Abstract
Recent evidence from our laboratory demonstrates that platelets synthesize numerous proteins in a signal-dependent fashion (Pabla, R., Weyrich, A. S., Dixon, D. A., Bray, P. F., McIntyre, T. M., Prescott, S. M., and Zimmerman, G. A. (1999) J. Cell Biol. 144, 175-184; Weyrich, A. S., Dixon, D. A., Pabla, R., Elstad, M. R., McIntyre, T. M., Prescott, S. M., and Zimmerman, G. A. (1998) Proc. Natl. Acad. Sci. U. S. A. 95, 5556-5561). Protein synthesis in platelets is controlled at the translational level; however, the mechanisms of regulation are not known. Here we demonstrate that translation initiation factors are redistributed to mRNA-rich areas in aggregated platelets, an event that induces protein synthesis. Interrogation of cDNA arrays revealed that platelet-derived mRNAs are primarily associated with the cytoskeletal core. In contrast, eukaryotic initiation factor 4E (eIF4E), the essential mRNA cap-binding protein that controls global translation rates, is localized in the membrane skeleton and soluble fraction of platelets, physically separated from most mRNAs. Platelet activation redistributes eIF4E to the cytoskeleton and increases interactions of eIF4E with mRNA cap structures. Redistribution of eIF4E to the mRNA-rich cytoskeleton coincides with a marked increase in protein synthesis, a process that is blocked when intracellular actin is disrupted. Additional studies demonstrated that beta(3) integrins are the primary membrane receptor that distributes eIF4E within the cell. These results imply that integrins link receptor-mediated pathways with mRNA-rich cytoskeletal domains and thereby modulate the organization of intracellular translational complexes. They also indicate that the functional status of eIF4E is regulated by its intracellular distribution.
Highlights
Recent evidence from our laboratory demonstrates that platelets synthesize numerous proteins in a signal-dependent fashion
A screen of a cDNA array demonstrates that platelets contain numerous mRNAs and the majority of these transcripts are associated with the cytoskeletal core of resting platelets (Fig. 1, left panel)
A prominent level of regulation occurs at the initiation step where eukaryotic initiation factors catalyze translation. eukaryotic initiation factor 4E (eIF4E) is the major rate-limiting initiation factor because it docks the eIF4F complex on the cap structure of the 5Ј-terminus of virtually all mRNAs
Summary
Additional studies demonstrated that 3 integrins are the primary membrane receptor that distributes eIF4E within the cell These results imply that integrins link receptor-mediated pathways with mRNA-rich cytoskeletal domains and thereby modulate the organization of intracellular translational complexes. Other studies have implicated integrins as well, demonstrating that adhesion to extracellular matrix induces the rapid translation of preexisting mRNAs in nucleated cells (6, 7) These results suggest that outside-in signals delivered by integrins, in addition to regulating a host of other postligand binding events, modulates protein synthesis at the translational level. Instead of directly influencing eIF4E activity, ␣IIb3 integrins target this initiation factor to subcellular cytoskeletal domains that contain numerous mRNAs. Redistribution of eIF4E is required for signal-dependent protein synthesis, providing evidence that intracellular spatial localization is an important determinant of eIF4E function. We recently demonstrated that cellular activation globally increases protein synthesis indicating that the
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