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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, cytohcsin-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-l-mediated cell adhesion and spreading on intercellular cell adhesion molecule 1 is strongly inhibited by a cytohcsin-1 mutant, which fails to catalyze ARF GDP-GTP exchange in vitro. Thus, cytohcsin-1 is involved in the activation of LFA-1, most probably through direct interaction with the integrin, and induces cell spreading by its ARF-C, EF 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. [ABSTRACT FROM AUTHOR]