mTOR-dependent synthesis of Bcl-3 controls the retraction of fibrin clots by activated human platelets.
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.
Weyrich
Andrew S
AS
Department of Internal Medicine, Eccles Institute of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA.
Denis
Melvin M
MM
Schwertz
Hansjorg
H
Tolley
Neal D
ND
Foulks
Jason
J
Spencer
Eliott
E
Kraiss
Larry W
LW
Albertine
Kurt H
KH
McIntyre
Thomas M
TM
Zimmerman
Guy A
GA
D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D000081242:B-Cell Lymphoma 3 Protein; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016466:CHO Cells; D002454:Cell Differentiation / Q000187:drug effects; D003018:Clot Retraction; D006224:Cricetinae; D003412:Cricetulus; D005337:Fibrin / Q000378:metabolism*; D017353:Gene Deletion; D006801:Humans; D039661:Integrin beta3 / Q000378:metabolism; D008533:Megakaryocytes / Q000166:cytology / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D015539:Platelet Activation; D040201:Platelet Membrane Glycoprotein IIb / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics
D018952:Antigens, CD34; D000081242:B-Cell Lymphoma 3 Protein; C000631344:BCL3 protein, human; C000631345:Bcl3 protein, mouse; D039661:Integrin beta3; D040201:Platelet Membrane Glycoprotein IIb; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D005337:Fibrin; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus