title: TSC1 stabilizes TSC2 by inhibiting the interaction between TSC2 and the HERC1 ubiquitin ligase.
abstract: 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.
authors.affiliation: Life Sciences Institute, Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Huira
authors.initials: H
authors.lastname: Chong-Kopera
authors.forename: Ken
authors.initials: K
authors.lastname: Inoki
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
authors.forename: Tianqing
authors.initials: T
authors.lastname: Zhu
authors.forename: Francesc R
authors.initials: FR
authors.lastname: Garcia-Gonzalo
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Rosa
authors.forename: Kun-Liang
authors.initials: KL
authors.lastname: Guan
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D001923:Brain Chemistry; D002457:Cell Extracts; D002460:Cell Line; D003513:Cycloheximide / Q000494:pharmacology; D017353:Gene Deletion; D020662:Guanine Nucleotide Exchange Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D006801:Humans; D008025:Ligases / Q000378:metabolism*; D051379:Mice; D011233:Precipitin Tests; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D016622:Silver Staining; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D002457:Cell Extracts; D020662:Guanine Nucleotide Exchange Factors; D021122:Protein Subunits; D011500:Protein Synthesis Inhibitors; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; C000624651:Tsc1 protein, mouse; C000624654:Tsc2 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; D003513:Cycloheximide; C102169:HERC1 protein, human; D044767:Ubiquitin-Protein Ligases; D008025:Ligases