TRANSDOMINANT INHIBITION OF INTEGRIN FUNCTION

Occupancy of integrin adhesion receptors can alter the functions of ot her integrins and cause partition of the ligand-occupied integrin into focal adhesions. Ligand binding also changes the conformation of inte grin 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 func tions of target integrins alpha(5) beta(1) and alpha(2) beta(1). We re port that binding of integrin-specific ligands to a suppressive integr in can inhibit the function of other target integrins (trans-dominant inhibition). Trans-dominant inhibition is due to a blockade of integri n signaling. Furthermore, this inhibition involves both a conformation al change in the extracellular domain and the presence of the beta cyt oplasmic tail in the suppressive integrin. Similarly, ligand-induced r ecruitment of alpha(IIb)beta(3) to focal adhesions also involves a con formational rearrangement of its extracellular domain. These findings imply that the ligand-induced conformational changes can propagate fro m an integrin's extracellular to its intracellular face. Trans-dominan t inhibition joy integrin ligands may coordinate integrin signaling an d can lead to unexpected biological effects of integrin-specific inhib itors.