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 Blood, 1 March 2007, Vol. 109, No. 5, pp. 1975-1983.
Prepublished online as a Blood First Edition Paper on November 16, 2006; DOI 10.1182/blood-2006-08-042192.

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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY

mTOR-dependent synthesis of Bcl-3 controls the retraction of fibrin clots by activated human platelets

Andrew S. Weyrich1,5, Melvin M. Denis2,5, Hansjorg Schwertz5, Neal D. Tolley5, Jason Foulks2,5, Eliott Spencer5, Larry W. Kraiss4,5, Kurt H. Albertine3, Thomas M. McIntyre1,2,5, and Guy A. Zimmerman1,5

1 Department of Internal Medicine, 2 Department of Pathology, 3 Department of Pediatrics, 4 Department of Surgery, and 5 Program in Human Molecular Biology and Genetics, Eccles Institute of Human Genetics, University of Utah, Salt Lake City

New activities of human platelets continue to emerge. One unexpected response is new synthesis of proteins from previously transcribed RNAs in response to activating signals. We previously reported that activated human platelets synthesize B-cell lymphoma-3 (Bcl-3) under translational control by mammalian target of rapamycin (mTOR). Characterization of the ontogeny and distribution of the mTOR signaling pathway in CD34+ stem cell–derived megakaryocytes now demonstrates that they transfer this regulatory system to developing proplatelets. We also found that Bcl-3 is required for condensation of fibrin by activated platelets, demonstrating functional significance for mTOR-regulated synthesis of the protein. Inhibition of mTOR by rapamycin blocks clot retraction by human platelets. Platelets from wild-type mice synthesize Bcl-3 in response to activation, as do human platelets, and platelets from mice with targeted deletion of Bcl-3 have defective retraction of fibrin in platelet-fibrin clots mimicking treatment of human platelets with rapamycin. In contrast, overexpression of Bcl-3 in a surrogate cell line enhanced clot retraction. These studies identify new features of post-transcriptional gene regulation and signal-dependant protein synthesis in activated platelets that may contribute to thrombus and wound remodeling and suggest that posttranscriptional pathways are targets for molecular intervention in thrombotic disorders.


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Full clot retraction: running on mTOR
Michael C. Berndt and Robert K. Andrews
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