Integrins regulate the intracellular distribution of eukaryotic initiationfactor 4E in platelets - A checkpoint for translational control

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., Pa bla, 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 synthesi s in platelets is controlled at the translational level; however, the mecha nisms of regulation are not known. Here we demonstrate that translation ini tiation factors are redistributed to mRNA-rich areas in aggregated platelet s, an event that induces protein synthesis. Interrogation of cDNA arrays re vealed that platelet-derived mRNAs are primarily associated with the cytosk eletal core. In contrast, eukaryotic initiation factor 4E (eIF4E), the esse ntial mRNA cap-binding protein that controls global translation rates, is l ocalized in the membrane skeleton and soluble fraction of platelets, physic ally separated from most mRNAs. Platelet activation redistributes eIF4E to the cytoskeleton and increases interactions of eIF4E with mRNA cap structur es. Redistribution of eIF4E to the mRNA-rich cytoskeleton coincides with a marked increase in protein synthesis, a process that is blocked when intrac ellular actin is disrupted. Additional studies demonstrated that ss (3) int egrins are the primary membrane receptor that distributes eIF4E within the cell. These results imply that integrins link receptor-mediated pathways wi th mRNA-rich cytoskeletal domains and thereby modulate the organization of intracellular translational complexes. They also indicate that the function al status of eIF4E is regulated by its intracellular distribution.