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  • The EMBO Journal (2000) 19, 2525 - 2536
  • doi:10.1093/emboj/19.11.2525

Cytohesin-1 regulates bold beta-2 integrin-mediated adhesion through both ARF-GEF function and interaction with LFA-1

Christiane Geiger1, Wolfgang Nagel1, Thomas Boehm1, Yvette van Kooyk2, Carl G. Figdor2, Elisabeth Kremmer3, Nancy Hogg4, Lutz Zeitlmann1, Henning Dierks1, Kim S.C. Weber5 and Waldemar Kolanus1

  1. Laboratorium für Molekulare Biologie, Genzentrum der Universität München, Feodor-Lynen-Strasse 25, D-81377 München, Germany
  2. Department of Tumor Immunology, University Hospital Nijmegen St Radboud, 6525 EX Nijmegen, The Netherlands
  3. GSF-National Research Center for Environment and Health, Marchioninistrasse 25, D-81377 München, Germany
  4. Leukocyte Adhesion Laboratory, Imperial Cancer Research Fund, London WC2A 3PX, UK
  5. Institut für Kreislaufprophylaxe, University of Munich Medical School, Pettenkoferstrasse 9, D-80336 München, Germany

Correspondence to:

Waldemar Kolanus, E-mail: kolanus@lmb.uni-muenchen.de

Received 30 August 1999; Accepted 11 April 2000; Revised 6 April 2000

Intracellular signaling pathways, which regulate the interactions of integrins with their ligands, affect a wide variety of biological functions. Here we provide evidence of how cytohesin-1, an integrin-binding protein and guanine-nucleotide exchange factor (GEF) for ARF GTPases, regulates cell adhesion. Mutational analyses of the beta-2 cytoplasmic domain revealed that the adhesive function of LFA-1 depends on its interaction with cytohesin-1, unless the integrin is activated by exogenous divalent cations. Secondly, cytohesin-1 induces expression of an extracellular activation epitope of LFA-1, and the exchange factor function is not essential for this activity. In contrast, LFA-1-mediated cell adhesion and spreading on intercellular cell adhesion molecule 1 is strongly inhibited by a cytohesin-1 mutant, which fails to catalyze ARF GDP–GTP exchange in vitro. Thus, cytohesin-1 is involved in the activation of LFA-1, most probably through direct interaction with the integrin, and induces cell spreading by its ARF-GEF activity. We therefore propose that both direct regulation of the integrin and concomitant changes in the membrane topology of adherent T cells are modulated by dissectable functions of cytohesin-1.

  • Keywords:

    • ARF GTPase,
    • cell adhesion,
    • cytohesin-1,
    • beta-2 integrin,
    • LFA-1