TY - JOUR
T1 - An important role of the Src family kinase lyn in stimulating platelet granule secretion
AU - Li, Zhenyu
AU - Zhang, Guoying
AU - Liu, Junling
AU - Stojanovic, Aleksandra
AU - Ruan, Changgeng
AU - Lowell, Clifford A.
AU - Du, Xiaoping
PY - 2010/4/23
Y1 - 2010/4/23
N2 - The Src family kinases (SFKs) have been proposed to play stimulatory and inhibitory roles in platelet activation. The mechanisms for these apparently contradictory roles are unclear. Here we show that SFK, mainly Lyn, is important in stimulating a common signaling pathway leading to secretion of platelet granules. Lyn knock-out or an isoform-nonselective SFK inhibitor, PP2, inhibited platelet secretion of both dense and α granules and the secretion-dependent platelet aggregation induced by thrombin, collagen, and thromboxane A2. The inhibitory effect of Lyn knock-out on platelet aggregation was reversed by supplementing granule content ADP, indicating that the primary role of Lyn is to stimulate granule secretion. Inhibitory effect of PP2 on platelet aggregation induced by thrombin and thromboxane A2 were also reversed by supplementing ADP. Furthermore, PP2 treatment or Lyn knock-out diminished agonist-induced Akt activation and cyclicGMPproduction. The inhibitory effect of PP2 or Lyn knock-out on platelet response can be corrected by supplementing cyclic GMP. These data indicate that Lyn stimulates platelet secretion by activating the phosphoinositide 3-kinase-Akt-nitric oxide (NO)-cyclic GMP pathway and also provide an explanation why Lyn can both stimulate and inhibit platelet activation.
AB - The Src family kinases (SFKs) have been proposed to play stimulatory and inhibitory roles in platelet activation. The mechanisms for these apparently contradictory roles are unclear. Here we show that SFK, mainly Lyn, is important in stimulating a common signaling pathway leading to secretion of platelet granules. Lyn knock-out or an isoform-nonselective SFK inhibitor, PP2, inhibited platelet secretion of both dense and α granules and the secretion-dependent platelet aggregation induced by thrombin, collagen, and thromboxane A2. The inhibitory effect of Lyn knock-out on platelet aggregation was reversed by supplementing granule content ADP, indicating that the primary role of Lyn is to stimulate granule secretion. Inhibitory effect of PP2 on platelet aggregation induced by thrombin and thromboxane A2 were also reversed by supplementing ADP. Furthermore, PP2 treatment or Lyn knock-out diminished agonist-induced Akt activation and cyclicGMPproduction. The inhibitory effect of PP2 or Lyn knock-out on platelet response can be corrected by supplementing cyclic GMP. These data indicate that Lyn stimulates platelet secretion by activating the phosphoinositide 3-kinase-Akt-nitric oxide (NO)-cyclic GMP pathway and also provide an explanation why Lyn can both stimulate and inhibit platelet activation.
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U2 - 10.1074/jbc.M109.098756
DO - 10.1074/jbc.M109.098756
M3 - Article
C2 - 20189992
AN - SCOPUS:77951241708
SN - 0021-9258
VL - 285
SP - 12559
EP - 12570
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 17
ER -