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      Mutational Evidence for Control of Cell Adhesion Through Integrin Diffusion/Clustering, Independent of Ligand Binding

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          Abstract

          Previous studies have shown that integrin α chain tails make strong positive contributions to integrin-mediated cell adhesion. We now show here that integrin α 4 tail deletion markedly impairs static cell adhesion by a mechanism that does not involve altered binding of soluble vascular cell adhesion molecule 1 ligand. Instead, truncation of the α 4 cytoplasmic domain caused a severe deficiency in integrin accumulation into cell surface clusters, as induced by ligand and/ or antibodies. Furthermore, α 4 tail deletion also significantly decreased the membrane diffusivity of α 4β 1, as determined by a single particle tracking technique. Notably, low doses of cytochalasin D partially restored the deficiency in cell adhesion seen upon α 4 tail deletion. Together, these results suggest that α 4 tail deletion exposes the β 1 cytoplasmic domain, leading to cytoskeletal associations that apparently restrict integrin lateral diffusion and accumulation into clusters, thus causing reduced static cell adhesion. Our demonstration of integrin adhesive activity regulated through receptor diffusion/clustering (rather than through altered ligand binding affinity) may be highly relevant towards the understanding of inside–out signaling mechanisms for β 1 integrins.

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          Most cited references41

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          Integrins: emerging paradigms of signal transduction.

          Integrins receive signals from other receptors that lead to activation of ligand binding (inside-out signaling) and matrix assembly. Upon binding ligands, they also activate intracellular signaling pathways. These signals converse with pathways that are initiated by soluble ligands to regulate cell functions. In this way, cell adhesion is coordinated with other events to orchestrate complex cellular behavior.
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            VCAM-1 on activated endothelium interacts with the leukocyte integrin VLA-4 at a site distinct from the VLA-4/fibronectin binding site.

            Cytokine-activated human endothelial cells express vascular cell adhesion molecule-1 (VCAM-1), which binds lymphocytes. We now identify the integrin VLA-4 as a receptor for VCAM-1 because VLA-4 surface expression on K-562 cells (following transfection of the VLA alpha 4 subunit cDNA) resulted in specific cell adhesion to VCAM-1, and anti-VLA-4 antibodies completely inhibited VCAM-1-dependent cell-cell attachment. In addition, VLA-4 expression allowed K-562 cells to attach to the heparin II binding region (FN-40) of fibronectin. However, VLA-4/VCAM-1 and VLA-4/FN-40 interactions are readily distinguishable: only the former was inhibited by the anti-VLA-4 monoclonal antibody HP1/3, and only the latter was inhibited by soluble FN-40. The VCAM-1/VLA-4 ligand-receptor pair may play a major role in the recruitment of mononuclear leukocytes to inflammatory sites in vivo.
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              The integrin VLA-4 supports tethering and rolling in flow on VCAM-1

              Selectins have previously been shown to tether a flowing leukocyte to a vessel wall and mediate rolling. Here, we report that an intergrin, VLA- 4, can also support tethering and rolling. Blood T lymphocytes and alpha 4 integrin-transfected cells can tether in shear flow, and then roll, through binding of the intergrin VLA-4 to purified VCAM-1 on the wall of a flow chamber. VLA-4 transfectants showed similar tethering and rolling on TNF-stimulated endothelium. Tethering efficiency, rolling velocity, and resistance to detachment are related to VCAM-1 density. Tethering and rolling did not occur on ICAM-1, fibronectin, or fibronectin fragments, and tethering did not require integrin activation or the presence of an alpha 4 cytoplasmic domain. Arrest of rolling cells on VCAM-1 occurred spontaneously, and/or was triggered by integrin activating agents Mn2+, phorbol ester, and mAb TS2/16. These agents, and the alpha 4 cytoplasmic domain, promoted increased resistance to detachment. Together the results show that VLA-4 is a versatile integrin that can mediate tethering, rolling, and firm arrest on VCAM-1.
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                Author and article information

                Journal
                J Exp Med
                The Journal of Experimental Medicine
                The Rockefeller University Press
                0022-1007
                1540-9538
                20 October 1997
                : 186
                : 8
                : 1347-1355
                Affiliations
                From the [* ]Division of Tumor Virology, and the []Division of Molecular and Cellular Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115; and the [§ ]Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710
                Author notes

                Address correspondence to Martin E. Hemler, Rm. M-613, Dana-Farber Cancer Institute, 44 Binney St., Boston, MA 02115.

                Article
                10.1084/jem.186.8.1347
                2199079
                9334374
                dd42d601-7931-4925-9409-f5bdbed493e2
                Copyright @ 1997
                History
                : 26 November 1996
                : 11 July 1997
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                Medicine
                Medicine

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