Affinage

TSC2

Tuberin · UniProt P49815

Length
1807 aa
Mass
200.6 kDa
Annotated
2026-06-10
100 papers in source corpus 41 papers cited in narrative 41 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TSC2 (tuberin) is a multifunctional tumor suppressor that integrates growth-factor, energy, and mechanical-stress signals to restrain cell growth, principally by acting as a GTPase-activating protein (GAP) that drives GTP hydrolysis on the small GTPase Rheb and thereby suppresses mTORC1 signaling (PMID:15340059, PMID:12045200). Its GAP activity resides in a C-terminal GAP-related domain and operates through a non-canonical catalytic 'asparagine thumb' mechanism, with TSC2 Asn1643 and Rheb Tyr35 forming the key active-site contacts defined structurally; missense mutations in this domain found in TSC patients disrupt growth control (PMID:15340059, PMID:32502382, PMID:9302281). TSC2 functions as a stable heterodimer with TSC1 (hamartin) through reciprocal coiled-coil interactions, and TSC1 binding stabilizes TSC2 by excluding ubiquitin ligases—HERC1 and the FBW5-DDB1-CUL4-ROC1 complex—that otherwise target TSC2 for degradation (PMID:9580671, PMID:16464865, PMID:18381890, PMID:11175345). The complex is a signaling hub controlled by direct phosphorylation: Akt, ERK, cyclin D-CDK, and PKG1 phosphorylate TSC2 at distinct sites to dissociate or destabilize the complex and tune mTORC1 output, while AMPK phosphorylation under energy stress enhances TSC2 activity (PMID:12172553, PMID:12172554, PMID:15851026, PMID:16357142, PMID:30700906, PMID:14651849); phospho-dependent 14-3-3 binding further inhibits TSC2 function (PMID:12364343, PMID:12468542). Reconstitution in TSC2-null cells establishes tuberin as a negative regulator of p70S6K, S6 phosphorylation, and DNA synthesis, downstream of which it controls cell size, proliferation, apoptosis, and metabolism (PMID:12045200, PMID:14651849, PMID:16702951). Beyond Rheb-mTORC1, TSC2 governs Rho/Rac-dependent actin dynamics, cell adhesion and migration, E-cadherin localization, EphA-ERK-mediated axon guidance, lysosomal biogenesis via RAGC-TFEB, and DNA-repair enzyme OGG1 expression through NF-YA, marking it as a broad integrator of cell physiology (PMID:15611338, PMID:16388022, PMID:20813961, PMID:20062052, PMID:34253722, PMID:17989114). Pathogenic TSC2 mutations that abolish the TSC1 interface or the GAP domain underlie tuberous sclerosis (PMID:11741833, PMID:9302281).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1995 High

    Established that the TSC2 product tuberin is an enzyme—a GAP—rather than merely a structural tumor suppressor, defining its biochemical class and localizing the activity to its C-terminus.

    Evidence In vitro GTPase assays with native immunoprecipitate and recombinant C-terminal fragment, substrate specificity panel, subcellular fractionation

    PMID:7608212

    Open questions at the time
    • Identified Rap1a, not Rheb, as substrate—the physiological substrate was unresolved
    • Did not connect GAP activity to a growth-control pathway
  2. 1996 High

    Placed tuberin at the Golgi with its then-presumed substrate Rap1, giving the first spatial context for its GAP function.

    Evidence Indirect immunofluorescence with Golgi markers and brefeldin A treatment, confocal microscopy

    PMID:8806680

    Open questions at the time
    • Golgi residence not reconciled with later mTORC1/lysosomal roles
    • Did not address whether localization is regulated
  3. 1998 High

    Showed that the TSC1 and TSC2 products physically associate via coiled-coils, defining the heterodimeric complex that is the functional unit.

    Evidence Co-immunoprecipitation from cell lysates and coiled-coil domain mapping

    PMID:9580671

    Open questions at the time
    • Functional consequence of the interaction not yet defined
    • Stoichiometry and complex architecture unresolved
  4. 2001 High

    Mapped the disease-relevant TSC1-binding interface on TSC2 and demonstrated that pathogenic but not benign mutations abolish complex formation, linking complex integrity to disease.

    Evidence Yeast two-hybrid and co-IP with deletion/point mutants discriminating pathogenic from polymorphic variants

    PMID:11741833

    Open questions at the time
    • Did not establish downstream effector pathway
    • Interface defined by mutagenesis, not structure
  5. 2001 High

    Positioned TSC1-TSC2 in the insulin/PI3K/Akt growth-control pathway through Drosophila genetics, establishing the physiological signaling context.

    Evidence Drosophila epistasis and double-mutant rescue of insulin receptor lethality

    PMID:11390358

    Open questions at the time
    • Molecular target downstream of TSC2 not yet identified
    • Direct biochemical link to Akt not shown in this work
  6. 2002 High

    Demonstrated that Akt directly phosphorylates TSC2 to destabilize the complex and relieve mTOR inhibition, defining the core growth-factor-responsive regulatory mechanism and connecting TSC2 to S6K/4E-BP1.

    Evidence In vitro kinase assays with site-directed mutagenesis (Ser924/Thr1518 in fly), co-IP, mTOR substrate and stability assays in cells and Drosophila

    PMID:12167664 PMID:12172553 PMID:12172554

    Open questions at the time
    • Direct GAP substrate downstream of mTOR inhibition not yet identified as Rheb
    • Relative contribution of destabilization vs. complex dissociation unresolved
  7. 2002 Medium

    Identified phospho-dependent 14-3-3 binding as an additional inhibitory input on TSC2, showing TSC2 activity is gated by multiple Akt-regulated mechanisms.

    Evidence Yeast two-hybrid, in vitro binding, co-IP with site-specific phospho-mutants, S6K functional assays

    PMID:12364343 PMID:12468542

    Open questions at the time
    • Single-lab studies with corroboration but no reconstitution
    • Quantitative contribution of 14-3-3 to physiological mTOR control unclear
  8. 2002 High

    Provided gain-of-function proof that tuberin re-expression suppresses S6/p70S6K signaling and DNA synthesis in TSC2-null cells, with rapamycin epistasis placing mTOR downstream of TSC2.

    Evidence Wild-type tuberin reconstitution in multiple TSC2-null cell lines, kinase and DNA synthesis assays, rapamycin treatment

    PMID:12045200

    Open questions at the time
    • Did not define the immediate GTPase substrate linking TSC2 to mTOR
  9. 2003 High

    Showed energy stress activates TSC2 through direct AMPK phosphorylation, establishing TSC2 as the node integrating energy status with translational control and cell size.

    Evidence In vitro AMPK kinase assay, phospho-mutant rescue, cell size and apoptosis assays under energy deprivation

    PMID:14651849

    Open questions at the time
    • Mechanism by which phosphorylation enhances GAP activity not resolved
    • Cross-talk with Akt sites not addressed
  10. 2004 High

    Identified Rheb as the physiological GAP substrate and defined the non-canonical asparagine-thumb catalytic mechanism, resolving how TSC2 controls mTORC1.

    Evidence Reconstituted in vitro GAP assays with TSC2 and Rheb mutants, cellular S6K functional validation; yeast ortholog epistasis on amino acid permeases

    PMID:14718525 PMID:15340059

    Open questions at the time
    • Atomic structure of catalytic site not yet available
    • Role of TSC1 in catalysis vs. regulation incompletely defined
  11. 2005 High

    Established ERK as a second growth-promoting kinase that phosphorylates TSC2 to dissociate the complex, with phospho-null TSC2 suppressing tumorigenicity, linking TSC2 regulation directly to oncogenic transformation.

    Evidence In vitro ERK kinase assay, phospho-mutant expression, co-IP for complex integrity, in vivo tumor growth assay

    PMID:15851026

    Open questions at the time
    • Interplay between ERK and Akt phosphorylation sites not dissected
    • Did not address tissue specificity of ERK input
  12. 2005 High

    Revealed an mTOR-independent role for TSC2 in actin cytoskeletal dynamics, cell adhesion, and migration through Rho/Rac regulation, broadening TSC2 function beyond growth control.

    Evidence Domain-specific (HBD/N-terminal) rescue in TSC2-null cells, Rho/Rac pull-down assays, TSC1 siRNA, migration/invasion assays; neuronal conditional knockout with LIM-kinase/cofilin readout

    PMID:15611338 PMID:16286931 PMID:16388022

    Open questions at the time
    • Mechanism by which TSC2 modulates Rho/Rac GTPases not biochemically defined
    • Relationship between GAP-independent and GAP-dependent functions unresolved
  13. 2008 High

    Defined the ubiquitin-ligase machinery controlling TSC2 stability and showed TSC1 protects TSC2 by excluding these ligases, establishing degradation as a key regulatory layer.

    Evidence Co-IP of FBW5-DDB1-CUL4-ROC1 with TSC2, siRNA depletion, stability assays, Drosophila genetics; earlier HERC1 competitive-binding work

    PMID:16464865 PMID:18381890

    Open questions at the time
    • Signals that trigger ligase-mediated TSC2 turnover not defined
    • Relative contribution of HERC1 vs. CUL4 ligase in vivo unclear
  14. 2010 High

    Connected TSC2 to neuronal development via EphA-ERK signaling and to epithelial integrity via E-cadherin localization, extending its role into axon guidance and EMT control.

    Evidence Tsc2+/- mouse retinogeniculate analysis with growth cone collapse assays; Tsc2-null cell E-cadherin/EMT analysis with rapamycin and CLIP170 knockdown

    PMID:20062052 PMID:20813961

    Open questions at the time
    • Direct phosphorylation hierarchy in vivo only partially mapped
    • E-cadherin pathway dissected in single-lab cell models
  15. 2019 High

    Identified PKG1 as a stress-specific kinase phosphorylating TSC2 at S1365/S1366 to bidirectionally tune mTORC1, providing in vivo genetic proof in the heart and a therapeutically tractable regulatory node.

    Evidence In vitro PKG1 kinase assay plus phospho-null and phosphomimetic knockin mouse cardiac pressure-overload and ischemia-reperfusion models with metabolic profiling

    PMID:30700906 PMID:33401933

    Open questions at the time
    • Generalizability of S1365 regulation beyond cardiac tissue not established
    • Mechanism by which these sites selectively affect stress-stimulated mTORC1 unresolved
  16. 2020 High

    Provided the crystal structure of the TSC2 GAP domain and a TSC2-Rheb model, validating the asparagine-thumb mechanism at atomic resolution and reinterpreting the roles of interface residues.

    Evidence X-ray crystallography, molecular dynamics simulations, pathogenic variant characterization

    PMID:32502382

    Open questions at the time
    • No experimental TSC1-TSC2-Rheb holocomplex structure
    • Conformational regulation by phosphorylation not captured
  17. 2021 Medium

    Uncovered a non-canonical TSC1/2 requirement for mTORC1-mediated TFEB phosphorylation, explaining elevated lysosomal biogenesis in TSC-deficient cells through the RAGC-TFEB axis.

    Evidence TFEB phosphorylation/localization assays in TSC1/2-deficient cells, FLCN and constitutively active RAGC rescue, TSC tumor tissue analysis

    PMID:34253722

    Open questions at the time
    • Single-lab study; mechanism by which TSC1/2 enables TFEB phosphorylation not fully defined
    • In vivo relevance of TFEB axis to TSC pathology incompletely established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the many phosphorylation inputs (Akt, ERK, AMPK, PKG1, cyclin D-CDK) are integrated combinatorially to set TSC2 GAP output in a given cell state, and how GAP-independent functions (Rho/Rac, adhesion, mitosis) are biochemically executed, remain unresolved.
  • No unified model of multi-site phosphorylation integration
  • Biochemical basis of GAP-independent cytoskeletal and mitotic roles undefined
  • No structure of the regulated holocomplex with bound effectors

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005634 nucleus 2 GO:0005794 Golgi apparatus 2 GO:0005829 cytosol 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1266738 Developmental Biology 2 R-HSA-1430728 Metabolism 2 R-HSA-9612973 Autophagy 2 R-HSA-5357801 Programmed Cell Death 1
Partners
AKT1AMPKFBW5MAPK1/ERKPRKG1RHEBTACC3TSC1
Complex memberships
DDB1-CUL4-ROC1-FBW5 ubiquitin ligase complexTSC1-TSC2 complex

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 TSC2 protein product tuberin (180 kDa) exhibits specific GTPase-activating protein (GAP) activity towards Rap1a in vitro, stimulating its intrinsic GTPase activity; this activity resides in the C-terminal fragment of tuberin. Tuberin did not stimulate GTPase activity of Rap2, Ha-Ras, Rac, or Rho. Subcellular fractionation revealed that most tuberin resides in a membrane/particulate (100,000×g) fraction. Immunoprecipitation of native tuberin followed by GTPase activity assay; bacterially and Sf9-expressed C-terminal fragment assays; subcellular fractionation The Journal of biological chemistry High 7608212
1996 Tuberin co-localizes with its substrate Rap1 in the Golgi apparatus of cultured cells, as demonstrated by co-localization with Golgi markers (mannosidase-II, furin) and disruption by brefeldin A treatment; tuberin shows punctate, perinuclear staining consistent with Golgi localization. Indirect immunofluorescence, double immunofluorescence with Golgi markers, brefeldin A treatment, confocal microscopy Oncogene High 8806680
1997 The GAP-related domain of tuberin (encoded by exons 34–38, ~160 amino acids) is a key functional region; missense mutations within this domain (in exons 36, 37, 38) identified in TSC patients disrupt tuberin's growth-regulatory function, confirming the GAP domain's critical role. SSCP mutation analysis, direct sequencing, de novo mutation confirmation in sporadic cases Human molecular genetics Medium 9302281
1998 Hamartin (TSC1 product) and tuberin (TSC2 product) physically interact in vivo, forming a complex; the interaction is mediated by predicted coiled-coil domains in each protein. Co-immunoprecipitation from cell lysates, coiled-coil domain prediction and mapping Human molecular genetics High 9580671
2000 Hamartin stabilizes tuberin by inhibiting its ubiquitination; tuberin is highly ubiquitinated in cells, but the fraction bound to hamartin is not ubiquitinated. Co-expression of TSC1 with TSC2 results in higher tuberin levels. The amino-terminal two-thirds of tuberin mediate its ubiquitination and hamartin stabilization. Transient transfection, co-immunoprecipitation, ubiquitination assay, domain deletion analysis Oncogene High 11175345
2001 TSC1 and TSC2 form a complex and function in a common pathway to control cellular growth; genetic analyses in Drosophila place the TSC genes in a pathway parallel to but converging downstream of Akt in insulin/PI3K signaling; TSC1 or TSC2 heterozygosity rescues lethality of loss-of-function insulin receptor mutants. Drosophila genetics, epistasis analysis, double-mutant rescue experiments Genes & development High 11390358
2001 Tuberin is phosphorylated at serine and tyrosine residues in response to serum and other factors. Disease-related TSC2 mutations (Y1571H, P1675L) reduce tuberin phosphorylation, disrupt TSC1-TSC2 interaction, and curtail tuberin's growth inhibitory activity, demonstrating that phosphorylation regulates TSC1-TSC2 complex formation and function. Immunoprecipitation, phosphorylation assays, co-immunoprecipitation with disease mutants, overexpression growth assays in COS1 cells The Journal of biological chemistry Medium 11290735
2001 Pathological mutations in TSC1 (N198_F199delinsI; 593-595delACT) and TSC2 (G294E, I365del) that lie within the binding interface abolish or dramatically reduce hamartin-tuberin interaction. The hamartin-binding domain maps to tuberin amino acids 1–418 (requiring a coiled-coil at aa 346–371 plus N-terminal residues); non-pathogenic polymorphisms at adjacent positions do not disrupt binding. Yeast two-hybrid with deletion/point mutant constructs, co-immunoprecipitation from COS7 cells Human molecular genetics High 11741833
2002 TSC2 is directly phosphorylated by Akt at multiple sites; Akt-dependent phosphorylation destabilizes TSC2 and disrupts its interaction with TSC1, thereby relieving TSC1-TSC2 inhibition of mTOR. TSC1-TSC2 inhibits S6K1 and activates 4E-BP1 through inhibition of mTOR. In vitro kinase assay (direct phosphorylation), co-immunoprecipitation, S6K and 4E-BP1 phosphorylation assays, TSC2 stability assays Nature cell biology High 12172553
2002 Drosophila Akt/PKB directly phosphorylates Tsc2 in vitro at conserved residues Ser924 and Thr1518; mutation of these sites renders Tsc2 insensitive to Akt signaling, increases stability of the Tsc1-Tsc2 complex, and blocks all Akt-dependent growth signals in vivo. In vitro kinase assay with recombinant Akt, site-directed mutagenesis, Drosophila genetics, co-immunoprecipitation, cell size measurements Nature cell biology High 12172554
2002 PI3K/Akt pathway phosphorylates tuberin in response to insulin/IGF-1; Akt associates with hamartin-tuberin complexes and promotes tuberin phosphorylation and increased degradation of hamartin-tuberin complexes. Akt-phosphorylated tuberin loses ability to inhibit CDK2 activity via p27(kip1) degradation suppression. Co-immunoprecipitation, kinase assays with constitutively active PI3K/Akt constructs, PI3K inhibitor LY294002, p27 stability assays The Journal of biological chemistry High 12167664
2002 Tuberin associates with 14-3-3 proteins in vivo; phosphorylation of Ser1210 in TSC2 is required for this interaction. 14-3-3 association inhibits TSC2 function (mTOR pathway inhibition); 14-3-3 interaction is regulated by Akt-mediated phosphorylation of tuberin. Co-immunoprecipitation, phospho-mutant analysis, S6K phosphorylation functional assay The Journal of biological chemistry Medium 12364343
2002 14-3-3zeta binds tuberin at multiple sites in an Akt-phosphorylation-regulated manner; 14-3-3zeta can form a ternary complex with TSC1-TSC2 without interfering with TSC1-TSC2 binding. Overexpression of 14-3-3beta antagonizes TSC1-TSC2 inhibition of S6K phosphorylation in a TSC2-interaction-dependent manner. Yeast two-hybrid screening, in vitro binding assay, co-immunoprecipitation, S6K phosphorylation assay with mutant TSC2 The Journal of biological chemistry Medium 12468542
2002 Tuberin re-expression in TSC2-null LAM-derived and ELT3 cells abolishes hyperphosphorylation of ribosomal protein S6 and significantly inhibits p70S6K activity and DNA synthesis, establishing tuberin as a specific negative regulator of S6/p70S6K. Rapamycin mimics this effect, placing mTOR downstream of tuberin. Re-expression of wild-type tuberin in TSC2-null cell lines, p70S6K activity assay, S6 phosphorylation by immunoblot, DNA synthesis assay, rapamycin treatment The Journal of biological chemistry High 12045200
2003 TSC2 regulates HIF-1alpha levels and VEGF expression through both mTOR-dependent and mTOR-independent pathways. Loss of TSC2 results in HIF-1alpha accumulation and increased VEGF; rapamycin normalizes HIF but only partially reduces VEGF, indicating an additional mTOR-independent chromatin remodeling pathway. TSC2-null cell analysis, rapamycin treatment, HDAC inhibitor trichostatin A treatment, HIF-1alpha and VEGF reporter assays Cancer cell Medium 12957289
2003 Under energy starvation, AMPK directly phosphorylates TSC2 and enhances its activity. This AMPK-mediated phosphorylation of TSC2 is required for translational regulation and cell size control in response to energy deprivation, and protects cells from energy deprivation-induced apoptosis. In vitro kinase assay (AMPK phosphorylates TSC2), phospho-mutant rescue experiments, cell size measurements, apoptosis assays under energy starvation Cell High 14651849
2004 TSC2 has GAP activity specifically towards the small GTPase Rheb (not using the canonical arginine finger mechanism), instead employing a catalytic 'asparagine thumb'; Asn residues in TSC2 are essential for GAP activity. Rheb Arg15 (equivalent to Gly12 in Ras) is important for TSC2-stimulated hydrolysis. TSC1 is not required for TSC2 GAP activity but may serve as a regulatory component. In vitro GTPase assay with recombinant proteins, site-directed mutagenesis of TSC2 and Rheb, S6K phosphorylation functional assay, TSC1-binding defective mutant analysis Molecular and cellular biology High 15340059
2004 TSC2 modulates actin dynamics and cell adhesion through its TSC1-binding domain (TSC2-HBD); expression of TSC2 or TSC2-HBD in TSC2-null cells promotes Rac1 activation, inhibition of RhoA, stress fiber disassembly, and focal adhesion remodeling. TSC1 inhibits Rac1, and TSC2 blocks this TSC1 activity. Re-expression of TSC2 and deletion constructs in TSC2-null cells, Rho/Rac pull-down activity assays, TSC1 siRNA knockdown, immunofluorescence of actin/focal adhesions The Journal of cell biology High 15611338
2004 Tuberin (TSC2) expression increases B-Raf kinase activity and p42/44 MAPK phosphorylation via an mTOR-independent mechanism. Rheb (TSC2 GAP substrate) inhibits wild-type but not activated B-Raf, and interacts with endogenous B-Raf; B-Raf inhibition by Rheb is rapamycin-resistant, dissociable from S6K activation. TSC2 siRNA knockdown, B-Raf kinase assay, co-immunoprecipitation of Rheb and B-Raf, rapamycin treatment, farnesylation-defective Rheb mutant The Journal of biological chemistry Medium 15150271
2004 Tuberin is a component of lipid rafts and co-fractionates with caveolin-1 in low-density Triton X-100-resistant fractions; tuberin regulates caveolin-1 localization to the plasma membrane and caveolae formation. Loss of tuberin displaces caveolin-1 to a post-Golgi compartment; TSC2 re-expression reverses this. TSC2 also regulates post-Golgi vesicle transport (VSVG-GFP trafficking). Sucrose gradient fractionation, immunofluorescence, BFA-sensitive compartment analysis, Tsc2-/- cell re-expression, VSVG-GFP trafficking assay Experimental cell research Medium 15093748
2005 Erk directly phosphorylates TSC2, leading to TSC1-TSC2 complex dissociation and markedly impaired TSC2 ability to inhibit mTOR signaling, cell proliferation, and oncogenic transformation. Expression of an Erk non-phosphorylatable TSC2 mutant in TSC2+/- tumor cells blocks tumorigenicity in vivo, while wild-type TSC2 is ineffective. In vitro kinase assay (Erk phosphorylates TSC2), phospho-mutant expression, co-immunoprecipitation for complex integrity, mTOR substrate assays, in vivo tumor growth assay Cell High 15851026
2005 Loss of Tsc1 or Tsc2 in hippocampal neurons triggers enlargement of somas and dendritic spines and alters glutamatergic synapse properties. Morphological changes require regulation of cofilin via LIM-kinase phosphorylation, which is increased by loss of Tsc2, placing TSC2 upstream of the LIM-kinase/cofilin actin regulatory pathway in neurons. Conditional knockout mouse neurons (CA1 pyramidal cells), spine size imaging, electrophysiology, LIM-kinase phospho-cofilin western blotting, rescue experiments Nature neuroscience High 16286931
2005 TSC2 is a cyclin D binding protein; coexpression of cyclin D1-CDK4/6 leads to increased TSC2 phosphorylation and decreased levels of both TSC2 and TSC1 proteins, promoting mTOR substrate phosphorylation (4E-BP1, S6K1). Cyclin D1 can regulate TSC1-TSC2 independently of CDK4/6 catalytic activity. Co-immunoprecipitation, phosphorylation assays, TSC protein level measurements, CDK inhibitor and kinase-dead CDK6, mTOR substrate phosphorylation, cell size assay Cancer research Medium 16357142
2006 TSC1 stabilizes TSC2 by excluding the HERC1 ubiquitin ligase (a 532-kDa HECT-domain E3) from the TSC2 complex; disease mutations in TSC2 that result in protein destabilization allow HERC1 binding even in the presence of TSC1, revealing a mechanism by which TSC1 protects TSC2 from ubiquitin-mediated degradation. Co-immunoprecipitation identifying HERC1 as TSC2-interacting protein, competitive binding assay with TSC1, disease mutant analysis, TSC2 stability measurements The Journal of biological chemistry Medium 16464865
2006 TSC1/TSC2 complex has negative and positive effects on TORC1 and TORC2 respectively. In Drosophila S2 cells, Rheb (TSC2's GAP substrate) inhibits dTORC2 activity via a dTORC1/dS6K feedback mechanism. In human cells, TSC1/2 positively affects TORC2 activity (measured by Akt-Ser473 phosphorylation). S6K and Akt phosphorylation assays as functional readouts for TORC1/2 in Drosophila S2 cells and HEK293 cells, siRNA knockdown Proceedings of the National Academy of Sciences of the United States of America Medium 16627617
2006 Akt phosphorylation of tuberin triggers cytoplasmic retention of tuberin (downregulation of nuclear tuberin). In arrested G0 cells with low Akt activity, significant tuberin fraction localizes to the nucleus. Tuberin retains ability to regulate p70S6K in both cytoplasm and nucleus independently of mTOR/p70S6K regulation of p27. Nuclear/cytoplasmic fractionation, immunofluorescence, Akt inhibition and activation, cell cycle synchronization (G0 arrest) Oncogene Medium 16862180
2006 Tuberin triggers apoptosis via a pathway involving downregulation of p70S6K, reduction of BAD Ser136 phosphorylation, and upregulation of BAD/BCL-2 and BAD/BCL-XL interactions. BAD-knockout cells establish BAD as a required mediator of tuberin's pro-apoptotic effects. AKT phosphorylation negatively regulates tuberin's ability to trigger apoptosis. Tuberin overexpression, BAD-/- MEFs, co-immunoprecipitation of BAD/BCL-2/BCL-XL, p70S6K and BAD phosphorylation assays, apoptosis measurements Oncogene Medium 16702951
2008 FBW5, a DDB1-binding WD40 protein, recruits TSC2 to the DDB1-CUL4-ROC1 E3 ubiquitin ligase complex to promote TSC2 ubiquitination and degradation. Overexpression of FBW5 or CUL4A promotes TSC2 degradation, which is abrogated by TSC1 co-expression. Depletion of FBW5, DDB1, or CUL4A/B stabilizes TSC2. Drosophila Ddb1/Cul4 mutations cause Gigas/TSC2 accumulation. Co-immunoprecipitation (FBW5-TSC2-DDB1-CUL4-ROC1), siRNA knockdown, TSC2 stability assays, Drosophila genetic analysis Genes & development High 18381890
2002 Hamartin and tuberin are multicompartmental proteins found in cytosolic, microsomal, and cytoskeletal fractions where they form a stable complex. Within the microsomal fraction they behave as peripheral membrane proteins. Immunoisolation of tuberin-bound vesicles shows enrichment of Rap1, Rab5, and caveolin-1. Cell fractionation, co-immunoprecipitation in each fraction, immunoisolation with magnetic beads, colocalization immunofluorescence Archives of biochemistry and biophysics Medium 12147258
2005 Cell migration and invasiveness of LAM cells is increased and is abolished by TSC2 re-expression. TSC2 inhibits cell migration through its N-terminus (independent of GAP activity) by associating with TSC1 and regulating RhoA activity; RhoA is activated in LAM cells and its pharmacological inhibition abolishes LAM cell migration. Migration and invasion assays, TSC2 re-expression, N-terminal domain constructs, TSC1 siRNA knockdown, RhoA pull-down activity assay, Rho inhibitor pharmacology American journal of respiratory cell and molecular biology Medium 16388022
2007 Tuberin regulates expression of the DNA repair enzyme OGG1 via the transcription factor NF-YA; TSC2-null cells have markedly decreased OGG1 mRNA, protein and activity, accumulate 8-oxodG, and show reduced NF-YA binding to the OGG1 promoter. Re-introduction of TSC2 cDNA into tuberin-deficient cells restores NF-YA and OGG1 expression. siRNA knockdown of TSC2, TSC2-null MEFs (TSC2-/- and +/-), ChIP, EMSA (gel shift), OGG1 promoter reporter assay, TSC2 cDNA rescue American journal of physiology. Renal physiology Medium 17989114
2009 Tsc2-null cells lacking TSC2 have attenuated mTORC2 activity. mTORC2 (via rictor) modulates TSC2-null cell proliferation and survival through RhoA GTPase and Bcl2 proteins. Constitutively active V14RhoA reverses growth inhibition induced by rictor siRNA or TSC2 re-expression, placing RhoA downstream of mTORC2 in TSC2-null cells. siRNA knockdown of mTOR pathway components (raptor, rictor, Rheb), constitutively active RhoA rescue, apoptosis assays, RhoA pull-down, in vivo tumor growth Molecular and cellular biology Medium 21482669
2010 Tsc2 haploinsufficiency in mice causes aberrant retinogeniculate projections (EphA-dependent axon guidance defects). EphA receptor activation by ephrin-A ligands inhibits ERK1/2 and decreases ERK1/2-mediated inhibition of Tsc2, thereby inactivating the mTOR pathway. Tsc2 deficiency and hyperactive Rheb constitutively activate mTOR and inhibit ephrin-induced growth cone collapse. Tsc2+/- mouse retinogeniculate projection analysis, ephrin-A stimulation, ERK1/2 and Tsc2 phosphorylation assays, growth cone collapse assay, constitutively active Rheb expression Nature neuroscience High 20062052
2010 Tuberin regulates E-cadherin localization to the plasma membrane via an Akt/mTORC1/CLIP170-dependent, rapamycin-sensitive pathway; Tsc2-null cells display loss of plasma membrane E-cadherin leading to reduced cell-cell adhesion, EMT markers (loss of E-cadherin/occludin, gain of Snail/SMA), and anchorage-independent growth. Tsc2-/- cell analysis, rapamycin treatment, CLIP170 knockdown, E-cadherin localization by immunofluorescence, EMT marker western blots, anoikis assay The American journal of pathology Medium 20813961
2010 TACC3 physically interacts with TSC2; they co-localize and co-purify with nuclear envelope components. TACC3 is required for proper localization of phospho-Ser939 TSC2 at spindle poles and cytokinetic bridges. Tsc2-deficient cells show abscission defects and increased binucleated cells; TSC2 acts epistatically to TACC3 in regulating cell division. TACC3 interactome mapping (co-IP/MS), co-localization microscopy, Tsc2/Tacc3 siRNA knockdown, cell division phenotype analysis, epistasis analysis Cell cycle (Georgetown, Tex.) Medium 20237422
2010 Loss of tuberin in TSC2-null cells promotes invasion through a β-catenin-dependent mechanism; tuberin-null cells express cleaved forms of β-catenin that are transcriptionally active and drive MMP7 expression, which mediates invasion. β-catenin reporter assay, MMP7 expression analysis, invasion assays, TSC2-null cell analysis, LAM tissue immunostaining American journal of respiratory cell and molecular biology Medium 20042714
2019 PKG1 (protein kinase G1, a primary effector of nitric oxide and natriuretic peptide signaling) directly phosphorylates TSC2 at S1365/S1366 (mouse; S1364/S1365 human). Phosphorylation at these sites bidirectionally controls stress-stimulated (but not basal) mTORC1 activity, suppressing hypertrophy and stimulating autophagy in cardiomyocytes. Phospho-null knockin (TSC2-S1365A) mice develop worse heart disease after pressure overload; phosphomimetic (TSC2-S1365E) mice are protected. In vitro kinase assay (PKG1 phosphorylates TSC2), phospho-null and phosphomimetic knockin mouse models, cardiac pressure overload model, cardiomyocyte hypertrophy and autophagy assays Nature High 30700906
2020 Crystal structure of the TSC2 GAP domain determined; structure-based modeling of the TSC2-Rheb complex and molecular dynamics simulations identify TSC2 Asn1643 and Rheb Tyr35 as key active site residues; Rheb Arg15 and Asp65 contribute to the interface and indirectly aid catalysis rather than being catalytic residues. The GAP domain is stabilized by interactions with other TSC2 domains. X-ray crystallography, molecular dynamics simulations, TSC2-Rheb complex modeling, characterization of pathogenic TSC2 variants Structure (London, England : 1993) High 32502382
2021 Lysosomal biogenesis is increased in TSC1/2-deficient cells via a TFEB-dependent mechanism that is non-canonical: in the absence of TSC1/2, TFEB is hypo-phosphorylated at mTORC1 sites because mTORC1 cannot phosphorylate TFEB without the TSC1/2 complex. Overexpression of FLCN (a RAGC GAP) or constitutively active RAGC increases TFEB phosphorylation and cytoplasmic relocalization in TSC2-deficient cells. TFEB phosphorylation assays in TSC1/2-deficient cells, FLCN overexpression, constitutively active RAGC expression, TFEB localization microscopy, TSC renal tumor/LAM tissue analysis Nature communications Medium 34253722
2021 TSC2 S1365 phosphorylation status controls myocardial substrate utilization during ischemia-reperfusion; TSC2-S1365A (phospho-null) hearts have amplified mTORC1 activation, increased glycolytic capacity, and protection against IR injury; TSC2-S1365E (phosphomimetic) hearts fail to activate mTORC1 with ischemic preconditioning and show worse IR outcomes when glucose is limiting. TSC2-S1365A and S1365E knockin mouse IR model (ex vivo and in vivo), metabolic flux measurements (OCR, EACR), lactate and acylcarnitine metabolomics, mTORC1 substrate phosphorylation Circulation research High 33401933
2004 In S. pombe (fission yeast), the defect in arginine uptake in tsc2+ mutant cells (decreased expression of amino acid permeases) is rescued by dominant-negative rhb1+ (Rheb homolog) but not wild-type rhb1+, and is not rescued by a GAP-domain mutant TSC2, placing TSC2 GAP activity toward Rheb upstream of amino acid permease regulation. S. pombe tsc2+ mutant analysis, dominant-negative and wild-type rhb1+ rescue, patient-derived GAP-domain TSC2 mutant complementation, amino acid uptake assay The Journal of biological chemistry Medium 14718525

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 TSC2 mediates cellular energy response to control cell growth and survival. Cell 3191 14651849
2002 TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nature cell biology 2524 12172553
2005 Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell 1071 15851026
2008 The TSC1-TSC2 complex: a molecular switchboard controlling cell growth. The Biochemical journal 1001 18466115
2002 Akt regulates growth by directly phosphorylating Tsc2. Nature cell biology 783 12172554
2009 A complex interplay between Akt, TSC2 and the two mTOR complexes. Biochemical Society transactions 595 19143635
2003 TSC2 regulates VEGF through mTOR-dependent and -independent pathways. Cancer cell 456 12957289
1998 Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products. Human molecular genetics 438 9580671
2005 Regulation of neuronal morphology and function by the tumor suppressors Tsc1 and Tsc2. Nature neuroscience 393 16286931
2001 TSC1 and TSC2 tumor suppressors antagonize insulin signaling in cell growth. Genes & development 380 11390358
2002 Tuberin regulates p70 S6 kinase activation and ribosomal protein S6 phosphorylation. A role for the TSC2 tumor suppressor gene in pulmonary lymphangioleiomyomatosis (LAM). The Journal of biological chemistry 368 12045200
2004 TSC2: filling the GAP in the mTOR signaling pathway. Trends in biochemical sciences 342 14729330
1995 Identification of tuberin, the tuberous sclerosis-2 product. Tuberin possesses specific Rap1GAP activity. The Journal of biological chemistry 324 7608212
2002 Phosphatidylinositol 3-kinase/Akt pathway regulates tuberous sclerosis tumor suppressor complex by phosphorylation of tuberin. The Journal of biological chemistry 312 12167664
2003 Rhebbing up mTOR: new insights on TSC1 and TSC2, and the pathogenesis of tuberous sclerosis. Cancer biology & therapy 271 14614311
2004 Biochemical and functional characterizations of small GTPase Rheb and TSC2 GAP activity. Molecular and cellular biology 208 15340059
2000 The tuberous sclerosis-1 (TSC1) gene product hamartin suppresses cell growth and augments the expression of the TSC2 product tuberin by inhibiting its ubiquitination. Oncogene 204 11175345
2010 Tsc2-Rheb signaling regulates EphA-mediated axon guidance. Nature neuroscience 198 20062052
2006 TSC1 stabilizes TSC2 by inhibiting the interaction between TSC2 and the HERC1 ubiquitin ligase. The Journal of biological chemistry 186 16464865
2017 Somatic Mutations in TSC1 and TSC2 Cause Focal Cortical Dysplasia. American journal of human genetics 158 28215400
2006 TSC1/TSC2 and Rheb have different effects on TORC1 and TORC2 activity. Proceedings of the National Academy of Sciences of the United States of America 149 16627617
2008 WD40 protein FBW5 promotes ubiquitination of tumor suppressor TSC2 by DDB1-CUL4-ROC1 ligase. Genes & development 142 18381890
2002 Mutation analysis of the TSC1 and TSC2 genes in Japanese patients with pulmonary lymphangioleiomyomatosis. Journal of human genetics 115 11829138
1997 The GAP-related domain of tuberin, the product of the TSC2 gene, is a target for missense mutations in tuberous sclerosis. Human molecular genetics 115 9302281
2019 PKG1-modified TSC2 regulates mTORC1 activity to counter adverse cardiac stress. Nature 114 30700906
2011 mTORC2 is required for proliferation and survival of TSC2-null cells. Molecular and cellular biology 109 21482669
2003 Tumour suppressors hamartin and tuberin: intracellular signalling. Cellular signalling 105 12781866
2008 The tuberous sclerosis gene products hamartin and tuberin are multifunctional proteins with a wide spectrum of interacting partners. Mutation research 103 18291711
2006 Essential role of tuberous sclerosis genes TSC1 and TSC2 in NF-kappaB activation and cell survival. Cancer cell 103 16959613
1996 Co-localization of the TSC2 product tuberin with its target Rap1 in the Golgi apparatus. Oncogene 94 8806680
2004 TSC2 modulates actin cytoskeleton and focal adhesion through TSC1-binding domain and the Rac1 GTPase. The Journal of cell biology 93 15611338
2002 Regulation of TSC2 by 14-3-3 binding. The Journal of biological chemistry 93 12364343
2001 Pathological mutations in TSC1 and TSC2 disrupt the interaction between hamartin and tuberin. Human molecular genetics 92 11741833
2011 TSC1/TSC2 signaling in the CNS. FEBS letters 87 21329690
2020 AMPK regulation of Raptor and TSC2 mediate metformin effects on transcriptional control of anabolism and inflammation. Genes & development 86 32912901
2004 Tsc1+ and tsc2+ regulate arginine uptake and metabolism in Schizosaccharomyces pombe. The Journal of biological chemistry 86 14718525
2007 Overlapping neurologic and cognitive phenotypes in patients with TSC1 or TSC2 mutations. Neurology 82 18032745
2001 Tuberin phosphorylation regulates its interaction with hamartin. Two proteins involved in tuberous sclerosis. The Journal of biological chemistry 82 11290735
2021 TSC2 regulates lysosome biogenesis via a non-canonical RAGC and TFEB-dependent mechanism. Nature communications 81 34253722
2004 Regulation of B-Raf kinase activity by tuberin and Rheb is mammalian target of rapamycin (mTOR)-independent. The Journal of biological chemistry 81 15150271
1999 Polycystin-1 expression in PKD1, early-onset PKD1, and TSC2/PKD1 cystic tissue. Kidney international 81 10504485
2003 Pam and its ortholog highwire interact with and may negatively regulate the TSC1.TSC2 complex. The Journal of biological chemistry 70 14559897
1997 Expression of the TSC2 product tuberin and its target Rap1 in normal human tissues. The American journal of pathology 70 9006320
2002 14-3-3beta binds to and negatively regulates the tuberous sclerosis complex 2 (TSC2) tumor suppressor gene product, tuberin. The Journal of biological chemistry 67 12468542
2005 Negative regulation of TSC1-TSC2 by mammalian D-type cyclins. Cancer research 66 16357142
2002 Identification and characterization of the interaction between tuberin and 14-3-3zeta. The Journal of biological chemistry 65 12176984
2005 Modulation of cell migration and invasiveness by tumor suppressor TSC2 in lymphangioleiomyomatosis. American journal of respiratory cell and molecular biology 64 16388022
2006 Hamartin and tuberin: working together for tumour suppression. International journal of cancer 63 16206276
2015 TSC2/mTORC1 signaling controls Paneth and goblet cell differentiation in the intestinal epithelium. Cell death & disease 60 25654764
2014 Estradiol and mTORC2 cooperate to enhance prostaglandin biosynthesis and tumorigenesis in TSC2-deficient LAM cells. The Journal of experimental medicine 60 24395886
2009 TSC1 and TSC2 mutations in patients with lymphangioleiomyomatosis and tuberous sclerosis complex. Journal of medical genetics 60 19419980
1999 Co-localization of TSC1 and TSC2 gene products in tubers of patients with tuberous sclerosis. Brain pathology (Zurich, Switzerland) 60 9989450
2001 Mutational analysis of TSC1 and TSC2 genes in gangliogliomas. Neuropathology and applied neurobiology 59 11437991
1995 Alternative splicing of the tuberous sclerosis 2 (TSC2) gene in human and mouse tissues. Genomics 55 7558029
2011 Loss of the tuberous sclerosis complex protein tuberin causes Purkinje cell degeneration. Neurobiology of disease 54 21419848
2010 Tuberin regulates E-cadherin localization: implications in epithelial-mesenchymal transition. The American journal of pathology 53 20813961
2006 Akt regulates nuclear/cytoplasmic localization of tuberin. Oncogene 52 16862180
2014 Tsc2 is a molecular checkpoint controlling osteoblast development and glucose homeostasis. Molecular and cellular biology 51 24591652
2010 Zebrafish model of tuberous sclerosis complex reveals cell-autonomous and non-cell-autonomous functions of mutant tuberin. Disease models & mechanisms 47 20959633
2001 Hamartin and tuberin expression in human tissues. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 45 11266527
2006 Tuberin activates the proapoptotic molecule BAD. Oncogene 44 16702951
2019 Alpinetin improves intestinal barrier homeostasis via regulating AhR/suv39h1/TSC2/mTORC1/autophagy pathway. Toxicology and applied pharmacology 43 31676321
2021 MTORC1-Regulated Metabolism Controlled by TSC2 Limits Cardiac Reperfusion Injury. Circulation research 42 33401933
2002 Phosphatidylinositol 3-kinase but not tuberin is required for PDGF-induced cell migration. American journal of physiology. Lung cellular and molecular physiology 40 11880313
2018 TSC1 and TSC2 regulate cilia length and canonical Hedgehog signaling via different mechanisms. Cellular and molecular life sciences : CMLS 39 29396625
2014 Hyperactivation of Akt/mTOR and deficiency in tuberin increased the oxidative DNA damage in kidney cancer patients with diabetes. Oncotarget 38 24797175
2004 Tuberin is a component of lipid rafts and mediates caveolin-1 localization: role of TSC2 in post-Golgi transport. Experimental cell research 38 15093748
1997 Reduced TSC2 RNA and protein in sporadic astrocytomas and ependymomas. Annals of neurology 35 9266734
1997 Tuberin immunohistochemistry in brain, kidneys and heart with or without tuberous sclerosis. Acta neuropathologica 35 9444353
2022 Quercetin mediates TSC2-RHEB-mTOR pathway to regulate chondrocytes autophagy in knee osteoarthritis. Gene 34 35093450
2016 Autophagy activated by tuberin/mTOR/p70S6K suppression is a protective mechanism against local anaesthetics neurotoxicity. Journal of cellular and molecular medicine 34 27860187
2010 TACC3-TSC2 maintains nuclear envelope structure and controls cell division. Cell cycle (Georgetown, Tex.) 34 20237422
2002 Multicompartmental distribution of the tuberous sclerosis gene products, hamartin and tuberin. Archives of biochemistry and biophysics 33 12147258
2001 Loss of tuberin, the tuberous-sclerosis-complex-2 gene product is associated with angiogenesis. Journal of cutaneous pathology 32 11553313
2000 Simultaneous loss of hamartin and tuberin from the cerebrum, kidney and heart with tuberous sclerosis. Acta neuropathologica 32 10805093
2007 Tuberin regulates the DNA repair enzyme OGG1. American journal of physiology. Renal physiology 31 17989114
2000 Similarities and differences in the subcellular localization of hamartin and tuberin in the kidney. American journal of physiology. Renal physiology 31 10807585
2005 Phosphorylation and binding partner analysis of the TSC1-TSC2 complex. Biochemical and biophysical research communications 30 15963462
1996 The tuberin (TSC2), autosomal dominant polycystic kidney disease (PKD1), and somatostatin type V receptor (SSTR5) genes form a synteny group in the Fugu genome. Genomics 30 8954784
2021 Myopathy associated LDB3 mutation causes Z-disc disassembly and protein aggregation through PKCα and TSC2-mTOR downregulation. Communications biology 29 33742095
2009 Aberrant expression of TSC2 gene in the newly diagnosed acute leukemia. Leukemia research 29 19250671
2020 Structure of the TSC2 GAP Domain: Mechanistic Insight into Catalysis and Pathogenic Mutations. Structure (London, England : 1993) 27 32502382
2017 Heterozygous loss of TSC2 alters p53 signaling and human stem cell reprogramming. Human molecular genetics 27 28973543
2016 VPS34 regulates TSC1/TSC2 heterodimer to mediate RheB and mTORC1/S6K1 activation and cellular transformation. Oncotarget 25 27409169
2010 Lymphangioleiomyomatosis and TSC2-/- cells. Lymphatic research and biology 25 20235888
2008 A reliable cell-based assay for testing unclassified TSC2 gene variants. European journal of human genetics : EJHG 25 18854862
2001 Developmental expression of the tuberous sclerosis proteins tuberin and hamartin. Acta neuropathologica 25 11307618
1995 Mutation analysis of the TSC2 gene in an African-American family. Human molecular genetics 25 8634701
2016 Tuberous sclerosis complex: Hamartin and tuberin expression in renal cysts and its discordant expression in renal neoplasms. Pathology, research and practice 24 27640314
2022 Cross-talk between TSC2 and the extracellular matrix controls pulmonary vascular proliferation and pulmonary hypertension. Science signaling 23 36473049
2021 Interleukin-6 mediates PSAT1 expression and serine metabolism in TSC2-deficient cells. Proceedings of the National Academy of Sciences of the United States of America 23 34544857
2020 Neutrophil elastase from myeloid cells promotes TSC2-null tumor growth. Endocrine-related cancer 23 32045362
2016 RIP3 antagonizes a TSC2-mediated pro-survival pathway in glioblastoma cell death. Biochimica et biophysica acta. Molecular cell research 23 27984090
2013 Comparative analysis of Tsc1 and Tsc2 single and double radial glial cell mutants. The Journal of comparative neurology 23 23749404
2018 Autophagy mediators (FOXO1, SESN3 and TSC2) in Lewy body disease and aging. Neuroscience letters 22 29966750
2013 Conditional and domain-specific inactivation of the Tsc2 gene in neural progenitor cells. Genesis (New York, N.Y. : 2000) 22 23359422
2009 TSC2 deficiency increases PTEN via HIF1alpha. The Journal of biological chemistry 22 19648120
2006 Hamartin and tuberin modulate gene transcription via beta-catenin. Journal of neuro-oncology 21 16552619
2023 The role of TSC2 in breast cancer: a literature review. Frontiers in oncology 20 37251941
2009 The loss of tuberin promotes cell invasion through the ß-catenin pathway. American journal of respiratory cell and molecular biology 19 20042714

Missed literature

Know a paper Affinage missed for TSC2? Flag it for the maintainers and the community.

No submissions yet.