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

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Abstract
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 β‐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.