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Dok-2 adaptor protein regulates the shear-dependent adhesive function of platelet integrin αIIbβ3 in mice

Sascha C Hughan1, Christopher M Spring, Simone M Schoenwaelder

  • 1From the Australian Centre for Blood Diseases, Faculty of Medicine, Nursing, and Health Sciences, Monash University, Alfred Medical Research and Education Precinct, Commercial Road, Melbourne, Victoria 3004.

The Journal of Biological Chemistry
|January 4, 2014
PubMed

Insights

Dok-2 deficiency enhances platelet adhesion and thrombus growth by altering integrin signaling. This study reveals a novel prothrombotic mechanism in platelets not detected by standard assays.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Hematology

Background:

  • Dok proteins are adaptor molecules involved in cellular processes.
  • Dok-2 is found in platelets and phosphorylated downstream of integrin αIIbβ3.
  • Dok-2's role in platelet function, particularly integrin signaling, is not fully understood.

Purpose of the Study:

  • To investigate the role of Dok-2 in platelet function and integrin αIIbβ3 signaling.
  • To determine the kinase responsible for Dok-2 phosphorylation in platelets.
  • To elucidate the in vivo consequences of Dok-2 deficiency on thrombosis.

Main Methods:

  • Analysis of Dok-2 phosphorylation in platelets.
  • Assessment of integrin αIIbβ3-dependent signaling pathways (calcium flux, PI(3,4)P2 accumulation) in Dok-2 deficient platelets.
  • Evaluation of platelet adhesion and aggregation under flow conditions.
  • In vivo thrombosis models to assess thrombus growth.

Main Results:

  • Dok-2 is primarily phosphorylated by Lyn kinase in platelets.
  • Dok-2 deficiency dysregulates integrin αIIbβ3-dependent calcium flux and PI(3,4)P2 accumulation.
  • Dok-2 deficient platelets exhibit enhanced shear-dependent adhesion and platelet-fibrinogen/platelet-platelet interactions.
  • Dok-2 deficiency leads to accelerated thrombus growth in vivo due to increased platelet aggregation.

Conclusions:

  • Dok-2 plays a critical role in regulating the biomechanical adhesive function of platelets.
  • Dok-2 deficiency promotes a prothrombotic state through a mechanism not identified by conventional assays.
  • Lyn kinase-mediated phosphorylation of Dok-2 is crucial for normal platelet function and thrombosis regulation.
Keywords:
Adaptor ProteinsIntegrinsMechanotransductionPlateletsShear Stress

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