Abstract
In intestinal cells, arginine (Arg) is 1 of the 2 most potent amino acid activators of p70s6k, 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 p70s6k activation in response to Arg, and production of nitric oxide (NO). When treated with Arg, cdx2-IEC increased in phosphorylation on Thr-389 of p70s6k (pp70s6k) compared with control (P < 0.01). Phospho-Thr-421/Ser-424-p70s6k was located in the nucleus shortly after Arg treatment. Arg enhanced pp70s6k, cell migration (55% wound coverage), and NO production. In comparison, the branched-chain amino acid leucine (Leu) activated pp70s6k, 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 p70s6k 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 pp70s6k (in the nucleus) and NO release to enhance intestinal epithelial cell migration, which may be relevant to diseases that involve intestinal villous injury.
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