 activates CD97 in leukocytes, we incubated CD55-deficient splenocytes with wildtype erythrocytes under rigorous agitation as described above.…”

“…Subsequently identified aGPCR ligands were dermatan sulfate, a5b1 integrin, tissue transglutaminase 2, phosphatidylserine, LPS, C1q, lasso/teneurin-2, collagen III, and Thy-1/CD90 (12)(13)(14)(15)(16)(17)(18)(19)(20). Evidence was obtained that aGPCRs have a role in cell positioning and tissue organization in various organ systems (21,22); however, in the strictest sense, aGPCRs are still functional orphans. The main problem is a lack of understanding of how these atypical GPCRs are activated.…”

F4/80 and the related adhesion‐GPCRs

“…Please refer to [31,43] for more details. matrix contacts, a concept that fits with the presumed activity of other adhesion-GPCRs in the positioning and guidance of cells in different organ systems [38].…”

CD97 is a multifunctional leukocyte receptor with distinct roles in human cancers

“…Within enterocytes, CD97 is an important mediator of E-cadherinbased adherens junctions, thus playing an important role in maintaining the integrity of the intestinal epithelium (58). Becker et al showed that CD97 participates in regulating the localization and stability of β-catenin, which is critical for the maintaining adherens junctions (58). The cellular distribution of β-catenin is important since it can translocate into the nucleus and induce expression of pro-oncogenic genes (59).…”