Structure of S6 kinase 1 determines whether raptor-mTOR or rictor-mTOR phosphorylates its hydrophobic motif site
ABSTRACT The mTOR protein kinase is the target of the immunosuppressive and anti-cancer drug rapamycin and is increasingly recognized as a key regulator of cell growth in mammals. S6 kinase 1 (S6K1) is the best characterized effector of mTOR, and its regulation serves as a model for mTOR signaling. Nutrients and growth factors activate S6K1 by inducing the phosphorylation of threonine 389 in the hydrophobic motif of S6K1. As phosphorylation of Thr(389) is rapamycin sensitive and mTOR can phosphorylate the same site in vitro, it has been suggested that mTOR is the physiological Thr(389) kinase. This proposal is not supported, however, by the existence of mutants of S6K1 that are phosphorylated in vivo on Thr(389) in a rapamycin-resistant fashion. Here, we demonstrate that the raptor-mTOR complex phosphorylates the rapamycin-sensitive forms of S6K1, while the distinct rictor-mTOR complex phosphorylates the rapamycin-resistant mutants of S6K1. Phosphorylation of Thr(389) by rictor-mTOR is independent of the TOR signaling motif and depends on removal of the carboxyl terminal domain of S6K1. Because many members of the AGC family of kinases lack an analogous domain, rictor-mTOR may phosphorylate the hydrophobic motifs of other kinases.
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ABSTRACT: The mTOR inhibitor sirolimus is effective in reducing incidence of graft-versus-disease (GVHD) following allogeneic hematopoietic stem cell transplantation (HSCT). Agents that inhibit the mTOR pathway are known to be associated with significant and potentially dose-limiting toxicities, including stomatitis. The objective of this study was to report the clinical features and management outcomes of sirolimus associated-oral ulcers in the context of post-HSCT prophylaxis of GVHD. Seventeen patients, from a study cohort of 967, treated with sirolimus as prophylaxis for GVHD following allogeneic HSCT at the Dana-Farber/Brigham and Women's Cancer Center developed oral ulcers and were referred to the oral medicine clinic for evaluation and treatment over a period of 6 years. Clinical characteristics (appearance, anatomic site, size) and therapeutic outcomes (time to complete resolution) were documented. Median time to onset of oral ulceration was 55 days post-allogeneic HSCT (range 6-387 days); 92.9% of ulcers were located on non-keratinized mucosa, with the ventrolateral tongue the most common site of involvement. Thirteen patients were treated with topical corticosteroid therapy; twelve of these patients also required intralesional corticosteroid injections. Clinical improvement (resolution of the lesions and improvement of symptoms) was noted in all cases, with no reported adverse events. Median time to complete resolution following onset of therapy was 14 days (range 2-70 days). Patients receiving sirolimus for GVHD prophylaxis may develop painful oral ulcerations which can be effectively managed with topical steroid treatment. Further prospective studies are needed to better elucidate the incidence of this complication, identify risk factors, and evaluate the effectiveness of interventions. Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 12/2014; 21(3). DOI:10.1016/j.bbmt.2014.11.680 · 3.35 Impact Factor
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ABSTRACT: mTOR is a central nutrient sensor that signals a cell to grow and proliferate. Through distinct protein complexes it regulates different levels of available cellular energy substrates required for cell growth. One of the important functions of the complex is to maintain available amino acid pool by regulating protein translation. Dysregulation of mTOR pathway leads to aberrant protein translation which manifests into various pathological states. Our review focuses on the role mTOR signaling plays in protein translation and its physiological role. It also throws some light on available data that show translation dysregulation as a cause of pathological complexities like cancer and the available drugs that target the pathway for cancer treatment.01/2014; 2014:686984. DOI:10.1155/2014/686984