American Society of Hematology, Blood, 2(109), p. 595-602, 2006
DOI: 10.1182/blood-2005-11-011775
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Platelet integrins alpha(2)beta(1) and alpha(11b)beta(3) play critical roles in platelet adhesion and thrombus formation after vascular injury. On resting platelets, both integrins are in a low-affinity state. However, agonist stimulation results in conformational changes that enable ligand binding that can be detected with conformation dependent monoclonal antibodies (mAbs). By using such conformation-dependent mAbs, we could demonstrate that activation of integrin alpha(11b)beta(3) is not only sufficient, but also a prerequisite for alpha(2)beta(1) activation. Compared with platelets in plasma, stimulation of washed platelets resulted in only a minor activation of alpha(2)beta(1), as detected with the activation-sensitive mAb IAC-1. Addition of fibrinogen to stimulated washed platelets greatly potentiated activation of this integrin. Also, treatment of alpha(11b)beta(3) with the ligand-mimetic peptide RGDS, resulting in outside-in signaling, led to a powerful alpha(2)beta(1) activation, even in the absence of overall platelet activation, involving tyrosine kinase activity but no protein kinase C activation. The absolute necessity of alpha(11b)beta(3) for proper alpha(2)beta(1) activation on platelets was demonstrated by using the alpha(11b)beta(3) antagonist aggrastat, which was able to completely abolish alpha(2)beta(1) activation, both under static and flow conditions. In addition, analogous experiments with Glanzmann platelets lacking alpha(11b)beta(3) confirmed the indispensability of alpha(11b)beta(3) for alpha(2)beta(1) activation.