Unknown

Dataset Information

0

Dok-2 adaptor protein regulates the shear-dependent adhesive function of platelet integrin ?IIb?3 in mice.


ABSTRACT: 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 ?IIb?3, raising the possibility that it participates in integrin ?IIb?3 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 ?IIb?3-dependent cytosolic calcium flux and phosphatidylinositol(3,4)P2 accumulation. Although agonist-induced integrin ?IIb?3 affinity regulation was unaltered in Dok-2(-/-) platelets, Dok-2 deficiency was associated with a shear-dependent increase in integrin ?IIb?3 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.

SUBMITTER: Hughan SC 

PROVIDER: S-EPMC3931064 | BioStudies | 2014-01-01T00:00:00Z

REPOSITORIES: biostudies

Similar Datasets

2016-01-01 | S-EPMC4854776 | BioStudies
2018-01-01 | S-EPMC5852038 | BioStudies
2019-01-01 | S-EPMC6437653 | BioStudies
1993-01-01 | S-EPMC1137731 | BioStudies
2000-01-01 | S-EPMC377457 | BioStudies
2010-01-01 | S-EPMC3701458 | BioStudies
2014-01-01 | S-EPMC4167429 | BioStudies
2011-01-01 | S-EPMC3234770 | BioStudies
1000-01-01 | S-EPMC3274813 | BioStudies
1000-01-01 | S-EPMC3739031 | BioStudies