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 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.

• Publication year

  2006

• Venue

  Journal of Biological Chemistry

• Publication date

  2006-03-31

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1074/jbc.C500451200PMID 16464865
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• The HERC proteins: functional and evolutionary insights

  2005cited by this paper
• Signaling by Target of Rapamycin Proteins in Cell Growth Control

  2005cited by this paper
• Distinct effects of single amino-acid changes to tuberin on the function of the tuberin–hamartin complex

  2005cited by this paper
• Upstream and downstream of mTOR.

  2004cited by this paper
• Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression

  2004cited by this paper
• Pam and Its Ortholog Highwire Interact with and May Negatively Regulate the TSC1·TSC2 Complex*

  2004cited by this paper
• TSC2: filling the GAP in the mTOR signaling pathway.

  2004cited by this paper
• The Rheb family of GTP-binding proteins.

  2004cited by this paper
• Tuberous sclerosis complex: from Drosophila to human disease.

  2004cited by this paper
• Human Papillomavirus 16 E6 Oncoprotein Interferences with Insulin Signaling Pathway by Binding to Tuberin*

  2004cited by this paper
• Loss of Tsc1/Tsc2 activates mTOR and disrupts PI3K-Akt signaling through downregulation of PDGFR.

  2003cited by this paper
• Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins

  2003cited by this paper
• Tumour suppressors hamartin and tuberin: intracellular signalling.

  2003cited by this paper
• Tuberous Sclerosis: from Tubers to mTOR

  2003cited by this paper
• Rheb fills a GAP between TSC and TOR.

  2003cited by this paper
• Tsc tumour suppressor proteins antagonize amino-acid–TOR signalling

  2002cited by this paper
• The S6 kinase signaling pathway in the control of development and growth.

  2002cited by this paper
• Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling

  2002cited by this paper
• Akt regulates growth by directly phosphorylating Tsc2

  2002cited by this paper
• TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling

  2002cited by this paper
• A mouse model of TSC1 reveals sex-dependent lethality from liver hemangiomas, and up-regulation of p70S6 kinase activity in Tsc1 null cells.

  2002cited by this paper
• Pathological mutations in TSC1 and TSC2 disrupt the interaction between hamartin and tuberin.

  2001cited by this paper
• The tuberous sclerosis-1 (TSC1) gene product hamartin suppresses cell growth and augments the expression of the TSC2 product tuberin by inhibiting its ubiquitination

  2000cited by this paper
• The lore of the RINGs: substrate recognition and catalysis by ubiquitin ligases.

  2000cited by this paper
• Tsc2(+/-) mice develop tumors in multiple sites that express gelsolin and are influenced by genetic background.

  1999cited by this paper
• Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products.

  1998cited by this paper
• A giant protein that stimulates guanine nucleotide exchange on ARF1 and Rab proteins forms a cytosolic ternary complex with clathrin and Hsp70

  1997cited by this paper
• p619, a giant protein related to the chromosome condensation regulator RCC1, stimulates guanine nucleotide exchange on ARF1 and Rab proteins.

  1996cited by this paper
• Predisposition to renal carcinoma in the Eker rat is determined by germ-line mutation of the tuberous sclerosis 2 (TSC2) gene.

  1994cited by this paper
• Catalysis of guanine nucleotide exchange on Ran by the mitotic regulator RCC1

  1991cited by this paper

• TSC1 phosphorylation by lysosomal mTORC1 establishes a minimal autoregulatory feedback loop

  2026cites this paper
• Examination of the Histogenesis of Epithelial Cysts in Angiomyolipoma with Epithelial Cysts (AMLEC) Using GPNMB and TSC2 Immunostains.

  2025cites this paper
• The Golgi Stacking Protein GORASP2 Regulates Mouse Primordial Follicle Activation by Suppressing the Autophagy Lysosome Pathway via RAP1 Competing With mTOR for RAPTOR Binding

  2025cites this paper
• HERC1 E3 Ubiquitin Ligase Is Necessary for Autophagy Processes and for the Maintenance and Homeostasis of Vesicles in Motor Nerve Terminals, but Not for Proteasomal Activity

  2025cites this paper
• New insights into tuberous sclerosis complex: from structure to pathogenesis

  2025cites this paper
• A Perspective on Therapeutic Targeting Against Ubiquitin Ligases to Stabilize Tumor Suppressor Proteins

  2025cites this paper
• TSC2 loss in neural progenitor cells suppresses mRNA translation of neurodevelopmental genes.

  2025cites this paper
• The evolution and diversification of the Hsp90 co-chaperone system

  2025cites this paper
• The dual role of the TSC complex in cancer.

  2024cites this paper
• The E3 ubiquitin ligase Herc1 modulates the response to nucleoside analogs in acute myeloid leukemia

  2024cites this paper
• First Case of Macrocephaly, Dysmorphic Facies, and Psychomotor Retardation Harboring Co-inherited Variants in HERC1 and PMP22 Genes from Iran: Two Novel Variants

  2024cites this paper
• Molecular chaperones: Guardians of tumor suppressor stability and function

  2024cites this paper
• The role of TSC1 and TSC2 proteins in neuronal axons

  2024cites this paper
• The role of TSC2 in breast cancer: a literature review

  2023cites this paper
• Impact of Co-chaperones and Posttranslational Modifications Toward Hsp90 Drug Sensitivity.

  2023cites this paper
• TSC2 regulates tumor susceptibility to TRAIL‐mediated T‐cell killing by orchestrating mTOR signaling

  2023cites this paper
• Enhanced mTORC1 signaling and protein synthesis in pathologic α-synuclein cellular and animal models of Parkinson’s disease

  2023cites this paper
• Increasing glutathione levels by a novel posttranslational mechanism inhibits neuronal hyperexcitability

  2023cites this paper
• Rare coding variants in 10 genes confer substantial risk for schizophrenia

  2023cites this paper
• Identi�cation of Potential Biomarkers for Nonsurvivor Sepsis Patients via Microarray Technology: A Study Based on GEO Datasets

  2023cites this paper
• Signaling pathway intervention in premature ovarian failure

  2022cites this paper
• Association analysis of risk genes identified by SCHEMA with schizophrenia in the Chinese Han population

  2022cites this paper
• Emerging Link between Tsc1 and FNIP Co-Chaperones of Hsp90 and Cancer

  2022cites this paper
• Rheb regulates nuclear mTORC1 activity independent of farnesylation.

  2022cites this paper
• Cross-talk between TSC2 and the extracellular matrix controls pulmonary vascular proliferation and pulmonary hypertension

  2022influential citation
• E3 ubiquitin ligases and cerebral cortex development in health and disease

  2022cites this paper
• mTORC1 Activity in Psoriatic Lesions Is Mediated by Aberrant Regulation through the Tuberous Sclerosis Complex

  2022cites this paper
• Identification of Hsp90 inhibitors as potential drugs for the treatment of TSC1/TSC2 deficient cancer

  2021cites this paper
• Mechanistic Target of Rapamycin Complex 1 Signaling Links Hypoxia to Increased IGFBP-1 Phosphorylation in Primary Human Decidualized Endometrial Stromal Cells

  2021cites this paper
• The TOR kinase pathway is relevant for nitrogen signaling and antagonism of the mycoparasite Trichoderma atroviride

  2021cites this paper
• Evaluation of Hsp90 and mTOR inhibitors as potential drugs for the treatment of TSC1/TSC2 deficient cancer

  2021cites this paper
• The HERC proteins and the nervous system.

  2021cites this paper
• Regulation of mTORC1 by amino acids in mammalian cells: A general picture of recent advances

  2021cites this paper
• RUNX1/EGFR pathway contributes to STAT3 activation and tumor growth caused by hyperactivated mTORC1

  2021cites this paper
• Amino acid sensory complex proteins in mTORC1 and macroautophagy regulation.

  2021cites this paper
• A multistep approach to the genotype-phenotype analysis of polish patients with tuberous sclerosis complex.

  2021cites this paper
• Aberrant mTOR/autophagy/Nurr1 signaling is critical for TSC-associated tumor development.

  2021cites this paper
• Tsc1 regulates tight junction independent of mTORC1

  2021cites this paper
• Cancer-associated dynamics and potential regulators of intronic polyadenylation revealed by IPAFinder using standard RNA-seq data

  2021cites this paper
• Myopathy associated LDB3 mutation causes Z-disc disassembly and protein aggregation through PKCα and TSC2-mTOR downregulation

  2021cites this paper
• Role of TSC1 in physiology and diseases

  2021cites this paper
• The Factors and Pathways Regulating the Activation of Mammalian Primordial Follicles in vivo

  2020cites this paper
• Regulation of mTORC1 by Upstream Stimuli

  2020cites this paper
• The HERC1 ubiquitin ligase regulates presynaptic membrane dynamics of central synapses

  2020cites this paper
• Ubiquitination and E3 Ubiquitin Ligases in Rare Neurological Diseases with Comorbid Epilepsy.

  2020cites this paper
• Architecture of the Tuberous Sclerosis Protein Complex

  2020cites this paper
• The E3 ubiquitin ligase Peli1 regulates the metabolic actions of mTORC1 to suppress antitumor T cell responses

  2020cites this paper
• Neurocutaneous disorders

  2020cites this paper
• Exome sequencing identifies rare coding variants in 10 genes which confer substantial risk for schizophrenia

  2020cites this paper
• The role of ubiquitination and deubiquitination in cancer metabolism

  2020cites this paper
• A new homozygous HERC1 gain-of-function variant in MDFPMR syndrome leads to mTORC1 hyperactivation and reduced autophagy during cell catabolism.

  2020cites this paper
• The Role of Heat Shock Protein-90 in the Pathogenesis of Birt-Hogg-Dubé and Tuberous Sclerosis Complex Syndromes.

  2020cites this paper
• Hamartin: An Endogenous Neuroprotective Molecule Induced by Hypoxic Preconditioning

  2020cites this paper
• Dérégulation de la synthèse protéique et dysfonction synaptique dans un modèle de souris d'autisme

  2019cites this paper
• HERCing: Structural and Functional Relevance of the Large HERC Ubiquitin Ligases

  2019cites this paper
• Translational Medicine Strategies in Drug Development for Neurodevelopmental Disorders

  2019cites this paper
• microRNA 92b-3p regulates primordial follicle assembly by targeting TSC1 in neonatal mouse ovaries

  2019cites this paper
• GPCR signaling inhibits mTORC1 via PKA phosphorylation of Raptor

  2019cites this paper
• mTORC1 feedback to AKT modulates lysosomal biogenesis through MiT/TFE regulation.

  2019cites this paper
• Mutational and functional study of Tuberous Sclerosis Complex 1 and 2 genes (TSC1 and TSC2)

  2019cites this paper
• Genetic Evaluation of Common Neurocutaneous Syndromes.

  2018cites this paper
• Atypical tuberous sclerosis complex presenting as familial renal cell carcinoma with leiomyomatous stroma

  2018cites this paper
• Molecular genetic diagnostics of tuberous sclerosis complex in Bulgaria: six novel mutations in the TSC1 and TSC2 genes

  2018cites this paper
• The E3 ubiquitin ligase HERC1 controls the ERK signaling pathway targeting C-RAF for degradation

  2018cites this paper
• PEX5 regulates autophagy via the mTORC1-TFEB axis during starvation

  2018cites this paper
• HERC1 Ubiquitin Ligase Is Required for Normal Axonal Myelination in the Peripheral Nervous System

  2018cites this paper
• mTORC1 signaling suppresses Wnt/β-catenin signaling through DVL-dependent regulation of Wnt receptor FZD level

  2018influential citation
• Sporadic renal angiomyolipoma in a patient with Birt-Hogg-Dubé: chaperones in pathogenesis

  2018cites this paper
• A family case with germline TSC1 and mtDNA mutations developing bilateral eosinophilic chromophobe renal cell carcinomas without other typical phenotype of tuberous sclerosis

  2018cites this paper
• Analysis of TSC1 mutation spectrum in mucosal melanoma

  2018cites this paper
• Genetically-engineered human cortical spheroid models of Tuberous Sclerosis

  2018cites this paper
• TRIM31 is upregulated in hepatocellular carcinoma and promotes disease progression by inducing ubiquitination of TSC1–TSC2 complex

  2018cites this paper
• Functional and Structural Characterization Reveals Novel FBXW7 Biology

  2018cites this paper
• mTOR signaling in stem and progenitor cells

  2018cites this paper
• Phakomatoses and Their Tumors: Genetics and New Treatment Options

  2017cites this paper
• Tumor suppressor Tsc1 is a new Hsp90 co‐chaperone that facilitates folding of kinase and non‐kinase clients

  2017cites this paper
• Deficient TSC 1 / TSC 2-complex suppression of SOX 9-osteopontin-AKT signalling cascade constrains tumour growth in tuberous sclerosis complex

  2017cites this paper
• HERC1 mutations in idiopathic intellectual disability.

  2017cites this paper
• Amino acid and small GTPase regulation of mTORC1

  2017cites this paper
• Atg9 antagonizes TOR signaling to regulate intestinal cell growth and epithelial homeostasis in Drosophila

  2017cites this paper
• Hereditary Renal Cell Carcinoma

  2017cites this paper
• miR-130a upregulates mTOR pathway by targeting TSC1 and is transactivated by NF-κB in high-grade serous ovarian carcinoma

  2017cites this paper
• Somatic Mutations in TSC1 and TSC2 Cause Focal Cortical Dysplasia.

  2017cites this paper
• TSC1 and TSC2 gene mutations and their implications for treatment in Tuberous Sclerosis Complex: a review

  2017cites this paper
• Importance of tuberin in carcinogenesis

  2017cites this paper
• Regulation of PERK–eIF2α signalling by tuberous sclerosis complex-1 controls homoeostasis and survival of myelinating oligodendrocytes

  2016cites this paper
• Impaired Mitochondrial Fat Oxidation Induces FGF21 in Muscle.

  2016cites this paper
• Combination Therapies Targeting the PI3K/AKT/mTOR Pathways

  2016cites this paper
• IMPLICATIONS OF MITOTIC ONSET REGULATION IN TUBEROUS SCLEROSIS

  2016cites this paper
• RING-, HECT-, and RBR-type E3 Ubiquitin Ligases: Involvement in Human Cancer.

  2016cites this paper
• Deficient TSC1/TSC2-complex suppression of SOX9-osteopontin-AKT signalling cascade constrains tumour growth in tuberous sclerosis complex

  2016cites this paper
• Structural basis of the TSC 1-TBC 1 D 7 interaction 1 Structural basis of the interaction between tuberous sclerosis complex 1 ( TSC 1 ) and Tre 2-Bub 2-Cdc 16 domain family member 7 ( TBC 1 D 7 )

  2016cites this paper
• A splice site mutation in HERC1 leads to syndromic intellectual disability with macrocephaly and facial dysmorphism: Further delineation of the phenotypic spectrum

  2016cites this paper
• mTOR Hyperactivation by Ablation of Tuberous Sclerosis Complex 2 in the Mouse Heart Induces Cardiac Dysfunction with the Increased Number of Small Mitochondria Mediated through the Down-Regulation of Autophagy

  2016cites this paper
• Structure of the TBC1D7-TSC1 complex reveals that TBC1D7 stabilizes dimerization of the TSC1 C-terminal coiled coil region.

  2016cites this paper
• Sustained activation of mTORC1 in macrophages increases AMPKα-dependent autophagy to maintain cellular homeostasis

  2016influential citation
• Structural Basis of the Interaction between Tuberous Sclerosis Complex 1 (TSC1) and Tre2-Bub2-Cdc16 Domain Family Member 7 (TBC1D7)*

  2016cites this paper
• Biological function derived from predicted structures in CASP11

  2016cites this paper
• The emerging role of m-TOR up-regulation in brain Astrocytoma.

  2016cites this paper
• Everolimus improves neuropsychiatric symptoms in a patient with tuberous sclerosis carrying a novel TSC2 mutation

  2016influential citation