Submitted on April 25, 2005
Accepted on February 12, 2006
ROLE OF mTOR SIGNALING IN INTESTINAL CELL MIGRATION
J. Marc Rhoads1*, Xiaomei Niu1, Jack Odle1, and Lee M Graves1
1 Pediatric Gastroenterology, Ochsner Clinic Foundation, New Orleans, Louisiana, United States; Animal Sciences, College of Veterinary Medicine, Raleigh, North Carolina, United States; Pharmacology, University of North Carolina, Chapel Hill, North Carolina, United States
* To whom correspondence should be addressed. E-mail: mrhoads{at}ochsner.org.
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 (p70s6k), 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 insulin-like growth factor-1 (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/p70s6k pathway inhibitors (rapamycin, wortmannin, and intracellular Ca++ chelation) inhibit cell migration; and (3) ARG activates migration under normal conditions and in the presence of endotoxin and activates mTOR/p70s6k (but not extracellular-related kinase (ERK)-2 or p38 MAP kinase) in migrating enterocytes; (4) Immunocytochemical staining reveals abundant p70s6k staining in cytoplasm, while phospho-p70s6k is virtually all intranuclear in resting cells but redistributes to the periphery upon activation by ARG. We conclude that mTOR/p70s6k 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.
