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

J Thromb Haemost. 2003 May;1(5):1062-70. 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, PLCgamma2, 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Diphosphate / pharmacology
  • Animals
  • Blood Platelets / enzymology
  • Collagen / pharmacology
  • Fusion Proteins, gag-onc / analysis
  • Fusion Proteins, gag-onc / physiology*
  • Humans
  • Mice
  • Mice, Transgenic
  • Phosphorylation / drug effects
  • 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


  • Fusion Proteins, gag-onc
  • Platelet Membrane Glycoproteins
  • Proto-Oncogene Proteins
  • Receptors, Cell Surface
  • platelet membrane glycoprotein VI
  • proto-oncogene protein c-fes-fps
  • Adenosine Diphosphate
  • Collagen
  • Protein-Tyrosine Kinases
  • v-fps oncogene protein, Fujinami sarcoma virus