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

Curr Biol. 2001 Dec 11;11(24):1969-74. doi: 10.1016/s0960-9822(01)00597-8.

Abstract

Cytohesin-1 is a regulatory interaction partner of the beta2 integrin alphaLbeta2 (LFA-1) and a guanine exchange factor (GEF) for ADP ribosylation factor (ARF)-GTPases. 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 beta2 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Adhesion Molecules / physiology*
  • Cell Movement / physiology*
  • Chemokines / physiology*
  • Endothelium / cytology
  • GTP Phosphohydrolases / metabolism
  • Guanine Nucleotide Exchange Factors / physiology
  • Leukocytes / cytology*
  • Lymphocyte Function-Associated Antigen-1 / physiology*

Substances

  • Cell Adhesion Molecules
  • Chemokines
  • Guanine Nucleotide Exchange Factors
  • Lymphocyte Function-Associated Antigen-1
  • cytohesin-1
  • GTP Phosphohydrolases