Activity of TSC2 is inhibited by AKT-mediated phosphorylation and membrane partitioning
Open accessAbstract
Loss of tuberin, the product of TSC2 gene, increases mammalian target of rapamycin (mTOR) signaling, promoting cell growth and tumor development. However, in cells expressing tuberin, it is not known how repression of mTOR signaling is relieved to activate this pathway in response to growth factors and how hamartin participates in this process. We show that hamartin colocalizes with hypophosphorylated tuberin at the membrane, where tuberin exerts its GTPase-activating protein (GAP) activity to repress Rheb signaling. In response to growth signals, tuberin is phosphorylated by AKT and translocates to the cytosol, relieving Rheb repression. Phosphorylation of tuberin at serines 939 and 981 does not alter its intrinsic GAP activity toward Rheb but partitions tuberin to the cytosol, where it is bound by 14-3-3 proteins. Thus, tuberin bound by 14-3-3 in response to AKT phosphorylation is sequestered away from its membrane-bound activation partner (hamartin) and its target GTPase (Rheb) to relieve the growth inhibitory effects of this tumor suppressor.
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Phosphorylation has been shown to cause dispersion of TSC2 from membrane-localized TSC1 punctae to the cytosol in a manner dependent on interaction with 14-3-3 proteins.
“Phosphorylation has been shown to cause dispersion of TSC2 from membrane-localized TSC1 punctae to the cytosol (Cai et al., 2006), in a manner dependent on interaction with 14-3-3 proteins.”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Cai et al., 2006
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References 47 · Cited by 359
Research works printed but not linked: 1
- Gomez, M.R., J.R. Sampson, and V.H. Whittemore. 1999 Tuberous sclerosis complex. In Developmental Perspectives in Psychiatry. J.C. Harris, editor. Oxford University Press, Oxford, UK. 10–23, 275–312.
- Authors
- Cai, S.-L., Tee, A. R., Short, J. D., Bergeron, J. M., Kim, J., Shen, J., Guo, R., Johnson, C. L., Kiguchi, K., & Walker, C. L.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- University of Dundee (GB)
- Venue
- The Journal of Cell Biology
- Publisher
- Rockefeller University Press
- Published
- 2006-04-24
- Volume
- 173
- Issue
- 2
- Pages
- 279-289
- ISSN
- 0021-9525 (ISSN-L)
- 1540-8140
- PMC
- PMC2063818
- OpenAlex
- W2113288593
- Cited by
- 359
- References
- 47
- Citations by year
- 2026: 8 · 2025: 11 · 2024: 10 · 2023: 15 · 2022: 16 · 2021: 15 · 2020: 20 · 2019: 7 · 2018: 16 · 2017: 19 · 2016: 13 · 2015: 21 · 2014: 21 · 2013: 14 · 2012: 26
- FWCI
- 10.61
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- cc-by-nc-sa
- Locations
- The Journal of Cell Biology (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (CA 63613, CA-16672, R01CA063613, P30CA016672)
- National Institute of Environmental Health Sciences (#ES07784, P30ES007784, ES08263-06S1, R01ES008263)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD046282, HD46282)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Physiology › Tuberous Sclerosis Complex Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Keywords
- tuberin, hamartin, TSC2, Akt phosphorylation, Rheb, mTOR signaling, GTPase-activating protein, 14-3-3 proteins, membrane partitioning, tumor suppressor, cell growth regulation, serine phosphorylation
- MeSH terms
- Tuberous Sclerosis Complex 1 Protein, Tuberous Sclerosis Complex 2 Protein, Cell Line, Cell Membrane, Growth Substances, HeLa Cells, Humans, Models, Biological, Phosphorylation, Microscopy, Confocal, ras Proteins, Tumor Suppressor Proteins, Proto-Oncogene Proteins c-akt
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