title: LFA-1 integrin antibodies inhibit leukocyte α4β1-mediated adhesion by intracellular signaling.
abstract: Binding of intercellular adhesion molecule-1 to the β2-integrin leukocyte function associated antigen-1 (LFA-1) is known to induce cross-talk to the α4β1 integrin. Using different LFA-1 monoclonal antibodies, we have been able to study the requirement and mechanism of action for the cross-talk in considerable detail. LFA-1-activating antibodies and those inhibitory antibodies that signal to α4β1 induce phosphorylation of Thr-758 on the β2-chain, which is followed by binding of 14-3-3 proteins and signaling through the G protein exchange factor Tiam1. This results in dephosphorylation of Thr-788/789 on the β1-chain of α4β1 and loss of binding to its ligand vascular cell adhesion molecule-1. The results show that with LFA-1 antibodies, we can activate LFA-1 and inhibit α4β1, inhibit both LFA-1 and α4β1, inhibit LFA-1 but not α4β1, or not affect LFA-1 or α4β1 These findings are important for the understanding of integrin regulation and for the interpretation of the effect of integrin antibodies and their use in clinical applications.
authors.affiliation: Division of Biochemistry and Biotechnology, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland.
authors.forename: Mikaela
authors.initials: M
authors.lastname: Grönholm
authors.affiliation: Division of Biochemistry and Biotechnology, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland.
authors.forename: Farhana
authors.initials: F
authors.lastname: Jahan
authors.affiliation: Division of Biochemistry and Biotechnology, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland.
authors.forename: Ekaterina A
authors.initials: EA
authors.lastname: Bryushkova
authors.affiliation: Division of Biochemistry and Biotechnology, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland.
authors.forename: Sudarrshan
authors.initials: S
authors.lastname: Madhavan
authors.affiliation: Division of Biochemistry and Biotechnology, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland.
authors.forename: Francesca
authors.initials: F
authors.lastname: Aglialoro
authors.affiliation: Division of Biochemistry and Biotechnology, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland.
authors.forename: Laura
authors.initials: L
authors.lastname: Soto Hinojosa
authors.affiliation: Division of Biochemistry and Biotechnology, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland.
authors.forename: Liisa M
authors.initials: LM
authors.lastname: Uotila
authors.affiliation: Division of Biochemistry and Biotechnology, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland.
authors.forename: Carl G
authors.initials: CG
authors.lastname: Gahmberg
mesh_terms: D000906:Antibodies / Q000276:immunology / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects / Q000276:immunology; D002460:Cell Line; D006801:Humans; D039041:Integrin alpha4beta1 / Q000276:immunology*; D007962:Leukocytes / Q000166:cytology / Q000276:immunology*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology*; D010766:Phosphorylation / Q000187:drug effects / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology
chemical_list: D000906:Antibodies; D039041:Integrin alpha4beta1; D016169:Lymphocyte Function-Associated Antigen-1