Hematopoietic lineage cell specific protein 1 (HS1) is a functionally important signaling molecule in platelet activation.
Collagen activates platelets through an intracellular signaling cascade downstream of glycoprotein VI (GPVI). We have investigated the contribution of hematopoietic lineage cell-specific protein 1 (HS1) downstream of GPVI in platelet activation. Stimulation of GPVI leads to tyrosine phosphorylation of HS1, which is blocked by Src-family kinase inhibitors. Coimmunoprecipitation experiments revealed that HS1 associates with Syk and phosphatidylinositol 3-kinases. HS1-null mice displayed increased bleeding times and increased time to occlusion in the FeCl(3) in vivo thrombosis model compared with their wild-type littermates. In addition, aggregation and secretion responses were diminished in HS1-null mouse platelets after stimulation of GPVI and protease-activated receptor 4 (PAR-4) agonists compared with wild-type littermate mouse platelets. Finally, Akt phosphorylation was diminished after GPVI or PAR-4 stimulation in platelets from HS1-null mice compared with their wild-type littermates. These results demonstrate that phosphorylation of the HS1 protein occurs downstream of GPVI stimulation and that HS1 plays a significant functional role in platelet activation downstream of GPVI and PARs.
Kahner
Bryan N
BN
Department of Physiology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Dorsam
Robert T
RT
Mada
Sripal R
SR
Kim
Soochong
S
Stalker
Timothy J
TJ
Brass
Lawrence F
LF
Daniel
James L
JL
Kitamura
Daisuke
D
Kunapuli
Satya P
SP
D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D016179:Granulocyte Colony-Stimulating Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D015539:Platelet Activation / Q000187:drug effects; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000819:agonists / Q000378:metabolism; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D015398:Signal Transduction
D010980:Platelet Membrane Glycoproteins; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; C524015:hematopoietic lineage cell-specific protein 1, mouse; C098341:platelet membrane glycoprotein VI; D016179:Granulocyte Colony-Stimulating Factor; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt