ADAP is required for normal alpha IIb beta 3 activation by VWF/GP Ib-IX-V and other agonists

作者：Kasirer Friede Ana^*; Moran Barry; Nagrampa Orje Jennifer; Swanson Ken; Ruggeri Zaverio M; Schraven Burkhart; Neel Benjamin G; Koretzky Gary; Shattil Sanford J

来源：Blood, 2007, 109(3): 1018-1025.

DOI：10.1182/blood-2006-05-022301

Interaction between von Willebrand factor (VWF) and platelet GP Ib-IX-V is required for hemostasis, in part because intracellular signals from VWF/GP Ib-IX-V activate the ligand-binding function of integrin alpha IIb beta 3. Because they also induce tyrosine phosphorylation of the ADAP adapter, we investigated ADAP's role in GP Ib-IX-V signal transduction. Fibrinogen or ligand-mimetic POW-2 Fab binding to alpha IIb beta 3 was stimulated by adhesion of ADAP(+/+) murine platelets to dimeric VWF A1A2 but was significantly reduced in ADAP(-/-) platelets (P < .01). alpha IIb beta 3 activation by ADP or a Par4 thrombin receptor agonist was also decreased in ADAP(-/-) platelets. ADAP stabilized the expression of another adapter, SKAP-HOM, via interaction with the latter's SH3 domain. However, no abnormalities in alpha IIb beta 3 activation were observed in SKAP-HOM-/- platelets, which express normal ADAP levels, further implicating ADAP as a modulator of alpha IIb beta 3 function. Under shear flow conditions over a combined surface of VWF A1A2 and fibronectin to test inter-actions involving GP Ib-IX-V and alpha IIb beta 3, respectively, ADAP(-/-) platelets displayed reduced alpha IIb beta 3-dependent stable adhesion. Furthermore, ADAP(-/-) mice demonstrated increased rebleeding from tail wounds. These studies establish ADAP as a component of inside-out signaling pathways that couple GP Ib-IX-V and other platelet agonist receptors to alpha IIb beta 3 activation.

• 出版日期2007-2-1