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  • The EMBO Journal (2007) 26, 505 - 515
  • doi:10.1038/sj.emboj.7601522

PSGL-1 and mTOR regulate translation of ROCK-1 and physiological functions of macrophages

Richard Fox1, Thomas Q Nhan1, G Lynn Law2, David R Morris2, W Conrad Liles1,3 and Stephen M Schwartz1

  1. Department of Pathology, University of Washington, Seattle, WA, USA
  2. Department of Biochemistry, University of Washington, Seattle, WA, USA
  3. Department of Medicine, University of Toronto/University Health Network, Toronto General Hospital, Toronto, Ontario, Canada

Correspondence to:

Richard Fox, Department of Pathology, University of Washington, 815 Mercer Street, Seattle, WA 98109, USA. Tel.: +1 206 390 2997; Fax: +1 206 897 1540; E-mail: richardfox.fox@gmail.com

Stephen M Schwartz, Department of Pathology, University of Washington, 815 Mercer Street, Room 421, Seattle, WA 98109-4714, USA. Tel.: +1 206 543 0258; Fax: +1 206 897 1540; E-mail: steves@u.washington.edu

Received 13 March 2006; Accepted 30 November 2006

Rho-associated kinases (ROCKs) are critical molecules involved in the physiological functions of macrophages, such as chemotaxis and phagocytosis. We demonstrate that macrophage adherence promotes rapid changes in physiological functions that depend on translational upregulation of preformed ROCK-1 mRNA, but not ROCK-2 mRNA. Before adherence, both ROCK mRNAs were present in the cytoplasm of macrophages, whereas ROCK proteins were undetectable. Macrophage adherence promoted signaling through P-selectin glycoprotein ligand-1 (PSGL-1)/Akt/mTOR that resulted in synthesis of ROCK-1, but not ROCK-2. Following synthesis, ROCK-1 was catalytically active. In addition, there was a rapamycin/sirolimus-sensitive enhanced loading of ribosomes on preformed ROCK-1 mRNAs. Inhibition of mTOR by rapamycin abolished ROCK-1 synthesis in macrophages resulting in an inhibition of chemotaxis and phagocytosis. Macrophages from PSGL-1-deficient mice recapitulated pharmacological inhibitor studies. These results indicate that receptor-mediated regulation at the level of translation is a component of a rapid set of mechanisms required to direct the macrophage phenotype upon adherence and suggest a mechanism for the immunosuppressive and anti-inflammatory effects of rapamycin/sirolimus.

  • Keywords:

    • mTOR,
    • rapamycin–sirolimus,
    • ROCK-1,
    • translation