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RGS10 restricts upregulation by chemokines of T cell adhesion mediated by α4β1 and αLβ2 Integrins.

AuthorsGarcía-Bernal, David ; Dios-Esponera, Ana ; Sotillo-Mallo, Elena; García-Verdugo, Rosa; Arellano-Sánchez, Nohemí ; Teixidó, Joaquín
Issue Date1-Aug-2011
PublisherAmerican Association of Immunologists
CitationJournal of Immunology 187(3):1264-72(2011)
AbstractChemokines rapidly and transiently upregulate α4β1 and αLβ2 integrin-mediated adhesion during T lymphocyte extravasation by activating Gα-dependent inside-out signaling. To limit and terminate Gα-mediated signaling, cells can use several mechanisms, including the action of regulator of G protein signaling (RGS) proteins, which accelerate the GTPase activity of Gα subunits. Using human T cells silenced for or overexpressing RGS10, we show in this article that RGS10 functions as an inhibitor of Gαi-dependent, chemokine-upregulated T cell adhesion mediated by α4β1 and αLβ2. Shear stress-dependent detachment and cell spreading analyses revealed that RGS10 action mainly targets the adhesion strengthening and spreading phases of α4β1-mediated cell attachment. Associated with these observations, chemokine-stimulated Vav1–Rac1 activation was longer sustained and of higher intensity in RGS10-silenced T cells, or inhibited in cells overexpressing RGS10. Of importance, expression of constitutively activated Rac1 forms in cells overexpressing RGS10 led to the rescue of CXCL12-stimulated adhesion to VCAM-1 to levels similar to those in control transfectants. Instead, adhesion under flow conditions, soluble binding experiment, flow cytometry, and biochemical analyses revealed that the earlier chemokine-triggered integrin activation step was mostly independent of RGS10 actions. The data strongly suggest that RGS10 opposes activation by chemokines of the Vav1–Rac1 pathway in T cells, leading to repression of adhesion strengthening mediated by α4β1. In addition to control chemokine-upregulated T cell attachment, RGS10 also limited adhesion-independent cell chemotaxis and activation of cdc42. These results identify RGS10 as a key molecule that contributes to the termination of Gα-dependent signaling during chemokine-activated α4β1- and αLβ2-dependent T cell adhesion
Description9 páginas, 6 figuras -- PAGS nros. 1264-1272
Publisher version (URL)http:dx.doi.org/10.4049/​jimmunol.1002960
Appears in Collections:(CIB) Artículos
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