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Nutrient Physiology, Metabolism, and Nutrient-Nutrient Interactions

Arginine Stimulates cdx2-Transformed Intestinal Epithelial Cell Migration via a Mechanism Requiring Both Nitric Oxide and Phosphorylation of p70 S6 Kinase^1,2

³ Department of Pediatrics, University of Texas Health Science Center, Houston, TX 77030; ⁴ Ochsner Clinic Foundation, Research Institute, Department of Pediatrics, Section of Pediatric Gastroenterology, New Orleans, LA 70121; and ⁵ Department of Animal Science and Faculty of Nutrition, Texas A&M University, College Station, TX 77843

In intestinal cells, arginine (Arg) is 1 of the 2 most potent amino acid activators of p70^s6k, a key regulator of 5'- terminal oligopyrimidine mRNA translation, a necessary condition for increased cell migration. To investigate the mechanism of response to Arg, we used the rat crypt cell line cdx2-transformed IEC-6 cells (cdx2-IEC) and measured cell migration, immunocytochemical analysis of p70^s6k activation in response to Arg, and production of nitric oxide (NO). When treated with Arg, cdx2-IEC increased in phosphorylation on Thr-389 of p70^s6k (pp70^s6k) compared with control (P < 0.01). Phospho-Thr-421/Ser-424-p70^s6k was located in the nucleus shortly after Arg treatment. Arg enhanced pp70^s6k, cell migration (55% wound coverage), and NO production. In comparison, the branched-chain amino acid leucine (Leu) activated pp70^s6k, was a weaker stimulator of migration (23% coverage), and did not increase NO. A total of 25 µmol/L DETA-NONOate (DETA/NO) did not significantly enhance phosphorylation of p70^s6k but enhanced the rate of cell migration by 25%. Wound coverage with Leu plus DETA/NO (25 µmol/L) was greater than coverage with DETA/NO alone (P < 0.01). These and our previous studies lead to a model in which Arg must stimulate both pp70^s6k (in the nucleus) and NO release to enhance intestinal epithelial cell migration, which may be relevant to diseases that involve intestinal villous injury.

^* To whom correspondence should be addressed. E-mail: j.marc.rhoads{at}uth.tmc.edu.

Manuscript received 18 March 2008. Initial review completed 28 April 2008. Revision accepted 18 June 2008.