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      RhoG regulates endothelial apical cup assembly downstream from ICAM1 engagement and is involved in leukocyte trans-endothelial migration

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          Abstract

          During trans-endothelial migration (TEM), leukocytes use adhesion receptors such as intercellular adhesion molecule-1 (ICAM1) to adhere to the endothelium. In response to this interaction, the endothelium throws up dynamic membrane protrusions, forming a cup that partially surrounds the adherent leukocyte. Little is known about the signaling pathways that regulate cup formation. In this study, we show that RhoG is activated downstream from ICAM1 engagement. This activation requires the intracellular domain of ICAM1. ICAM1 colocalizes with RhoG and binds to the RhoG-specific SH3-containing guanine-nucleotide exchange factor (SGEF). The SH3 domain of SGEF mediates this interaction. Depletion of endothelial RhoG by small interfering RNA does not affect leukocyte adhesion but decreases cup formation and inhibits leukocyte TEM. Silencing SGEF also results in a substantial reduction in RhoG activity, cup formation, and TEM. Together, these results identify a new signaling pathway involving RhoG and its exchange factor SGEF downstream from ICAM1 that is critical for leukocyte TEM.

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          Most cited references 30

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          GEF means go: turning on RHO GTPases with guanine nucleotide-exchange factors.

          Guanine nucleotide-exchange factors (GEFs) are directly responsible for the activation of Rho-family GTPases in response to diverse extracellular stimuli, and ultimately regulate numerous cellular responses such as proliferation, differentiation and movement. With 69 distinct homologues, Dbl-related GEFs represent the largest family of direct activators of Rho GTPases in humans, and they activate Rho GTPases within particular spatio-temporal contexts. The failure to do so can have significant consequences and is reflected in the aberrant function of Dbl-family GEFs in some human diseases.
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            A transmigratory cup in leukocyte diapedesis both through individual vascular endothelial cells and between them

            The basic route and mechanisms for leukocyte migration across the endothelium remain poorly defined. We provide definitive evidence for transcellular (i.e., through individual endothelial cells) diapedesis in vitro and demonstrate that virtually all, both para- and transcellular, diapedesis occurs in the context of a novel “cuplike” transmigratory structure. This endothelial structure was comprised of highly intercellular adhesion molecule-1– and vascular cell adhesion molecule-1–enriched vertical microvilli-like projections that surrounded transmigrating leukocytes and drove redistribution of their integrins into linear tracks oriented parallel to the direction of diapedesis. Disruption of projections was highly correlated with inhibition of transmigration. These findings suggest a novel mechanism, the “transmigratory cup”, by which the endothelium provides directional guidance to leukocytes for extravasation.
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              Leukocyte-endothelial-cell interactions in leukocyte transmigration and the inflammatory response.

              Both the innate and adaptive immune responses are dependent on the migration of leukocytes across endothelial cells. The process of diapedesis, in which the leukocyte crawls between tightly apposed endothelial cells, is a unique and complex process. Several molecules concentrated at the junctions of endothelial cells, originally described as having a role in holding the endothelial monolayer together, have also been shown to have a role in the emigration of leukocytes. Several mechanisms have been proposed for 'loosening' the junctions between endothelial cells to enable leukocyte passage. These leukocyte-endothelial-cell adhesion molecules are probably involved in regulating the signaling as well as the adhesion events of diapedesis. In addition, this Review introduces a new and unified nomenclature for the junctional adhesion molecule (JAM) family.
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                Author and article information

                Affiliations
                [1 ]Department of Cell and Developmental Biology and [2 ]Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599
                [3 ]Cardiovascular Research Center and [4 ]Department of Microbiology, Mellon Prostate Cancer Institute, University of Virginia, Charlottesville, VA 22908
                Author notes

                Correspondence to Jaap D. van Buul: j.vanbuul@ 123456sanquin.nl ; or Keith Burridge: keith_burridge@ 123456med.unc.edu

                Journal
                J Cell Biol
                jcb
                The Journal of Cell Biology
                The Rockefeller University Press
                0021-9525
                1540-8140
                24 September 2007
                : 178
                : 7
                : 1279-1293
                2064659
                200612053
                10.1083/jcb.200612053
                17875742
                Copyright © 2007, The Rockefeller University Press
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                Cell biology

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