mTOR kinase structure, mechanism and regulation (original) (raw)
Zoncu, R., Efeyan, A. & Sabatini, D. M. mTOR: from growth signal integration to cancer, diabetes and ageing. Nature Rev. Mol. Cell Biol.12, 21–35 (2011) ArticleCAS Google Scholar
Shaw, R. J. & Cantley, L. C. Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature441, 424–430 (2006) ArticleADSCAS Google Scholar
Keith, C. T. & Schreiber, S. L. PIK-related kinases: DNA repair, recombination, and cell cycle checkpoints. Science270, 50–51 (1995) ArticleADSCAS Google Scholar
Hara, K. et al. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell110, 177–189 (2002) ArticleCAS Google Scholar
Kim, D. H. et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell110, 163–175 (2002) ArticleCAS Google Scholar
Loewith, R. et al. Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol. Cell10, 457–468 (2002) ArticleCAS Google Scholar
Sarbassov, D. D. et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr. Biol.14, 1296–1302 (2004) ArticleCAS Google Scholar
Chen, E. J. & Kaiser, C. A. LST8 negatively regulates amino acid biosynthesis as a component of the TOR pathway. J. Cell Biol.161, 333–347 (2003) ArticleCAS Google Scholar
Kim, D. H. et al. GβL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol. Cell11, 895–904 (2003) ArticleCAS Google Scholar
Sancak, Y. et al. The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science320, 1496–1501 (2008) ArticleADSCAS Google Scholar
Kim, E., Goraksha-Hicks, P., Li, L., Neufeld, T. P. & Guan, K. L. Regulation of TORC1 by Rag GTPases in nutrient response. Nature Cell Biol.10, 935–945 (2008) ArticleCAS Google Scholar
Saucedo, L. J. et al. Rheb promotes cell growth as a component of the insulin/TOR signalling network. Nature Cell Biol.5, 566–571 (2003) ArticleCAS Google Scholar
Stocker, H. et al. Rheb is an essential regulator of S6K in controlling cell growth in Drosophila . Nature Cell Biol.5, 559–566 (2003) ArticleCAS Google Scholar
Long, X., Lin, Y., Ortiz-Vega, S., Yonezawa, K. & Avruch, J. Rheb binds and regulates the mTOR kinase. Curr. Biol.15, 702–713 (2005) ArticleCAS Google Scholar
Sato, T., Nakashima, A., Guo, L. & Tamanoi, F. Specific activation of mTORC1 by Rheb G-protein in vitro involves enhanced recruitment of its substrate protein. J. Biol. Chem.284, 12783–12791 (2009) ArticleCAS Google Scholar
Sancak, Y. et al. PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol. Cell25, 903–915 (2007) ArticleCAS Google Scholar
Zhang, Y. et al. Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins. Nature Cell Biol.5, 578–581 (2003) ArticleCAS Google Scholar
Ma, X. M. & Blenis, J. Molecular mechanisms of mTOR-mediated translational control. Nature Rev. Mol. Cell Biol.10, 307–318 (2009) Article Google Scholar
Schalm, S. S., Fingar, D. C., Sabatini, D. M. & Blenis, J. TOS motif-mediated raptor binding regulates 4E–BP1 multisite phosphorylation and function. Curr. Biol.13, 797–806 (2003) ArticleCAS Google Scholar
Nojima, H. et al. The mammalian target of rapamycin (mTOR) partner, raptor, binds the mTOR substrates p70 S6 kinase and 4E–BP1 through their TOR signaling (TOS) motif. J. Biol. Chem.278, 15461–15464 (2003) ArticleCAS Google Scholar
Oshiro, N. et al. The proline-rich Akt substrate of 40 kDa (PRAS40) is a physiological substrate of mammalian target of rapamycin complex 1. J. Biol. Chem.282, 20329–20339 (2007) ArticleCAS Google Scholar
Fonseca, B. D., Smith, E. M., Lee, V. H., MacKintosh, C. & Proud, C. G. PRAS40 is a target for mammalian target of rapamycin complex 1 and is required for signaling downstream of this complex. J. Biol. Chem.282, 24514–24524 (2007) ArticleCAS Google Scholar
Jacinto, E. et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nature Cell Biol.6, 1122–1128 (2004) ArticleCAS Google Scholar
Choi, J., Chen, J., Schreiber, S. L. & Clardy, J. Structure of the FKBP12-rapamycin complex interacting with the binding domain of human FRAP. Science273, 239–242 (1996) ArticleADSCAS Google Scholar
Choo, A. Y. & Blenis, J. Not all substrates are treated equally: implications for mTOR, rapamycin-resistance and cancer therapy. Cell Cycle8, 567–572 (2009) ArticleCAS Google Scholar
Wander, S. A., Hennessy, B. T. & Slingerland, J. M. Next-generation mTOR inhibitors in clinical oncology: how pathway complexity informs therapeutic strategy. J. Clin. Invest.121, 1231–1241 (2011) ArticleCAS Google Scholar
Lovejoy, C. A. & Cortez, D. Common mechanisms of PIKK regulation. DNA Repair (Amst.)8, 1004–1008 (2009) ArticleCAS Google Scholar
Bosotti, R., Isacchi, A. & Sonnhammer, E. L. FAT: a novel domain in PIK-related kinases. Trends Biochem. Sci.25, 225–227 (2000) ArticleCAS Google Scholar
Walker, E. H., Perisic, O., Ried, C., Stephens, L. & Williams, R. L. Structural insights into phosphoinositide 3-kinase catalysis and signalling. Nature402, 313–320 (1999) ArticleADSCAS Google Scholar
Sibanda, B. L., Chirgadze, D. Y. & Blundell, T. L. Crystal structure of DNA-PKcs reveals a large open-ring cradle comprised of HEAT repeats. Nature463, 118–121 (2010) ArticleADSCAS Google Scholar
Nolen, B., Taylor, S. & Ghosh, G. Regulation of protein kinases; controlling activity through activation segment conformation. Mol. Cell15, 661–675 (2004) ArticleCAS Google Scholar
Miller, S. et al. Shaping development of autophagy inhibitors with the structure of the lipid kinase Vps34. Science327, 1638–1642 (2010) ArticleADSCAS Google Scholar
McMahon, L. P., Choi, K. M., Lin, T. A., Abraham, R. T. & Lawrence, J. C., Jr The rapamycin-binding domain governs substrate selectivity by the mammalian target of rapamycin. Mol. Cell. Biol.22, 7428–7438 (2002) ArticleCAS Google Scholar
Sekulic, A. et al. A direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and the mammalian target of rapamycin in mitogen-stimulated and transformed cells. Cancer Res.60, 3504–3513 (2000) CASPubMed Google Scholar
Edinger, A. L. & Thompson, C. B. An activated mTOR mutant supports growth factor-independent, nutrient-dependent cell survival. Oncogene23, 5654–5663 (2004) ArticleCAS Google Scholar
Bao, Z. Q., Jacobsen, D. M. & Young, M. A. Briefly bound to activate: transient binding of a second catalytic magnesium activates the structure and dynamics of CDK2 kinase for catalysis. Structure19, 675–690 (2011) ArticleCAS Google Scholar
Madhusudan, A. P. Xuong, N. H. & Taylor, S. S. Crystal structure of a transition state mimic of the catalytic subunit of cAMP-dependent protein kinase. Nature Struct. Biol.9, 273–277 (2002) ArticleCAS Google Scholar
Brown, E. J. et al. Control of p70 s6 kinase by kinase activity of FRAP in vivo . Nature377, 441–446 (1995) ArticleADSCAS Google Scholar
Hsu, P. P. et al. The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling. Science332, 1317–1322 (2011) ArticleADSCAS Google Scholar
Vilella-Bach, M., Nuzzi, P., Fang, Y. & Chen, J. The FKBP12-rapamycin-binding domain is required for FKBP12-rapamycin-associated protein kinase activity and G1 progression. J. Biol. Chem.274, 4266–4272 (1999) ArticleCAS Google Scholar
Shor, B. et al. A new pharmacologic action of CCI-779 involves FKBP12-independent inhibition of mTOR kinase activity and profound repression of global protein synthesis. Cancer Res.68, 2934–2943 (2008) ArticleCAS Google Scholar
Rodríguez, A. et al. A conserved docking surface on calcineurin mediates interaction with substrates and immunosuppressants. Mol. Cell33, 616–626 (2009) Article Google Scholar
Ohne, Y. et al. Isolation of hyperactive mutants of mammalian target of rapamycin. J. Biol. Chem.283, 31861–31870 (2008) ArticleCAS Google Scholar
Reinke, A., Chen, J. C., Aronova, S. & Powers, T. Caffeine targets TOR complex I and provides evidence for a regulatory link between the FRB and kinase domains of Tor1p. J. Biol. Chem.281, 31616–31626 (2006) ArticleCAS Google Scholar
Urano, J. et al. Point mutations in TOR confer Rheb-independent growth in fission yeast and nutrient-independent mammalian TOR signaling in mammalian cells. Proc. Natl Acad. Sci. USA104, 3514–3519 (2007) ArticleADSCAS Google Scholar
Liu, Q. et al. Discovery of 9-(6-aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo[h_][1,6]naphthyridin-2(1_H)-one (Torin2) as a potent, selective, and orally available mammalian target of rapamycin (mTOR) inhibitor for treatment of cancer. J. Med. Chem.54, 1473–1480 (2011) ArticleADSCAS Google Scholar
Apsel, B. et al. Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases. Nature Chem. Biol.4, 691–699 (2008) ArticleCAS Google Scholar
Knight, Z. A. et al. A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling. Cell125, 733–747 (2006) ArticleCAS Google Scholar
Otwinowski, Z. & Minor, W. Processing of X-ray diffraction data collected in oscillation mode. Methods Enzymol.276, 307–326 (1997) ArticleCAS Google Scholar
Bricogne, G., Vonrhein, C., Flensburg, C., Schiltz, M. & Paciorek, W. Generation, representation and flow of phase information in structure determination: recent developments in and around SHARP 2.0. Acta Crystallogr. D59, 2023–2030 (2003) ArticleCAS Google Scholar
Collaborative Computational Project, 4. The CCP4 suite: programs for protein crystallography. Acta Crystallogr. D50, 760–763 (1994) Article Google Scholar
Jones, T. A., Zou, J. Y., Cowan, S. W. & Kjeldgaard, M. Improved methods for building protein models in electron density maps and the location of errors in these models. Acta Crystallogr. A47, 110–119 (1991) Article Google Scholar
Adams, P. D. et al. PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr. D66, 213–221 (2010) ArticleCAS Google Scholar