title: Signal-dependent translation of a regulatory protein, Bcl-3, in activated human platelets.
abstract: Circulating human platelets lack nuclei, cannot synthesize mRNA, and are considered incapable of regulated protein synthesis. We found that thrombin-activated, but not resting, platelets synthesize Bcl-3, a member of the IkappaB-alpha family of regulatory proteins. The time- and concentration-dependent generation of Bcl-3 in platelets signaled by thrombin was blocked by translational inhibitors, by rapamycin, and by inhibitors of phosphatidylinositol-3-kinase, indicating that it occurs via a specialized translational control pathway that involves phosphorylation of the inhibitory protein 4E-BP1. After its synthesis in activated platelets Bcl-3 binds to the SH3 domain of Fyn (p59(fyn)), a Src-related tyrosine kinase. This, along with its expression in anucleate cells, suggests that Bcl-3 has previously unrecognized functions aside from modulation of transcription. We also demonstrate that platelets synthesize and secrete numerous proteins besides Bcl-3 after they adhere to fibrinogen, which mediates adhesion and outside-in signaling of these cells by engagement of alphaIIb/beta3 integrin. Taken together, these data demonstrate that regulated synthesis of proteins is a signal-dependent activation response of human platelets.
authors.affiliation: Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT 84112, USA. andrew_weyrich@gatormail.cvrti.utah.edu
authors.forename: A S
authors.initials: AS
authors.lastname: Weyrich
authors.forename: D A
authors.initials: DA
authors.lastname: Dixon
authors.forename: R
authors.initials: R
authors.lastname: Pabla
authors.forename: M R
authors.initials: MR
authors.lastname: Elstad
authors.forename: T M
authors.initials: TM
authors.lastname: McIntyre
authors.forename: S M
authors.initials: SM
authors.lastname: Prescott
authors.forename: G A
authors.initials: GA
authors.lastname: Zimmerman
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000081242:B-Cell Lymphoma 3 Protein; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D010448:Peptide Initiation Factors / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D015539:Platelet Activation; D011090:Polyenes / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D014176:Protein Biosynthesis; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics / Q000378:metabolism; D051076:Proto-Oncogene Proteins c-fyn; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus; D014157:Transcription Factors; D014162:Transfection; D018909:src Homology Domains
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000081242:B-Cell Lymphoma 3 Protein; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D010448:Peptide Initiation Factors; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins; D011090:Polyenes; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051076:Proto-Oncogene Proteins c-fyn; D012097:Repressor Proteins; D020123:Sirolimus; D014157:Transcription Factors; C000631344:BCL3 protein, human; C087000:EIF4EBP1 protein, human; C494957:FYN protein, human