title: Differential regulation of alpha 4 integrin-dependent binding to domains 1 and 4 of vascular cell adhesion molecule-1.
abstract: The vascular cell adhesion molecule-1 (VCAM-1) plays an important role in diverse physiological and pathological processes. The homologous first and fourth immunoglobulin-like domains of the seven domain form of VCAM-1 present binding motifs for alpha 4 beta 1 integrin. Using a panel of VCAM-1 domain deletion mutants we show that alpha 4 beta 7 integrin interacts with both domains 1 and 4. In contrast to their identical domain usage, alpha 4 beta 1 and alpha 4 beta 7 integrins differ in the activation states required for binding to domains 1 and 4 of VCAM-1. We show that integrin alpha 4 beta 1 required significantly higher concentrations of Mn2+ than integrin alpha 4 beta 7 to support half-maximal adhesion to domain 4. Moreover, a clear difference in the capacity of integrins alpha 4 beta 1 and alpha 4 beta 7 to interact with domain 4 was detected in the presence of Ca2+ and Mg2+ cations. Adhesion to domain 1 of VCAM-1, however, was not affected by integrin heterodimer composition. Instead, the activity level of integrin alpha 4 beta 1 for domain 1 binding was regulated by CD24 expression. Binding to seven domain VCAM-1 was not altered significantly by beta 1 and beta 7 subunits or CD24. These data indicate that integrin heterodimer composition and CD24 expression differentially modulate integrin binding to domains 1 and 4 of VCAM-1. Mechanisms that alter integrin binding specificity or monovalent versus divalent interactions may affect the strength of adhesion as well as signal transmission in adherent cells and may therefore be critical to controlling the cellular response to integrin occupancy.
authors.affiliation: Institute for Medical Microbiology and Hygiene, Technical University, Munich, Federal Republic of Germany.
authors.forename: G
authors.initials: G
authors.lastname: Kilger
authors.forename: L A
authors.initials: LA
authors.lastname: Needham
authors.forename: P J
authors.initials: PJ
authors.lastname: Nielsen
authors.forename: J
authors.initials: J
authors.lastname: Clements
authors.forename: D
authors.initials: D
authors.lastname: Vestweber
authors.forename: B
authors.initials: B
authors.lastname: Holzmann
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D001665:Binding Sites; D051927:CD24 Antigen; D016466:CHO Cells; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000737:chemistry* / Q000378:metabolism*; D002460:Cell Line; D006224:Cricetinae; D005434:Flow Cytometry; D039441:Integrin alpha4; D016023:Integrins / Q000378:metabolism*; D016393:Lymphoma, B-Cell; D016399:Lymphoma, T-Cell; D046911:Macromolecular Substances; D008345:Manganese / Q000494:pharmacology; D008562:Membrane Glycoproteins; D051379:Mice; D051381:Rats; D017384:Sequence Deletion; D014162:Transfection; D014407:Tumor Cells, Cultured; D019010:Vascular Cell Adhesion Molecule-1
chemical_list: D015703:Antigens, CD; D051927:CD24 Antigen; C497890:Cd24a protein, mouse; D015815:Cell Adhesion Molecules; D016023:Integrins; D046911:Macromolecular Substances; D008562:Membrane Glycoproteins; D019010:Vascular Cell Adhesion Molecule-1; D039441:Integrin alpha4; D008345:Manganese