The DOI matches its Crossref record; 10 of the 10 references it cites were found in a registry or an index.
The TSC1-TSC2 Complex Is Required for Proper Activation of mTOR Complex 2
Open accessAbstract
The mammalian target of rapamycin (mTOR) is a protein kinase that forms two functionally distinct complexes important for nutrient and growth factor signaling. Both complexes phosphorylate a hydrophobic motif on downstream protein kinases, which contributes to the activation of these kinases. mTOR complex 1 (mTORC1) phosphorylates S6K1, while mTORC2 phosphorylates Akt. The TSC1-TSC2 complex is a critical negative regulator of mTORC1. However, how mTORC2 is regulated and whether the TSC1-TSC2 complex is involved are unknown. We find that mTORC2 isolated from a variety of cells lacking a functional TSC1-TSC2 complex is impaired in its kinase activity toward Akt. Importantly, the defect in mTORC2 activity in these cells can be separated from effects on mTORC1 signaling and known feedback mechanisms affecting insulin receptor substrate-1 and phosphatidylinositol 3-kinase. Our data also suggest that the TSC1-TSC2 complex positively regulates mTORC2 in a manner independent of its GTPase-activating protein activity toward Rheb. Finally, we find that the TSC1-TSC2 complex can physically associate with mTORC2 but not mTORC1. These data demonstrate that the TSC1-TSC2 complex inhibits mTORC1 and activates mTORC2, which through different mechanisms promotes Akt activation.
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Cites
Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex
Sarbassov, D. D., Guertin, D. A., Ali, S. M., & Sabatini, D. M. (2005) · Science · doi:10.1126/science.1106148 · Cited by 6,216
AKT/PKB signaling: navigating downstream
Manning, B. D., & Cantley, L. C. (2007) · Cell · doi:10.1016/j.cell.2007.06.009 · Cited by 6,115
Self-citationRheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling
Inoki, K., Li, Y., Xu, T., & Guan, K.-L. (2003) · Genes & Development · doi:10.1101/gad.1110003 · Cited by 1,911
Loewith, R., Jacinto, E., Wullschleger, S., Lorberg, A., Crespo, J. L., Bonenfant, D., Oppliger, W., Jenoe, P., & Hall, M. N. (2002) · Molecular Cell · doi:10.1016/s1097-2765(02)00636-6 · Cited by 1,886
The Tuberous Sclerosis Complex
Crino, P. B., Nathanson, K. L., & Henske, E. P. (2006) · New England Journal of Medicine · doi:10.1056/nejmra055323 · Cited by 1,793
Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity
Um, S. H., Frigerio, F., Watanabe, M., Picard, F., Joaquin, M., Sticker, M., Fumagalli, S., Allegrini, P. R., Kozma, S. C., Auwerx, J., et al. (2004) · Nature · doi:10.1038/nature02866 · Cited by 1,677
PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase
Sancak, Y., Thoreen, C. C., Peterson, T. R., Lindquist, R. A., Kang, S. A., Spooner, E., Carr, S. A., & Sabatini, D. M. (2007) · Molecular Cell · doi:10.1016/j.molcel.2007.03.003 · Cited by 1,236 · cited 1×
“GTP-bound Rheb potently activates the mammalian target of rapamycin complex 1 (mTORC1) (26, 35 ), which plays an evolutionarily conserved role in promoting cell growth and proliferation (49).”
BackgroundBhaskar, P. T., & Hay, N. (2007) · Developmental Cell · doi:10.1016/j.devcel.2007.03.020 · Cited by 798
mTOR, translation initiation and cancer
Mamane, Y., Petroulakis, E., LeBacquer, O., & Sonenberg, N. (2006) · Oncogene · doi:10.1038/sj.onc.1209888 · Cited by 607
TSC1 Stabilizes TSC2 by Inhibiting the Interaction between TSC2 and the HERC1 Ubiquitin Ligase
Chong-Kopera, H., Inoki, K., Li, Y., Zhu, T., Garcia-Gonzalo, F. R., Rosa, J. L., & Guan, K.-L. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.c500451200 · Cited by 234
Cited by
AKT/PKB Signaling: Navigating the Network
Manning, B. D., & Toker, A. (2017) · Cell · doi:10.1016/j.cell.2017.04.001 · Cited by 3,772
Self-citationActivation of a metabolic gene regulatory network downstream of mTOR complex 1
Düvel, K., Yecies, J. L., Menon, S., Raman, P., Lipovsky, A. I., Souza, A. L., Triantafellow, E., Ma, Q., Gorski, R., Cleaver, S., et al. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.06.022 · Cited by 2,020
Self-citationNorthrup, H., Krueger, D. A., Northrup, H., Krueger, D. A., Roberds, S., Smith, K., Sampson, J., Korf, B., Kwiatkowski, D. J., Mowat, D., et al. (2013) · Pediatric Neurology · doi:10.1016/j.pediatrneurol.2013.08.001 · Cited by 1,502
The TSC1–TSC2 complex: a molecular switchboard controlling cell growth
Huang, J., & Manning, B. D. (2008) · Biochemical Journal · doi:10.1042/bj20080281 · Cited by 1,237
Self-citationSREBP-regulated lipid metabolism: convergent physiology - divergent pathophysiology
Shimano, H., & Sato, R. (2017) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2017.91 · Cited by 1,174
Metadata
- Authors
- Huang, J., Dibble, C. C., Matsuzaki, M., & Manning, B. D.
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2008-06-01
- Volume
- 28
- Issue
- 12
- Pages
- 4104-4115
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- OpenAlex
- W2099031084
- Cited by
- 511
- References
- 10
- FWCI
- 16.01
- Type
- journal article
- Language
- en
- Open access
- green
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