Tissue transglutaminase regulates β‐catenin signaling through a c‐Src‐dependent mechanism
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Abstract:
Tissue transglutaminase (TG2) is a multifunctional enzyme involved in protein cross-linking and cell adhesion to fibronectin (FN). In cancer, TG2 induces an epithelial to mesenchymal transition, contributing to metastasis. Because cadherins bind β-catenin at cell-cell junctions, disruption of adherens junctions destabilizes cadherin-catenin complexes. The goal of the present study was to analyze whether and how TG2 interacts with and regulates β-catenin signaling in ovarian cancer (OC) cells. We observed a significant correlation between TG2 and β-catenin expression levels in OC cells and tumors. TG2 augmented Wnt/β-catenin signaling, as evidenced by enhanced β-catenin transcriptional activity, inducing transcription of target genes cyclin D1 and c-Myc. By promoting integrin-mediated cell adhesion to FN, TG2 physically associates with and recruits c-Src, which in turn phosphorylates β-catenin at Tyr(654), releasing it from E-cadherin and rendering it available for transcriptional regulation. By interacting with FN and enhancing β-catenin signaling, complexed TG2 stimulates OC cell proliferation. In summary, our data demonstrate that TG2 regulates β-catenin expression and function in OC cells and define the c-Src-dependent mechanism through which this occurs.Keywords:
Adherens junction
Beta-catenin
Adherens junction
Nectin
Cell–cell interaction
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VE-cadherin
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Adherens junction
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Capillary endothelial cells express Vascular Endothelial (VE)‐ and Neural (N)‐cadherin, with overlapping functions. VE‐cadherin forms homotypic adhesion between endothelial cells whereas N‐cadherin forms heterotypic adhesion with the surrounding pericytes in capillary endothelia. Endothelial specific deletions of Cdh2 (N‐cadherin) or Cdh5 (VE‐cadherin) in mice demonstrated poorly formed leaky capillaries and in utero death at E9.5 due to defective angiogenesis. These findings raise the question of whether N‐ and VE‐cadherin function independently or whether N‐cadherin activated signaling regulates the assembly of VE‐cadherin and thereby the formation of adherens junctions. We investigated the role of N‐cadherin in the formation of VE‐cadherin junctions using mouse genetic models and identifying N‐cadherin signaling pathways in endothelial monolayers. We show that N‐cadherin functions by interacting with the RhoGEF Trio to activate the RhoGTPases Rac1 and RhoA in nascent adherens junctions, inducing the recruitment of VE‐cadherin. This N‐cadherin activated signaling pathway is essential for maximal VE‐cadherin assembly and the formation of the endothelial junctional barrier. Support or Funding Information Supported by NIH grant R01 HL103922 to Y.A.K.; AHA AWARD 16PRE27260230 to K.K. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
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Invasion and metastasis are main characters in malignant tumor,which include several mechanisms.E-cadherin,beta-catenin and E-cadherin/catenin complex were related to the invasion and metastasis of tumor.This paper will review the relationship between the E-cadherin,beta-catenin and E-cadherin/cateninComplex in occurrence and progression of tumor.
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The mechanism that coordinates different adhesion receptors is poorly understood. We investigated this mechanism by focusing on the nectin-2 and E-cadherin adherens junction receptors. Cadherin is not required for the basic process of nectin junction formation since nectin-2 forms junctions in cadherin-deficient A431D cells. Formation of nectin junctions in these cells, however, becomes regulated by cadherin as soon as E-cadherin is reconstituted. E-cadherin recruits nectin-2 into adherens junctions, where both proteins form distinct but tightly associated clusters. Live-cell imaging showed that the appearance of cadherin clusters often precedes that of nectin clusters at sites of junction assembly. Inactivation of cadherin clustering by different strategies concomitantly suppresses the formation of nectin clusters. Furthermore, cadherin significantly increases the stability of nectin clusters, thereby making them resistant to the BC-12 antibody, which targets the nectin-2 adhesion interface. By testing different cadherin-α-catenin chimeras, we showed that the recruitment of nectin into chimera junctions is mediated by the actin-binding domain of α-catenin. Our data suggests that cadherin regulates-assembly of nectin junctions through α-catenin-induced remodeling of the actin cytoskeleton around the cadherin clusters.
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