title: Trans-dominant inhibition of integrin function.
abstract: Occupancy of integrin adhesion receptors can alter the functions of other integrins and cause partition of the ligand-occupied integrin into focal adhesions. Ligand binding also changes the conformation of integrin extracellular domains. To explore the relationship between ligand-induced conformational change and integrin signaling, we examined the effect of ligands specific for integrin alpha IIb beta 3 on the functions of target integrins alpha 5 beta 1 and alpha 2 beta 1. We report that binding of integrin-specific ligands to a suppressive integrin can inhibit the function of other target integrins (trans-dominant inhibition). Trans-dominant inhibition is due to a blockade of integrin signaling. Furthermore, this inhibition involves both a conformational change in the extracellular domain and the presence of the beta cytoplasmic tail in the suppressive integrin. Similarly, ligand-induced recruitment of alpha IIb beta 3 to focal adhesions also involves a conformational rearrangement of its extracellular domain. These findings imply that the ligand-induced conformational changes can propagate from an integrin's extracellular to its intracellular face. Trans-dominant inhibition by integrin ligands may coordinate integrin signaling and can lead to unexpected biological effects of integrin-specific inhibitors.
authors.affiliation: Department of Vascular Biology, Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: F
authors.initials: F
authors.lastname: Díaz-González
authors.forename: J
authors.initials: J
authors.lastname: Forsyth
authors.forename: B
authors.initials: B
authors.lastname: Steiner
authors.forename: M H
authors.initials: MH
authors.lastname: Ginsberg
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D016466:CHO Cells; D006224:Cricetinae; D003593:Cytoplasm / Q000276:immunology; D006801:Humans; D016023:Integrins / Q000737:chemistry / Q000276:immunology*; D008024:Ligands; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000737:chemistry / Q000276:immunology*; D011487:Protein Conformation; D011817:Rabbits; D038981:Receptors, Collagen; D017469:Receptors, Fibronectin / Q000737:chemistry / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*
chemical_list: D016023:Integrins; D008024:Ligands; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D038981:Receptors, Collagen; D017469:Receptors, Fibronectin