ADAP is required for normal alphaIIbbeta3 activation by VWF/GP Ib-IX-V and other agonists

Blood. 2007 Feb 1;109(3):1018-25. doi: 10.1182/blood-2006-05-022301. Epub 2006 Sep 26.


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 alphaIIbbeta3. 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 alphaIIbbeta3 was stimulated by adhesion of ADAP+/+ murine platelets to dimeric VWF A1A2 but was significantly reduced in ADAP-/- platelets (P<.01). alphaIIbbeta3 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 alphaIIbbeta3 activation were observed in SKAP-HOM-/- platelets, which express normal ADAP levels, further implicating ADAP as a modulator of alphaIIbbeta3 function. Under shear flow conditions over a combined surface of VWF A1A2 and fibronectin to test interactions involving GP Ib-IX-V and alphaIIbbeta3, respectively, ADAP-/- platelets displayed reduced alphaIIbbeta3-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 alphaIIbbeta3 activation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / deficiency
  • Adaptor Proteins, Signal Transducing / physiology*
  • Animals
  • Fibrinogen / metabolism
  • Hemorrhage
  • Mice
  • Mice, Knockout
  • Platelet Adhesiveness
  • Platelet Glycoprotein GPIIb-IIIa Complex / agonists
  • Platelet Glycoprotein GPIIb-IIIa Complex / metabolism*
  • Platelet Glycoprotein GPIb-IX Complex / metabolism
  • Platelet Glycoprotein GPIb-IX Complex / physiology*
  • Signal Transduction
  • von Willebrand Factor / metabolism
  • von Willebrand Factor / physiology*


  • Adaptor Proteins, Signal Transducing
  • Fyb protein, mouse
  • Platelet Glycoprotein GPIIb-IIIa Complex
  • Platelet Glycoprotein GPIb-IX Complex
  • von Willebrand Factor
  • Fibrinogen