title: Cytohesin-1 regulates beta-2 integrin-mediated adhesion through both ARF-GEF function and interaction with LFA-1.
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 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.
authors.affiliation: Laboratorium für Molekulare Biologie, Genzentrum der Universität München, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Geiger
authors.forename: W
authors.initials: W
authors.lastname: Nagel
authors.forename: T
authors.initials: T
authors.lastname: Boehm
authors.forename: Y
authors.initials: Y
authors.lastname: van Kooyk
authors.forename: C G
authors.initials: CG
authors.lastname: Figdor
authors.forename: E
authors.initials: E
authors.lastname: Kremmer
authors.forename: N
authors.initials: N
authors.lastname: Hogg
authors.forename: L
authors.initials: L
authors.lastname: Zeitlmann
authors.forename: H
authors.initials: H
authors.lastname: Dierks
authors.forename: K S
authors.initials: KS
authors.lastname: Weber
authors.forename: W
authors.initials: W
authors.lastname: Kolanus
mesh_terms: D020727:ADP-Ribosylation Factors / Q000502:physiology*; D000818:Animals; D018821:CD18 Antigens / Q000502:physiology*; D002448:Cell Adhesion / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000502:physiology*; D048429:Cell Size; D000939:Epitopes / Q000737:chemistry; D020662:Guanine Nucleotide Exchange Factors; D006153:Guanosine Diphosphate / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000502:physiology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000502:physiology*; D046911:Macromolecular Substances; D051379:Mice; D008958:Models, Molecular; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000502:physiology; D013601:T-Lymphocytes / Q000166:cytology*; D020798:Two-Hybrid System Techniques
chemical_list: D018821:CD18 Antigens; D015815:Cell Adhesion Molecules; D000939:Epitopes; D020662:Guanine Nucleotide Exchange Factors; D016169:Lymphocyte Function-Associated Antigen-1; D046911:Macromolecular Substances; D011993:Recombinant Fusion Proteins; C100723:cytohesin-1; D018799:Intercellular Adhesion Molecule-1; D006153:Guanosine Diphosphate; D006160:Guanosine Triphosphate; D020727:ADP-Ribosylation Factors