Structure of S6 kinase 1 determines whether raptor-mTOR or rictor-mTOR phosphorylates its hydrophobic motif site - PubMed (original) (raw)
. 2005 May 20;280(20):19445-8.
doi: 10.1074/jbc.C500125200. Epub 2005 Apr 4.
Affiliations
- PMID: 15809305
- DOI: 10.1074/jbc.C500125200
Free article
Structure of S6 kinase 1 determines whether raptor-mTOR or rictor-mTOR phosphorylates its hydrophobic motif site
Siraj M Ali et al. J Biol Chem. 2005.
Free article
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.
Similar articles
- Identification of a conserved motif required for mTOR signaling.
Schalm SS, Blenis J. Schalm SS, et al. Curr Biol. 2002 Apr 16;12(8):632-9. doi: 10.1016/s0960-9822(02)00762-5. Curr Biol. 2002. PMID: 11967149 - Hydrophobic motif phosphorylation is not required for activation loop phosphorylation of p70 ribosomal protein S6 kinase 1 (S6K1).
Keshwani MM, von Daake S, Newton AC, Harris TK, Taylor SS. Keshwani MM, et al. J Biol Chem. 2011 Jul 1;286(26):23552-8. doi: 10.1074/jbc.M111.258004. Epub 2011 May 11. J Biol Chem. 2011. PMID: 21561857 Free PMC article. - TOS motif-mediated raptor binding regulates 4E-BP1 multisite phosphorylation and function.
Schalm SS, Fingar DC, Sabatini DM, Blenis J. Schalm SS, et al. Curr Biol. 2003 May 13;13(10):797-806. doi: 10.1016/s0960-9822(03)00329-4. Curr Biol. 2003. PMID: 12747827 - Kinase activities associated with mTOR.
Yonezawa K, Yoshino KI, Tokunaga C, Hara K. Yonezawa K, et al. Curr Top Microbiol Immunol. 2004;279:271-82. doi: 10.1007/978-3-642-18930-2_16. Curr Top Microbiol Immunol. 2004. PMID: 14560963 Review. - mTOR Complex1-S6K1 signaling: at the crossroads of obesity, diabetes and cancer.
Dann SG, Selvaraj A, Thomas G. Dann SG, et al. Trends Mol Med. 2007 Jun;13(6):252-9. doi: 10.1016/j.molmed.2007.04.002. Epub 2007 Apr 23. Trends Mol Med. 2007. PMID: 17452018 Review.
Cited by
- Pharmacologic inhibition of LAT1 predominantly suppresses transport of large neutral amino acids and downregulates global translation in cancer cells.
Nishikubo K, Ohgaki R, Okanishi H, Okuda S, Xu M, Endou H, Kanai Y. Nishikubo K, et al. J Cell Mol Med. 2022 Oct;26(20):5246-5256. doi: 10.1111/jcmm.17553. Epub 2022 Sep 7. J Cell Mol Med. 2022. PMID: 36071551 Free PMC article. - Epithelial-mesenchymal reprogramming by KLF4-regulated Rictor expression contributes to metastasis of non-small cell lung cancer cells.
Zhou H, Guan Q, Hou X, Liu L, Zhou L, Li W, Liu H. Zhou H, et al. Int J Biol Sci. 2022 Jul 18;18(13):4869-4883. doi: 10.7150/ijbs.73548. eCollection 2022. Int J Biol Sci. 2022. PMID: 35982899 Free PMC article. - Protein kinase C: release from quarantine by mTORC2.
Baffi TR, Newton AC. Baffi TR, et al. Trends Biochem Sci. 2022 Jun;47(6):518-530. doi: 10.1016/j.tibs.2022.03.003. Epub 2022 Mar 28. Trends Biochem Sci. 2022. PMID: 35361526 Free PMC article. Review. - mTOR Regulation of AGC Kinases: New Twist to an Old Tail.
Baffi TR, Newton AC. Baffi TR, et al. Mol Pharmacol. 2022 Apr;101(4):213-218. doi: 10.1124/molpharm.121.000310. Epub 2021 Jun 21. Mol Pharmacol. 2022. PMID: 34155089 Free PMC article. Review. - Metformin: review of epidemiology and mechanisms of action in pancreatic cancer.
Eibl G, Rozengurt E. Eibl G, et al. Cancer Metastasis Rev. 2021 Sep;40(3):865-878. doi: 10.1007/s10555-021-09977-z. Epub 2021 Jun 17. Cancer Metastasis Rev. 2021. PMID: 34142285 Free PMC article. Review.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Molecular Biology Databases
Research Materials
Miscellaneous