Fps/Fes and Fer non-receptor protein-tyrosine kinases regulate collagen- and ADP-induced platelet aggregation.
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.
Senis
Y A
YA
Department of Pathology, Queen's University, Kingston, Ontario, Canada.
Sangrar
W
W
Zirngibl
R A
RA
Craig
A W B
AW
Lee
D H
DH
Greer
P A
PA
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D001792:Blood Platelets / Q000201:enzymology; D003094:Collagen / Q000494:pharmacology; D015681:Fusion Proteins, gag-onc / Q000032:analysis / Q000502:physiology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D010980:Platelet Membrane Glycoproteins; D011505:Protein-Tyrosine Kinases / Q000032:analysis / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000502:physiology*; D011956:Receptors, Cell Surface; D015398:Signal Transduction
D015681:Fusion Proteins, gag-onc; D010980:Platelet Membrane Glycoproteins; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; C098341:platelet membrane glycoprotein VI; C052602:proto-oncogene protein c-fes-fps; D000244:Adenosine Diphosphate; D003094:Collagen; D011505:Protein-Tyrosine Kinases; C068415:v-fps oncogene protein, Fujinami sarcoma virus