The tyrosine phosphatase CD148 is an essential positive regulator of platelet activation and thrombosis.
Platelets play a fundamental role in hemostasis and thrombosis. They are also involved in pathologic conditions resulting from blocked blood vessels, including myocardial infarction and ischemic stroke. Platelet adhesion, activation, and aggregation at sites of vascular injury are regulated by a diverse repertoire of tyrosine kinase-linked and G protein-coupled receptors. Src family kinases (SFKs) play a central role in initiating and propagating signaling from several platelet surface receptors; however, the underlying mechanism of how SFK activity is regulated in platelets remains unclear. CD148 is the only receptor-like protein tyrosine phosphatase identified in platelets to date. In the present study, we show that mutant mice lacking CD148 exhibited a bleeding tendency and defective arterial thrombosis. Basal SFK activity was found to be markedly reduced in CD148-deficient platelets, resulting in a global hyporesponsiveness to agonists that signal through SFKs, including collagen and fibrinogen. G protein-coupled receptor responses to thrombin and other agonists were also marginally reduced. These results highlight CD148 as a global regulator of platelet activation and a novel antithrombotic drug target.
Senis
Yotis A
YA
Centre for Cardiovascular Sciences, Institute of Biomedical Research, University of Birmingham, United Kingdom. y.senis@bham.ac.uk
Tomlinson
Michael G
MG
Ellison
Stuart
S
Mazharian
Alexandra
A
Lim
Jenson
J
Zhao
Yan
Y
Kornerup
Kristin N
KN
Auger
Jocelyn M
JM
Thomas
Steve G
SG
Dhanjal
Tarvinder
T
Kalia
Neena
N
Zhu
Jing W
JW
Weiss
Arthur
A
Watson
Steve P
SP
D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D001792:Blood Platelets / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D005340:Fibrinogen / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015539:Platelet Activation / Q000235:genetics*; D010974:Platelet Aggregation / Q000187:drug effects; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism / Q000502:physiology; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000502:physiology; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D017452:Receptors, IgG / Q000235:genetics; D015398:Signal Transduction / Q000276:immunology; D013927:Thrombosis / Q000235:genetics*
D000954:Antigens, Surface; D010980:Platelet Membrane Glycoproteins; D017452:Receptors, IgG; C098341:platelet membrane glycoprotein VI; D005340:Fibrinogen; D017027:Protein Tyrosine Phosphatases; C098066:Ptprj protein, mouse; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3