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

• Published in: The EMBO journal Vol. 19; no. 11; p. 2525
• Main Authors: Geiger, Christiane, Nagel, Wolfgang, Boehm, Thomas, Yvette van Kooyk, Figdor, Carl G, Kremmer, Elisabeth, Hogg, Nancy, Zeitlmann, Lutz, Dierks, Henning, Kim S.C. Weber, Kolanus, Waldemar
• Format: Journal Article
• Language: English
• Published: Heidelberg Blackwell Publishing Ltd 01.06.2000
• Subjects: Adhesion; Cations; Topology
• ISSN: 0261-4189; 1460-2075

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.