Fps/Fes and Fer non‐receptor protein‐tyrosine kinases regulate collagen‐ and ADP‐induced platelet aggregation

• Published in: Journal of thrombosis and haemostasis 2003-05, Vol.1 (5), p.1062-1070
• Main Authors: Senis, Y. A., Sangrar, W., Zirngibl, R. A., Craig, A. W. B., Lee, D. H., Greer, P. A.
• Format: Article
• Language: English
• Subjects: Adenosine Diphosphate - pharmacology; Animals; Blood Platelets - enzymology; collagen; Collagen - pharmacology; Fusion Proteins, gag-onc - analysis; Fusion Proteins, gag-onc - physiology; glycoprotein VI; Humans; Mice; Mice, Transgenic; Phosphorylation - drug effects; platelet; Platelet Aggregation - drug effects; Platelet Membrane Glycoproteins; Protein-Tyrosine Kinases - analysis; Protein-Tyrosine Kinases - physiology; Proto-Oncogene Proteins - analysis; Proto-Oncogene Proteins - physiology; Receptors, Cell Surface; Signal Transduction; tyrosine kinase
• ISSN: 1538-7933; 1538-7836; 1538-7836
• DOI: 10.1046/j.1538-7836.2003.t01-1-00124.x

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.