Submitted August 18, 2008
Accepted February 17, 2009
The tyrosine phosphatase CD148 is an essential positive regulator of platelet activation and thrombosis
Yotis A. Senis*, Michael G. Tomlinson, Stuart Ellison, Alexandra Mazharian, Jenson Lim, Yan Zhao, Kristin N. Kornerup, Jocelyn M. Auger, Steve G. Thomas, Tarvinder Dhanjal, Neena Kalia, Jing W. Zhu, Arthur Weiss, and Steve P. Watson
Centre for Cardiovascular Sciences, Institute of Biomedical Research, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, United Kingdom
Department of Medicine, Howard Hughes Medical Institute, Rosalind Russell Medical Research Center for Arthritis, University of California at San Francisco, San Francisco, CA, United States
* Corresponding author; email: y.senis{at}bham.ac.uk.
Platelets play a fundamental role in haemostasis and thrombosis. They are also involved in pathological conditions resulting from blocked blood vessels, including myocardial infarction and ischemic stroke. Platelet adhesion, activation and aggregation at sites of vascular injury is 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 signalling 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 hypo-responsiveness 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 anti-thrombotic drug target.
