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Fps/Fes and Fer non‐receptor protein‐tyrosine kinases regulate collagen‐ and ADP‐induced platelet aggregation
Author(s) -
Senis Y. A.,
Sangrar W.,
Zirngibl R. A.,
Craig A. W. B.,
Lee D. H.,
Greer P. A.
Publication year - 2003
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 - 10.1046/j.1538-7836.2003.t01-1-00124.x
Subject(s) - receptor tyrosine kinase , tyrosine kinase , platelet aggregation , kinase , chemistry , proto oncogene tyrosine protein kinase src , microbiology and biotechnology , platelet , receptor , biochemistry , medicine , biology
Summary. Fps/Fes and Fer proto‐oncoproteins are structurally related non‐receptor protein‐tyrosine kinases implicated in signaling downstream from cytokines, growth factors and immune receptors. We show that Fps/Fes and Fer are expressed in human and mouse platelets, and are activated following stimulation with collagen and collagen‐related peptide (CRP), suggesting a role in GPVI receptor signaling. Fer was also activated following stimulation with thrombin and a protease‐activated receptor4 (PAR4)‐activating peptide, suggesting a role in signaling downstream from the G protein‐coupled PAR4. There were no detectable perturbations in CRP‐induced activation of Syk, PLCγ2, cortactin, Erk, Jnk, Akt or p38 in platelets from mice lacking Fps/Fes, Fer, or both kinases. Platelets lacking Fps/Fes, from a targeted fps/fes null strain of mice, showed increased rates and amplitudes of collagen‐induced aggregation, relative to wild‐type platelets. P‐Selectin expression was also elevated on the surface of Fps/Fes‐null platelets in response to CRP. Fer‐deficient platelets, from mice targeted with a kinase‐inactivating mutation, disaggregated more rapidly than wild‐type platelets in response to ADP. This report provides the first evidence that Fps/Fes and Fer are expressed in platelets and become activated downstream from the GPVI collagen receptor, and that Fer is activated downstream from a G‐protein coupled receptor. Furthermore, using targeted mouse models we show that deficiency in Fps/Fes or Fer resulted in disregulated platelet aggregation and disaggregation, demonstrating a role for these kinases in regulating platelet functions.