The DOI matches its Crossref record; 16 of the 16 references it cites were found in a registry or an index.
mTOR Drives Its Own Activation via SCFβTrCP-Dependent Degradation of the mTOR Inhibitor DEPTOR
Open accessAbstract
Summary The activities of both mTORC1 and mTORC2 are negatively regulated by their endogenous inhibitor, DEPTOR. As such, the abundance of DEPTOR is a critical determinant in the activity status of the mTOR network. DEPTOR stability is governed by the 26S-proteasome through a largely unknown mechanism. Here we describe an mTOR-dependent phosphorylation-driven pathway for DEPTOR destruction via SCFβ-TRCP. DEPTOR phosphorylation by mTOR in response to growth signals, and in collaboration with casein kinase I (CKI), generates a phosphodegron that binds β-TRCP. Failure to degrade DEPTOR through either degron mutation or β-TRCP depletion leads to reduced mTOR activity, reduced S6 kinase activity, and activation of autophagy to reduce cell growth. This work expands the current understanding of mTOR regulation by revealing a positive feedback loop involving mTOR and CKI-dependent turnover of its inhibitor, DEPTOR, suggesting that misregulation of the DEPTOR destruction pathway might contribute to aberrant activation of mTOR in disease.
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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
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AMPK Phosphorylation of Raptor Mediates a Metabolic Checkpoint
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TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling
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“…phosphorylation (Ghosh et al., 2008; Peterson et al., 2009), it has recently been shown that mTOR activation is linked to the lysosomal compartment (Sancak et al., 2010), raising the question of whether the effects of proteasome inhibition on mTOR activity reflects DEPTOR stabilization directly or…”
ULK-Atg13-FIP200 Complexes Mediate mTOR Signaling to the Autophagy Machinery
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Self-citation
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The oncometabolite 2-hydroxyglutarate activates the mTOR signalling pathway
Carbonneau, M., M. Gagné, L., Lalonde, M.-E., Germain, M.-A., Motorina, A., Guiot, M.-C., Secco, B., Vincent, E. E., Tumber, A., Hulea, L., et al. (2016) · Nature Communications · doi:10.1038/ncomms12700 · Cited by 180
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Metadata
- Authors
- Gao, D., Inuzuka, H., Tan, M.-K. M., Fukushima, H., Locasale, J. W., Liu, P., Wan, L., Zhai, B., Chin, Y. R., Shaik, S., Lyssiotis, C. A., Gygi, S. P., Toker, A., Cantley, L. C., Asara, J. M., Harper, J. W., & Wei, W.
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2011-10
- Volume
- 44
- Issue
- 2
- Pages
- 290-303
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W2122481965
- Cited by
- 248
- References
- 16
- FWCI
- 7.29
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Gao, D., Inuzuka, H., Tan, M.-K. M., Fukushima, H., Locasale, J. W., Liu, P., Wan, L., Zhai, B., Chin, Y. R., Shaik, S., Lyssiotis, C. A., Gygi, S. P., Toker, A., Cantley, L. C., Asara, J. M., Harper, J. W., & Wei, W. (2011). mTOR Drives Its Own Activation via SCFβTrCP-Dependent Degradation of the mTOR Inhibitor DEPTOR. Molecular Cell. https://doi.org/10.1016/j.molcel.2011.08.030
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