The DOI matches its Crossref record; 30 of the 30 references it cites were found in a registry or an index.
TSC1 Stabilizes TSC2 by Inhibiting the Interaction between TSC2 and the HERC1 Ubiquitin Ligase
Open accessAbstract
Tuberous sclerosis complex (TSC) is an autosomal dominant disease characterized by hamartoma formation in various organs. Two genes responsible for the disease, TSC1 and TSC2, have been identified. The TSC1 and TSC2 proteins, also called hamartin and tuberin, respectively, have been shown to regulate cell growth through inhibition of the mammalian target of rapamycin pathway. TSC1 is known to stabilize TSC2 by forming a complex with TSC2, which is a GTPase-activating protein for the Rheb small GTPase. We have identified HERC1 as a TSC2-interacting protein. HERC1 is a 532-kDa protein with an E3 ubiquitin ligase homology to E6AP carboxyl terminus (HECT) domain. We observed that the interaction of TSC1 with TSC2 appears to exclude TSC2 from interacting with HERC1. Disease mutations in TSC2, which result in its destabilization, allow binding to HERC1 in the presence of TSC1. Our study reveals a potential molecular mechanism of how TSC1 stabilizes TSC2 by excluding the HERC1 ubiquitin ligase from the TSC2 complex. Furthermore, these data reveal a possible biochemical basis of how certain disease mutations inactivate TSC2.
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“TSC1 is an HSP-90 co-chaperone and protects TSC2 from HERC1-mediated ubiquitination and degradation (29).”
From Enhanced mTORC1 signaling and Protein Synthesis in Parkinson’s Disease Pathogenesis Disease Pathogenesis (2022) · cites this paper as [29]
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Upstream and downstream of mTOR
Hay, N., & Sonenberg, N. (2004) · Genes & Development · doi:10.1101/gad.1212704 · Cited by 4,181
TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling
Inoki, K., Li, Y., Zhu, T., Wu, J., & Guan, K.-L. (2002) · Nature Cell Biology · doi:10.1038/ncb839 · Cited by 3,083
Self-citationFingar, D. C., & Blenis, J. (2004) · Oncogene · doi:10.1038/sj.onc.1207542 · Cited by 1,264
Akt regulates growth by directly phosphorylating Tsc2
Potter, C. J., Pedraza, L. G., & Xu, T. (2002) · Nature Cell Biology · doi:10.1038/ncb840 · Cited by 959
Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins
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Tee, A. R., Fingar, D. C., Manning, B. D., Kwiatkowski, D. J., Cantley, L. C., & Blenis, J. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.202476899 · Cited by 827
Catalysis of guanine nucleotide exchange on Ran by the mitotic regulator RCC1
Bischoff, F. R., & Ponstingl, H. (1991) · Nature · doi:10.1038/354080a0 · Cited by 711
Tsc tumour suppressor proteins antagonize amino-acid–TOR signalling
Gao, X., Zhang, Y., Arrazola, P., Hino, O., Kobayashi, T., Yeung, R. S. W., Ru, B., & Pan, D. (2002) · Nature Cell Biology · doi:10.1038/ncb847 · Cited by 689
Kwiatkowski, D. J. (2002) · Human Molecular Genetics · doi:10.1093/hmg/11.5.525 · Cited by 674
The lore of the RINGs: substrate recognition and catalysis by ubiquitin ligases
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Research works printed but not linked: 1
- Zhang, 2003, J. Clin. Invest., 112, 1223, 10.1172/JCI200317222 · DOI
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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
Physiological functions of the HECT family of ubiquitin ligases
Rotin, D., & Kumar, S. (2009) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2690 · Cited by 1,105
Rare coding variants in ten genes confer substantial risk for schizophrenia
Singh, T., Poterba, T., Curtis, D., Akil, H., Al Eissa, M., Barchas, J. D., Bass, N., Bigdeli, T. B., Breen, G., Bromet, E. J., et al. (2022) · Nature · doi:10.1038/s41586-022-04556-w · Cited by 983
IKKβ Suppression of TSC1 Links Inflammation and Tumor Angiogenesis via the mTOR Pathway
Lee, D., Kuo, H.-P., Chen, C., Hsu, J.-M., Chou, C., Wei, Y., Sun, H., Li, L., Ping, B., Huang, W., et al. (2007) · Cell · doi:10.1016/j.cell.2007.05.058 · Cited by 639
The TSC-mTOR pathway regulates macrophage polarization
Byles, V., Covarrubias, A. J., Ben‐Sahra, I., Lamming, D. W., Sabatini, D. M., Manning, B. D., & Horng, T. (2013) · Nature Communications · doi:10.1038/ncomms3834 · Cited by 646
Metadata
- Authors
- Chong-Kopera, H., Inoki, K., Li, Y., Zhu, T., Garcia-Gonzalo, F. R., Rosa, J. L., & Guan, K.-L.
- Affiliations
- University of Michigan (US)
- Corresponding author
- Guan, Kun-Liang
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2006-03
- Volume
- 281
- Issue
- 13
- Pages
- 8313-8316
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1984412362
- Cited by
- 234
- References
- 30
- Citations by year
- 2026: 9 · 2025: 9 · 2024: 4 · 2023: 6 · 2022: 10 · 2021: 13 · 2020: 11 · 2019: 6 · 2018: 11 · 2017: 14 · 2016: 18 · 2015: 7 · 2014: 11 · 2013: 12 · 2012: 21
- FWCI
- 10.19
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (submittedVersion, public-domain)
- Funders
- National Institute on Aging (T32-AG00114-18, T32AG000114)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK124709)
- Topics
- Health Sciences › Medicine › Genetics (clinical) › Tuberous Sclerosis Complex Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- tuberous sclerosis complex, TSC1, TSC2, hamartin, tuberin, HERC1, E3 ubiquitin ligase, protein-protein interaction, protein stabilization, HECT domain, pathogenic variants, mTOR signaling, hamartoma
- MeSH terms
- Tuberous Sclerosis Complex 1 Protein, Tuberous Sclerosis Complex 2 Protein, Amino Acid Sequence, Animals, Brain Chemistry, Cell Extracts, Cell Line, Cycloheximide, Humans, Ligases, Precipitin Tests, Protein Synthesis Inhibitors, Blotting, Western, Silver Staining, Gene Deletion, Protein Structure, Tertiary, Guanine Nucleotide Exchange Factors, Protein Subunits, Tumor Suppressor Proteins, Ubiquitin, Ubiquitin-Protein Ligases, Mice
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