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Differential regulation of adapter proteins Dok2 and Dok1 in platelets, leading to an association of Dok2 with integrin α IIb β 3
Author(s) -
HUGHAN S. C.,
WATSON S. P.
Publication year - 2007
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/j.1538-7836.2007.02307.x
Subject(s) - phosphorylation , integrin , proto oncogene tyrosine protein kinase src , gpvi , syk , tyrosine phosphorylation , microbiology and biotechnology , bruton's tyrosine kinase , signal transducing adaptor protein , lyn , platelet activation , chemistry , platelet glycoprotein gpiib iiia complex , cd49c , platelet , integrin, beta 6 , tyrosine kinase , signal transduction , biology , biochemistry , receptor , immunology
Summary. Background: We previously demonstrated that Dok2 is rapidly phosphorylated on tyrosine residues in platelets in response to thrombin, the immunoreceptor tyrosine‐based activation motif‐coupled collagen receptor glycoprotein (GP) VI, and by integrin α IIb β 3 . Objectives and methods: In this study we further delineate the regulation of phosphorylation of Dok2 and compare this to the related adapter Dok1. Results: We demonstrate expression of Dok1 in platelets and the unexpected observation that the adapter protein undergoes tyrosine phosphorylation in response to thrombin but not to GPVI or integrin α IIb β 3 . Furthermore, Dok1 phosphorylation is transient, peaking at 30 s and returning to basal by 5 min, whereas Dok2 phosphorylation is delayed but sustained. Dok2 phosphorylation, but not that of Dok1, is inhibited by Src kinase inhibitors and by chelation of intracellular calcium. Further, phosphorylation of Dok2 by thrombin and integrin α IIb β 3 in mouse platelets is independent of Syk and phospholipase Cγ2. Additionally, Dok2 coimmunoprecipitates with integrin α IIb β 3 downstream of Src kinases. Conclusions: These results demonstrate differential modes of regulation of Dok1 and Dok2 in platelets. Further, they raise the interesting possibility that Dok2 plays an important role in integrin outside‐in signaling through a physical and functional interaction with integrin α IIb β 3 .