title: Integrins regulate VE-cadherin and catenins: dependence of this regulation on Src, but not on Ras.
abstract: Adhesions of cells to extracellular matrix and adjacent cells are mediated by integrins and VE-cadherin, respectively. Although these adhesion processes play crucial roles in vascular cell migration and angiogenesis, it remains unclear as to how they are coordinated to regulate cellular functions. We report here that integrin engagement by treating bovine endothelial aortic cell monolayers with beads coated with fibronectin (Fn) led to disruption of the VE-cadherin-containing adherens junctions. This disruption was accompanied by increases of tyrosine phosphorylation of beta-catenin, gamma-catenin, and p120ctn, as well as the dissociation of alpha-catenin and gamma-catenin from VE-cadherin. We applied a membrane-targeted Src reporter based on the fluorescence resonance energy transfer technique to visualize the dynamic Src activation at subcellular levels in live cells. The integrin engagement induced by Fn-coated beads caused the activation of Src around the beads and at adherens junctions, which are subsequently disrupted. The inhibition of Src with PP1 blocked the effects of integrin engagement on adherens junctions. Although Ras can also modulate adherens junctions, the resulting patterns of phosphorylation and association of junction proteins were distinct from those induced by integrin engagement. The inhibition of Ras by RasN17 did not rescue the disruption of adherens junctions induced by integrin engagement or by Src activation. Integrin engagement by Fn-coated beads also induced a significant alteration of cortical actin filaments at adherens junctions. The results indicate that integrin engagement disrupts VE-cadherin-containing adherens junctions via the activation of Src, but not Ras, possibly as a result of modulation of the actin network.
authors.affiliation: Department of Bioengineering, The Whitaker Institute of Biomedical Engineering, University of California at San Diego, La Jolla, CA 92093, USA.
authors.forename: Yingxiao
authors.initials: Y
authors.lastname: Wang
authors.forename: Gang
authors.initials: G
authors.lastname: Jin
authors.forename: Hui
authors.initials: H
authors.lastname: Miao
authors.forename: Julie Y-S
authors.initials: JY
authors.lastname: Li
authors.forename: Shunichi
authors.initials: S
authors.lastname: Usami
authors.forename: Shu
authors.initials: S
authors.lastname: Chien
mesh_terms: D000199:Actins / Q000378:metabolism; D022005:Adherens Junctions / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD; D015820:Cadherins / Q000378:metabolism*; D051177:Catenins / Q000378:metabolism*; D002417:Cattle; D002478:Cells, Cultured; D016023:Integrins / Q000378:metabolism*; D008024:Ligands; D011485:Protein Binding; D018631:ras Proteins / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism*; D000099152:Cadherin 5
chemical_list: D000199:Actins; D015703:Antigens, CD; D015820:Cadherins; D051177:Catenins; D016023:Integrins; D008024:Ligands; D018631:ras Proteins; D019061:src-Family Kinases; D000099152:Cadherin 5