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Blood, 15 May 2008, Vol. 111, No. 10, pp. 4892-4901. Prepublished online as a Blood First Edition Paper on March 12, 2008; DOI 10.1182/blood-2007-11-125039. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2007-11-125039v1 111/10/4892    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Murooka, T. T. Articles by Fish, E. N. PubMed PubMed Citation Articles by Murooka, T. T. Articles by Fish, E. N. Related Collections Chemokines, Cytokines, and Interleukins Immunobiology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  CHEMOKINES, CYTOKINES, AND INTERLEUKINS CCL5-mediated T-cell chemotaxis involves the initiation of mRNA translation through mTOR/4E-BP1 Thomas T. Murooka1, Ramtin Rahbar1, Leonidas C. Platanias2, and Eleanor N. Fish1 1 Division of Cellular and Molecular Biology, Toronto General Research Institute, University Health Network and Department of Immunology, University of Toronto, Toronto, ON; and 2 Robert H. Lurie Comprehensive Cancer Center, Northwestern University Medical School, Chicago, IL The multistep, coordinated process of T-cell chemotaxis requires chemokines, and their chemokine receptors, to invoke signaling events to direct cell migration. Here, we examined the role for CCL5-mediated initiation of mRNA translation in CD4+ T-cell chemotaxis. Using rapamycin, an inhibitor of mTOR, our data show the importance of mTOR in CCL5-mediated T-cell migration. Cycloheximide, but not actinomycin D, significantly reduced chemotaxis, suggesting a possible role for mRNA translation in T-cell migration. CCL5 induced phosphorylation/activation of mTOR, p70 S6K1, and ribosomal protein S6. In addition, CCL5 induced PI-3'K–, phospholipase D (PLD)–, and mTOR-dependent phosphorylation and deactivation of the transcriptional repressor 4E-BP1, which resulted in its dissociation from the eukaryotic initiation factor-4E (eIF4E). Subsequently, eIF4E associated with scaffold protein eIF4G, forming the eIF4F translation initiation complex. Indeed, CCL5 initiated active translation of mRNA, shown by the increased presence of high-molecular-weight polysomes that were significantly reduced by rapamycin treatment. Notably, CCL5 induced protein translation of cyclin D1 and MMP-9, known mediators of migration. Taken together, we describe a novel mechanism by which CCL5 influences translation of rapamycin-sensitive mRNAs and "primes" CD4+ T cells for efficient chemotaxis. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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