TSC1 Stabilizes TSC2 by Inhibiting the Interaction between TSC2 and the HERC1 Ubiquitin Ligase

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 regulat...

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Published in:The Journal of biological chemistry 2006-03, Vol.281 (13), p.8313-8316
Main Authors: Chong-Kopera, Huira, Inoki, Ken, Li, Yong, Zhu, Tianqing, Garcia-Gonzalo, Francesc R., Rosa, Jose Luis, Guan, Kun-Liang
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Blotting, Western
Brain Chemistry
Cell Extracts
Cell Line
Cycloheximide - pharmacology
Gene Deletion
Guanine Nucleotide Exchange Factors - antagonists & inhibitors
Guanine Nucleotide Exchange Factors - chemistry
Guanine Nucleotide Exchange Factors - genetics
Humans
Ligases - metabolism
Mice
Precipitin Tests
Protein Structure, Tertiary
Protein Subunits - metabolism
Protein Synthesis Inhibitors - pharmacology
Silver Staining
Tuberous Sclerosis Complex 1 Protein
Tuberous Sclerosis Complex 2 Protein
Tumor Suppressor Proteins - chemistry
Tumor Suppressor Proteins - metabolism
Ubiquitin - metabolism
Ubiquitin-Protein Ligases - metabolism
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Summary: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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.C500451200