An important role of the SRC family kinase Lyn in stimulating platelet granule secretion.
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 alpha granules and the secretion-dependent platelet aggregation induced by thrombin, collagen, and thromboxane A(2). 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 A(2) were also reversed by supplementing ADP. Furthermore, PP2 treatment or Lyn knock-out diminished agonist-induced Akt activation and cyclic GMP production. 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.
Li
Zhenyu
Z
Department of Pharmacology, College of Medicine, University of Illinois, Chicago, Illinois 60612, USA. zhenyuli08@uky.edu
Zhang
Guoying
G
Liu
Junling
J
Stojanovic
Aleksandra
A
Ruan
Changgeng
C
Lowell
Clifford A
CA
Du
Xiaoping
X
D000244:Adenosine Diphosphate / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001792:Blood Platelets / Q000201:enzymology*; D015550:Cell Degranulation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D003094:Collagen / Q000378:metabolism / Q000494:pharmacology; D006157:Guanosine Monophosphate / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D022142:Secretory Vesicles / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D013917:Thrombin / Q000378:metabolism / Q000494:pharmacology; D013928:Thromboxane A2 / Q000378:metabolism / Q000494:pharmacology; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
C412373:AG 1879; D011743:Pyrimidines; D009569:Nitric Oxide; D013928:Thromboxane A2; D000244:Adenosine Diphosphate; D006157:Guanosine Monophosphate; D003094:Collagen; D019869:Phosphatidylinositol 3-Kinases; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D013917:Thrombin