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Cytohesin-1 is a dynamic regulator of distinct LFA-1 functions in leukocyte arrest and transmigration triggered by chemokines

By Kim S.C. Weber, Christian Weber, Georg Ostermann, Henning Dierks, Wolfgang Nagel and Waldemar Kolanus

Abstract

AbstractCytohesin-1 is a regulatory interaction partner of the β2 integrin αLβ2 (LFA-1) and a guanine exchange factor (GEF) for ADP ribosylation factor (ARF)-GTPases [1, 2]. However, a functional role of cytohesin-1 in leukocyte adhesion to activated endothelium and subsequent transmigration in response to chemokines has not been defined. Overexpression of cytohesin-1 increased LFA-1-dependent arrest of leukocytic cells triggered by chemokines on cytokine-activated endothelium in flow while reducing the fraction of rolling cells. Conversely, a dominant-negative PH domain construct of cytohesin-1 but not a mutant deficient in GEF activity impaired arrest, indicating an involvement of the PH domain while GEF function is not required. Expression of these constructs and a β2 mutant interrupting the interaction with cytohesin-1 indicated that shape change in flow and transendothelial chemotaxis involve both LFA-1 avidity regulation and GEF activity of cytohesin-1. As a potential downstream target, ARF6 but not ARF1 was identified to participate in chemotaxis. Our data suggest that cytohesin-1 and ARF6 are involved in the dynamic regulation of complex signaling pathways and cytoskeletal remodeling processes governing LFA-1 functions in leukocyte recruitment. Differential effects of cytohesin-1 and ARF6 mutants in our systems reveal that cytohesin-1 with its GEF activity controls both conversion of rolling into firm arrest and transmigration triggered by chemokines, whereas a cyclical activity of ARF6 plays a more important role in diapedesis

Publisher: Elsevier Science Ltd.
Year: 2001
DOI identifier: 10.1016/S0960-9822(01)00597-8
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