| First Author | Hughan SC | Year | 2014 |
| Journal | J Biol Chem | Volume | 289 |
| Issue | 8 | Pages | 5051-60 |
| PubMed ID | 24385425 | Mgi Jnum | J:209510 |
| Mgi Id | MGI:5568019 | Doi | 10.1074/jbc.M113.520148 |
| Citation | Hughan SC, et al. (2014) Dok-2 adaptor protein regulates the shear-dependent adhesive function of platelet integrin alphaIIbbeta3 in mice. J Biol Chem 289(8):5051-60 |
| abstractText | The Dok proteins are a family of adaptor molecules that have a well defined role in regulating cellular migration, immune responses, and tumor progression. Previous studies have demonstrated that Doks-1 to 3 are expressed in platelets and that Dok-2 is tyrosine-phosphorylated downstream of integrin alphaIIbbeta3, raising the possibility that it participates in integrin alphaIIbbeta3 outside-in signaling. We demonstrate that Dok-2 in platelets is primarily phosphorylated by Lyn kinase. Moreover, deficiency of Dok-2 leads to dysregulated integrin alphaIIbbeta3-dependent cytosolic calcium flux and phosphatidylinositol(3,4)P2 accumulation. Although agonist-induced integrin alphaIIbbeta3 affinity regulation was unaltered in Dok-2(-/-) platelets, Dok-2 deficiency was associated with a shear-dependent increase in integrin alphaIIbbeta3 adhesive function, resulting in enhanced platelet-fibrinogen and platelet-platelet adhesive interactions under flow. This increase in adhesion was restricted to discoid platelets and involved the shear-dependent regulation of membrane tethers. Dok-2 deficiency was associated with an increased rate of platelet aggregate formation on thrombogenic surfaces, leading to accelerated thrombus growth in vivo. Overall, this study defines an important role for Dok-2 in regulating biomechanical adhesive function of discoid platelets. Moreover, they define a previously unrecognized prothrombotic mechanism that is not detected by conventional platelet function assays. |
