Arginine and Leucine regulate p70 S6 kinase and 4E-BP1 in intestinal epithelial cells.
Amino acids, especially branched-chain amino acids such as l-Leucine, have been revealed to regulate activation of p70 S6 kinase and phosphorylation of 4E-BP1 through mTOR signaling pathway. In this study, we showed that a cationic amino acid, l-Arginine, also activated this signaling pathway in a rapamycin-sensitive manner in rat intestinal epithelial cells, and this l-Arginine-induced amino acid signal transduction involved the cationic amino acid transport system. The manner of l-Arginine- and l-Leucine-induced activation of p70 S6 kinase depended on the stimulation time and the concentration of each amino acid, which suggested that the mechanism of this amino acid signal acceptance might be saturable. l-Arginine and l-Leucine induced activation of p70 S6 kinase and phosphorylation of 4E-BP1 in a rapamycin-sensitive manner, which suggested the involvement of mTOR signaling pathway in these effects. l-Arginine-induced activation of p70 S6 kinase was inhibited by NG-Methyl-L-Arginine (NMMA) and L-N5-(1-Iminoethyl) Ornithine (NIO), inhibitors of nitric oxide synthase (NOS) which also block cationic amino acid transporters, system y(+). However, l-Leucine-induced activation of p70 S6 kinase was not affected with treatment of NOS inhibitors. In conclusion, l-Arginine regulates p70 S6 kinase activity and phosphorylation of 4E-BP1 through mTOR signaling pathway, which involves system y(+), cationic amino acid transporters.
Ban
Hidetoshi
H
Department of Gastroenterological Surgery, Transplant, and Surgical Oncology, Graduate School of Medicine and Dentistry, Okayama University, Okayama 700-8558, Japan.
Shigemitsu
Kaori
K
Yamatsuji
Tomoki
T
Haisa
Minoru
M
Nakajo
Tohru
T
Takaoka
Munenori
M
Nobuhisa
Tetsuji
T
Gunduz
Mehmet
M
Tanaka
Noriaki
N
Naomoto
Yoshio
Y
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001120:Arginine / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D002352:Carrier Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000378:metabolism*; D015151:Immunoblotting; D007422:Intestines / Q000473:pathology*; D047908:Intracellular Signaling Peptides and Proteins; D007930:Leucine / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D009952:Ornithine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D011233:Precipitin Tests; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism*; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D013997:Time Factors; D000077191:Wortmannin; D019323:omega-N-Methylarginine / Q000494:pharmacology
D000730:Androstadienes; D002352:Carrier Proteins; C499526:Eif4ebp1 protein, rat; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D019323:omega-N-Methylarginine; C065027:N(G)-iminoethylornithine; D001120:Arginine; D009952:Ornithine; D019001:Nitric Oxide Synthase; D011494:Protein Kinases; C546845:mTOR protein, rat; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D007930:Leucine; D020123:Sirolimus; D000077191:Wortmannin