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- W2557151284 abstract "Abstract The interaction between von Willebrand factor (VWF) and platelet GPIb-IX-V is a key biological mechanism in hemostasis. In a previous study of signal transduction between GPIb-IX-V and integrin α Iibβ 3, we observed that platelet adhesion to a dimeric VWF A1 domain fragment via GP Ib-IX-V induced the tyrosine phosphorylation of the adapter protein, ADAP (Slap-130, FYB). While this protein has been implicated in cell proliferation and integrin clustering in leukocytes, its role in platelet function has not been determined. Here we used ADAP knockout mice to address this issue. Initiation of signaling in platelets adherent to murine dimeric VWF A1 domain caused α Iibβ 3 activation in wild-type, ADAP+/+ platelets, as determined by the binding of FITC-fibrinogen or POW-2, an anti-α Iibβ 3 antibody Fab specific for high-affinity α Iibβ 3. However, α Iibβ 3 activation through GP Ib-IX-V was diminished by 70–80 % in ADAP−/− platelets (P <0.01), despite normal platelet adhesion under these static conditions. α Iibβ 3 activation by other agonist pathways, such as those stimulated through ADP or Par4 thrombin receptors was also decreased in ADAP−/− platelets (P < 0.05 and 0.01 respectively). In addition, following adhesion of ADAP−/− platelets to VWF A1, tyrosine phosphorylation of numerous proteins, including the ADAP binding partner, SLP-76, was markedly reduced. Surprisingly, deletion of ADAP also affected the expression of another ADAP binding partner, Skap-HOM, and transient transfection of CHO cells confirmed that ADAP expression regulated Skap-HOM protein levels. Platelets from Skap-HOM−/− mice, which have normal ADAP levels, showed normal α Iibβ 3 activation, indicating that the inside-out signaling defect in ADAP−/− platelets was specifically due to deficiency of ADAP and not Skap-HOM. ADAP−/− mice displayed more re-bleeding from tail wounds compared to ADAP+/+ mice (64% vs. 16%, p < 0.01). Under shear flow conditions over a combined matrix of VWF A1A2 and fibronectin to test interactions involving GP Ib-IX-V and α Iibβ 3, respectively, ADAP−/− platelets displayed reduced α IIbβ 3-dependent adhesion. These studies establish that ADAP is a necessary component of the inside-out signaling pathways downstream of GP Ib-IX-V and other receptors in platelets that regulate α IIbβ 3 affinity." @default.
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- W2557151284 date "2005-11-16" @default.
- W2557151284 modified "2023-10-16" @default.
- W2557151284 title "Inside-Out Signaling through ADAP Is Required for VWF-GPIb-IX-V Mediated Integrin AIibb3 Activation." @default.
- W2557151284 doi "https://doi.org/10.1182/blood.v106.11.379.379" @default.
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