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HORMONES AND SIGNALING

Role of mTOR signaling in intestinal cell migration

¹Department of Pediatrics and Research Institute, Ochsner Clinic Foundation, New Orleans, Louisiana; ²Department of Animal Sciences, North Carolina State University, Raleigh; and ³Department of Pharmacology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina

Submitted 26 April 2005 ; accepted in final form 12 February 2006

An early signaling event activated by amino acids and growth factors in many cell types is the phosphorylation of the mammalian target of rapamycin (mTOR; FRAP), which is functionally linked to ribosomal protein s6 kinase (p70^s6k), a kinase that plays a critical regulatory role in the translation of mRNAs and protein synthesis. We previously showed that intestinal cell migration, the initial event in epithelial restitution, is enhanced by L-arginine (ARG). In this study, we used amino acids as prototypic activators of mTOR and ARG, IGF-1, or serum as recognized stimulators of intestinal cell migration. We found that 1) protein synthesis is required for intestinal cell migration, 2) mTOR/p70^s6k pathway inhibitors (rapamycin, wortmannin, and intracellular Ca²⁺ chelation) inhibit cell migration, 3) ARG activates migration and mTOR/p70^s6k (but not ERK-2) in migrating enterocytes, and 4) immunocytochemistry reveals abundant p70^s6k staining in cytoplasm, whereas phospho-p70^s6k is virtually all intranuclear in resting cells but redistributes to the periphery on activation by ARG. We conclude that mTOR/p70^s6k signaling is essential to intestinal cell migration, is activated by ARG, involves both nuclear and cytoplasmic events, and may play a role in intestinal repair.

insulin-like growth factor-1; arginine; p70 s6 kinase; extracellular signal-regulated kinase-2; rapamycin

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