Affinage

TSC1

Hamartin · UniProt Q92574

Length
1164 aa
Mass
129.8 kDa
Annotated
2026-06-10
100 papers in source corpus 31 papers cited in narrative 31 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TSC1 (hamartin) is a tumor-suppressor protein that, in complex with TSC2 (tuberin), functions as the central negative regulator of mTORC1-driven cell growth and protein synthesis (PMID:9242607, PMID:12906785). TSC1 and TSC2 associate directly through coiled-coil interactions, and patient-derived mutations in the binding interface abolish this association, linking complex integrity to disease (PMID:9580671, PMID:11741833). Within the heterodimer, TSC2 supplies GTPase-activating activity toward the small GTPase Rheb, converting it to its inactive GDP-bound form to suppress mTORC1 and downstream S6K/4E-BP1 signaling (PMID:12906785). TSC1 contributes essential regulatory functions: its N-terminal HEAT-repeat domain binds lysosomal phosphoinositides, particularly PI(3,5)P2, to recruit the complex to the lysosome for starvation-induced mTORC1 inactivation, a central helical domain mediates oligomerization, and the C-terminal coiled-coil engages TSC2 (PMID:33974911). TSC1 stabilizes TSC2 by binding it and excluding the HERC1 E3 ubiquitin ligase, preventing TSC2 ubiquitination and degradation (PMID:11175345, PMID:16464865). This stabilization is reversed by signals that dismantle the complex: IKKβ phosphorylates TSC1 at Ser487/Ser511 to suppress its function and activate mTOR-driven angiogenesis and tumor growth (PMID:17693255), and a VPS34–PIKFYVE complex at the plasma membrane disengages TSC2 from TSC1 to drive its degradation and Rheb/mTORC1 activation (PMID:27409169). Beyond mTORC1 control, TSC1 acts independently of TSC2 to regulate cytoskeletal and signaling programs: it binds ERM proteins to activate Rho and promote stress fibers and focal adhesions (PMID:10806479), anchors the perijunctional actin cytoskeleton to β-catenin and ZO-1 via myosin 6 to enable tight junction formation in epithelia (PMID:34301883), restrains M1 macrophage polarization through a Ras–Raf1–MEK–ERK pathway (PMID:25175012), and participates in TGF-β–Smad2/3 signaling by associating with the receptor complex and Smads to control growth arrest and EMT (PMID:25727005). Through its mTORC1-regulatory and cytoskeletal roles, TSC1 governs diverse physiological outputs including autophagy-mediated neuronal protection from ischemia (PMID:23435171), osteocyte sclerostin secretion (PMID:31088250), and osteoclast podosome assembly (PMID:29358671).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1997 High

    Establishing TSC1 as a tumor suppressor defined the disease relevance and set the stage for mechanistic dissection of its growth-suppressive function.

    Evidence Positional cloning with LOH analysis in TSC-associated renal carcinoma

    PMID:9242607

    Open questions at the time
    • Molecular function of the encoded protein not yet defined
    • No binding partners or pathway identified
  2. 1998 High

    Demonstrating a direct hamartin-tuberin physical interaction via coiled-coil domains established that the two TSC gene products act as one complex rather than in parallel.

    Evidence Co-immunoprecipitation, yeast two-hybrid, and domain mapping

    PMID:9580671

    Open questions at the time
    • Biochemical activity of the complex unknown
    • Downstream effectors not identified
  3. 1998 Medium

    Showing hamartin localizes to membrane/particulate fractions independently of tuberin indicated TSC1 has subcellular targeting functions distinct from complex formation.

    Evidence Subcellular fractionation and immunofluorescence in tuberin-null Eker rat cells

    PMID:9809973

    Open questions at the time
    • Identity of the membrane compartment unresolved
    • Lipid- or protein-binding basis of localization unknown
  4. 2000 High

    Linking hamartin to ERM proteins and Rho activation revealed a TSC1 role in actin/adhesion regulation separable from canonical growth suppression.

    Evidence Co-IP, dominant-negative inhibition, Rho activity and actin/focal adhesion assays

    PMID:10806479

    Open questions at the time
    • Relationship to mTOR pathway not addressed
    • In vivo relevance not tested
  5. 2000 High

    Demonstrating that hamartin stabilizes tuberin by preventing its ubiquitination explained how TSC1 loss destabilizes the whole complex.

    Evidence Co-transfection, ubiquitination assay, pulse-chase

    PMID:11175345

    Open questions at the time
    • Identity of the responsible E3 ligase not yet known
    • Mechanism of protection (steric vs. competitive) unresolved
  6. 2001 High

    Fine-mapping the interaction interface and showing disease mutations disrupt binding connected complex integrity directly to TSC pathology.

    Evidence Yeast two-hybrid, Co-IP, and pathological mutation analysis

    PMID:11741833

    Open questions at the time
    • Structural basis of the interface not resolved at this stage
    • Effect on downstream signaling not measured
  7. 2003 High

    Identifying the TSC1-TSC2 complex as a Rheb GAP placed TSC1 at the heart of nutrient/mTOR signaling and unified its growth-suppressive role.

    Evidence In vitro GAP assay, epistasis, S6K1 readout, rapamycin sensitivity, patient mutants

    PMID:12906785

    Open questions at the time
    • TSC1's precise contribution to GAP activity vs. TSC2 not dissected
    • Spatial regulation of GAP function unknown
  8. 2003 Medium

    Connecting the complex to GSK3β/Axin and β-catenin degradation extended TSC1/TSC2 influence to Wnt signaling.

    Evidence Co-IP, luciferase reporter, β-catenin half-life measurement

    PMID:12511557

    Open questions at the time
    • Direct vs. indirect role of TSC1 in the degradation complex unclear
    • In vivo significance not established
  9. 2003 High

    Identifying CDK1-mediated phosphorylation of hamartin at G2/M sites established cell-cycle kinase control of complex activity.

    Evidence In vitro kinase assay, cell-cycle synchronization, site-directed mutagenesis, S6K readout

    PMID:14551205

    Open questions at the time
    • Physiological consequence of phosphorylation in vivo not defined
    • Whether phosphorylation alters localization not tested
  10. 2006 High

    Showing TSC1 excludes the HERC1 E3 ligase from TSC2 provided the molecular mechanism for TSC1-dependent stabilization of tuberin.

    Evidence Reciprocal Co-IP, ubiquitination assay, patient TSC2 mutant analysis

    PMID:16464865

    Open questions at the time
    • Regulation of HERC1 access under physiological signals unknown
    • Structural mode of exclusion not resolved
  11. 2006 Medium

    Distinguishing opposite effects of TSC1/TSC2 on mTORC1 versus mTORC2 refined the complex's role in two distinct mTOR outputs.

    Evidence Knockdown/overexpression in Drosophila S2 and HEK293 cells, S6K and Akt readouts

    PMID:16627617

    Open questions at the time
    • Mechanism of TORC2 activation by the complex unknown
    • TSC1-specific contribution not separated
  12. 2007 High

    Identifying IKKβ phosphorylation of TSC1 at Ser487/Ser511 linked inflammatory signaling to mTOR activation and tumor angiogenesis.

    Evidence Co-IP, in vitro kinase assay, site mutagenesis, tumor IHC and angiogenesis assays

    PMID:17693255

    Open questions at the time
    • How phosphorylation mechanistically suppresses TSC1 (degradation vs. dissociation) not fully resolved
    • Reversal/phosphatase not identified
  13. 2014 High

    Demonstrating mTOR-independent control of M1 macrophage polarization through Ras-Raf1-MEK-ERK established a genuinely TSC2/mTOR-independent TSC1 function.

    Evidence Myeloid-specific Tsc1 knockout mice, rapamycin and mTOR deletion, ERK pathway analysis

    PMID:25175012

    Open questions at the time
    • Direct molecular link between TSC1 and Ras-Raf1 unresolved
    • Whether TSC1 acts as scaffold or enzyme here unknown
  14. 2015 High

    Showing TSC1 acts independently of TSC2 within the TGF-β-Smad2/3 pathway broadened its signaling repertoire beyond mTOR.

    Evidence Co-IP with receptor complex and Smads, Smad phosphorylation, EMT and target gene assays

    PMID:25727005

    Open questions at the time
    • Structural basis of TSC1-Smad/receptor binding unknown
    • How TSC1 partitions between TSC2-dependent and -independent pools unresolved
  15. 2021 High

    Defining TSC1's three-domain architecture and PI(3,5)P2-dependent lysosomal recruitment revealed how TSC1 spatially targets the complex for starvation-induced mTORC1 inactivation.

    Evidence Domain mapping, PIP lipid-binding assay, lysosomal recruitment and mTORC1 activity assays, conservation analysis

    PMID:33974911

    Open questions at the time
    • Regulation of PI(3,5)P2 levels controlling recruitment not detailed
    • Dynamics of recruitment under fed vs. starved states not fully kinetically resolved
  16. 2021 High

    Demonstrating TSC1 translocation to cell junctions and myosin-6-dependent anchoring of perijunctional actin established a structural, mTORC1-independent role in epithelial barrier integrity.

    Evidence Live-cell imaging, Co-IP of myosin 6/β-catenin/ZO-1, intestine- and skin-specific knockout mice, patient tissue

    PMID:34301883

    Open questions at the time
    • Signal triggering TSC1 junctional translocation unknown
    • Relationship between junctional and lysosomal TSC1 pools unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TSC1 is partitioned among its distinct functional pools — lysosomal TSC2-bound GAP complex, junctional cytoskeletal anchor, and TSC2-independent signaling scaffold — and what governs switching between them remains unresolved.
  • No unified model of TSC1 pool allocation
  • Upstream determinants directing TSC1 to TSC2-independent functions unknown
  • Structural details of TSC1's TSC2-independent complexes lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0008092 cytoskeletal protein binding 2 GO:0060090 molecular adaptor activity 2 GO:0008289 lipid binding 1
Localization
GO:0005856 cytoskeleton 3 GO:0005829 cytosol 2 GO:0005886 plasma membrane 2 GO:0005764 lysosome 1 GO:0005794 Golgi apparatus 1 GO:0005815 microtubule organizing center 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 2 R-HSA-9612973 Autophagy 1
Partners
EZRHERC1IKBKBMYO6PLK1RHEBSMAD2TSC2
Complex memberships
TSC1-TSC2 (hamartin-tuberin) complexVPS34-PIKFYVE-TSC1 complex

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 TSC1 encodes a 130 kDa protein (hamartin) that acts as a tumor suppressor; somatic mutation of the wild-type allele was found in a TSC-associated renal carcinoma, consistent with a two-hit tumor suppressor model. Positional cloning, mutation analysis, loss-of-heterozygosity analysis in tumor tissue Science High 9242607
1998 Hamartin (TSC1) and tuberin (TSC2) physically associate in vivo, and this interaction is mediated by predicted coiled-coil domains in both proteins, indicating they function together in the same complex. Co-immunoprecipitation, yeast two-hybrid, domain mapping Human molecular genetics High 9580671
1998 Hamartin localizes to the membrane/particulate (P100) fraction of cells and displays a punctate cytoplasmic immunofluorescence pattern consistent with cytoplasmic vesicles; this localization is independent of tuberin. Subcellular fractionation, immunofluorescence microscopy Cancer research Medium 9809973
2000 Hamartin interacts with the ezrin-radixin-moesin (ERM) family of actin-binding proteins; overexpression of hamartin activates the small GTPase Rho, induces actin stress fiber assembly and focal adhesion formation, whereas inhibition of hamartin causes loss of adhesion. Endogenous hamartin-ERM interaction is required for Rho activation by serum or LPA. Co-immunoprecipitation, dominant-negative inhibition, overexpression, Rho activity assays, actin/focal adhesion staining Nature cell biology High 10806479
2000 Hamartin stabilizes tuberin by binding to it and preventing its ubiquitination; the fraction of tuberin bound to hamartin is not ubiquitinated, whereas unbound tuberin is highly ubiquitinated and degraded. Co-expression of tuberin also stabilizes hamartin. Co-transfection, immunoprecipitation, ubiquitination assay, pulse-chase Oncogene High 11175345
2000 Ectopic hamartin expression inhibits cell proliferation and arrests cells in G1 phase; this growth-inhibitory effect depends on the coiled-coil domain implicated in tuberin binding. Overexpression, cell proliferation assay, cell cycle analysis, domain-deletion constructs Human molecular genetics Medium 10915759
2001 Hamartin (amino acids 302–430) and tuberin (amino acids 1–418, requiring a coiled-coil region at 346–371 plus additional N-terminal residues) directly interact; TSC patient-derived pathological mutations within these binding regions abolish or dramatically reduce hamartin-tuberin interaction in yeast two-hybrid and co-IP assays. Yeast two-hybrid, co-immunoprecipitation, pathological mutation analysis Human molecular genetics High 11741833
2001 Tuberin phosphorylation at serine and tyrosine residues regulates its interaction with hamartin; disease-associated TSC2 mutations (Y1571H, P1675L) reduce tuberin phosphorylation, decrease TSC1-TSC2 interaction, and impair tuberin's growth-inhibitory function. Phosphorylation assays, co-immunoprecipitation, growth inhibition assays, patient-derived mutants The Journal of biological chemistry Medium 11290735
2001 Hamartin and tuberin interact with and co-localize with CDK1 (cdc2) and its regulatory partners cyclin B1 and cyclin A in multiple cell types, suggesting a direct role for both proteins in modulating CDK1 activity at the G2/M transition. Co-immunoprecipitation, confocal co-localization Journal of neuropathology and experimental neurology Low 11444800
2003 The TSC1-TSC2 (hamartin-tuberin) heterodimer acts as a GTPase-activating protein (GAP) for the small GTPase Rheb in vitro; Rheb mediates nutrient/mTOR signaling upstream of mTOR and downstream of TSC1/TSC2. Patient-derived tuberin GAP domain mutants could not inactivate Rheb, placing TSC1/TSC2 as a GAP complex for Rheb to negatively regulate mTORC1. In vitro GAP assay, overexpression epistasis, S6K1 phosphorylation readout, rapamycin sensitivity, patient-derived mutants Current biology High 12906785
2003 The tuberin-hamartin complex co-immunoprecipitates with glycogen synthase kinase 3β (GSK3β) and Axin in a Wnt-1-dependent manner and negatively regulates β-catenin stability and TCF/LEF transcriptional activity by participating in the β-catenin degradation complex. Co-immunoprecipitation, luciferase reporter assay, β-catenin stability/half-life measurement The Journal of biological chemistry Medium 12511557
2003 Cyclin-dependent kinase 1 (CDK1)/cyclin B phosphorylates hamartin at Thr417 (within the hamartin-tuberin interaction domain) and two other sites during G2/M; phospho-hamartin still interacts with tuberin; alanine mutations at all three CDK1 sites increase the inhibitory activity of the hamartin-tuberin complex on p70S6K. In vitro kinase assay, cell-cycle synchronization, site-directed mutagenesis, S6K phosphorylation assay The Journal of biological chemistry High 14551205
2004 TSC2 modulates actin dynamics and focal adhesion through the TSC1-binding domain (HBD); TSC2 expression promotes Rac1 activation and inhibits Rho, leading to stress fiber disassembly. TSC1 siRNA knockdown in TSC2-null cells activates Rac1, demonstrating that TSC1 inhibits Rac1 and TSC2 blocks this TSC1 activity. siRNA knockdown, Rac1/Rho activity assays, domain constructs, actin/focal adhesion staining The Journal of cell biology Medium 15611338
2005 Hamartin localizes to the centrosome and interacts with polo-like kinase 1 (Plk1) in a phosphorylation-dependent manner; the interaction requires phosphorylation of Thr310 on hamartin. Hamartin negatively regulates Plk1 protein levels. Tsc1-null MEFs exhibit increased centrosome number and DNA content, rescued by rapamycin but not Plk1 RNAi. Immunofluorescence (centrosome localization), co-immunoprecipitation, site-directed mutagenesis (T310A), immunoblot, rapamycin rescue, RNAi Human molecular genetics Medium 16339216
2005 Cyclin D1 (and other D-type cyclins) negatively regulate TSC1-TSC2: coexpression of cyclin D1-CDK4/6 increases phosphorylation and decreases steady-state levels of both TSC2 and TSC1, and promotes phosphorylation of mTOR substrates 4E-BP1 and S6K1. Cyclin D1 also down-regulates TSC proteins independently of CDK4/6. Co-expression, immunoblot, mTOR substrate phosphorylation assay, CDK4/6-independent mutant cyclin D1 Cancer research Medium 16357142
2006 TSC1 stabilizes TSC2 by excluding the HERC1 E3 ubiquitin ligase from the TSC2 complex; disease mutations in TSC2 that cause its destabilization allow HERC1 binding even in the presence of TSC1. Co-immunoprecipitation, ubiquitination assay, patient-derived TSC2 mutant analysis The Journal of biological chemistry High 16464865
2006 TSC1/TSC2 loss impairs NF-κB activation and cell survival after DNA damage or TNFα; rapamycin-mediated inhibition of deregulated mTOR activity in TSC2-null cells restores NF-κB activation and survival, identifying a crosstalk between the TSC/Rheb/mTOR and NF-κB pathways. TSC1/TSC2-deficient MEFs, NF-κB reporter assay, survival assay, rapamycin treatment, reconstitution Cancer cell Medium 16959613
2006 TSC1/TSC2 have differential effects on mTORC1 and mTORC2: TSC1/TSC2 negatively regulates TORC1 and positively regulates TORC2 activity; Rheb activates TORC1 but inhibits TORC2 (via a feedback through TORC1/S6K). Genetic knockdown/overexpression in Drosophila S2 cells and HEK293 cells, S6K and Akt phosphorylation as TORC1/2 readouts Proceedings of the National Academy of Sciences of the United States of America Medium 16627617
2007 IKKβ physically interacts with and phosphorylates TSC1 at Ser487 and Ser511, resulting in suppression of TSC1 function and consequent mTOR pathway activation, enhanced angiogenesis, and tumor development. Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis, IHC in tumor samples, functional angiogenesis/tumor assays Cell High 17693255
2007 TSC1 loss causes increased translation of nucleophosmin mRNA via mTOR activation, leading to greater nucleophosmin protein, enhanced nuclear export of ribosome subunits, higher overall rates of protein synthesis, and increased proliferation; TSC1 re-introduction suppresses nucleophosmin accumulation. Tsc1 genetic ablation, polysome profiling, ribosome export assay, TSC1 reconstitution, rapamycin treatment Cancer research Medium 17308101
2008 Zebrafish tsc1a morpholino knockdown causes ciliary phenotypes (kidney cysts, left-right asymmetry defects) and elongated cilia; tsc1a acts synthetically with ciliary genes; Tsc1a localizes to the Golgi; mTOR pathway is aberrantly activated in ciliary mutants resembling tsc1a knockdown; rapamycin blocks cyst formation in ciliary mutants. Morpholino knockdown, genetic interaction (synthetic lethality), immunofluorescence localization, rapamycin rescue Human molecular genetics Medium 19008302
2014 TSC1 inhibits M1 macrophage polarization via a Ras GTPase-Raf1-MEK-ERK pathway independently of mTOR, and promotes M2 polarization via an mTOR-dependent C/EBPβ pathway; deletion of mTOR fails to reverse the enhanced M1 response of TSC1-deficient macrophages. Myeloid-specific TSC1 knockout mice, rapamycin treatment, mTOR deletion, ERK pathway analysis, cytokine assays, asthma model Nature communications High 25175012
2015 TSC1 functions independently of TSC2 as a component of the TGF-β-Smad2/3 pathway: TSC1 interacts with the TGF-β receptor complex and Smad2/3, is required for their association, and regulates TGF-β-induced Smad2/3 phosphorylation, target gene expression, growth arrest, and EMT. Hyperactive Akt activates TSC1-dependent cytostatic Smad signaling. Co-immunoprecipitation, Smad phosphorylation assay, gene expression (target genes), loss-of-function (TSC1 KD), EMT assay, Akt activation Developmental cell High 25727005
2021 TSC1 contains three structural domains: a C-terminal coiled-coil interacting with TSC2, a central helical domain mediating TSC1 oligomerization, and an N-terminal HEAT repeat domain that binds lysosomal phosphatidylinositol phosphates (PIPs), particularly PI3,5P2. Lysosomal recruitment of the TSC complex and subsequent mTORC1 inactivation upon starvation require TSC1 binding to PI3,5P2. TSC1 architecture and membrane binding are conserved from fungi to humans. Structural characterization (domain mapping), lipid-binding assay (PIP binding), lysosomal recruitment assay, mTORC1 activity assay under starvation, conservation analysis Molecular cell High 33974911
2021 TSC1, but not TSC2, migrates from the cytoplasm to junctional membranes when epithelial cells establish contact; at junctions, TSC1 binds myosin 6 to anchor the perijunctional actin cytoskeleton to β-catenin and ZO-1, enabling tight junction formation independent of mTORC1. Intestine- or skin-specific Tsc1 ablation disrupts tight/adherens junction structures causing Crohn's disease-like or psoriasis-like phenotypes. Live-cell imaging/fractionation (translocation), co-immunoprecipitation (myosin 6, β-catenin, ZO-1), conditional knockout mice (intestine-specific, inducible whole-body), patient tissue analysis Proceedings of the National Academy of Sciences of the United States of America High 34301883
2019 In osteocytes, TSC1 promotes sclerostin secretion through inhibition of mTORC1 and downregulation of Sirt1 (a repressor of the sclerostin gene Sost); Tsc1 osteocyte-specific knockout constitutively activates mTORC1 and reduces sclerostin production, causing osteosclerosis; rapamycin restores sclerostin expression. Conditional knockout (DMP1-Cre), rapamycin treatment, TSC1 knockdown in osteocyte cell line, mTORC1 activity assay, sclerostin/Sost expression assay, mechanical loading Open biology Medium 31088250
2018 TSC1 is required for podosome belt formation in osteoclasts; TSC1 deletion reduces podosome superstructure assembly by releasing mTORC1-dependent negative feedback inhibition of Rac1/Cdc42, leading to bone resorption deficiency and osteopetrosis; rapamycin and active Rac1/Cdc42 restore podosome organization. Conditional knockout (osteoclast-specific), podosome/sealing zone imaging, Rac1/Cdc42 activity assays, rapamycin rescue, in vivo bone phenotype Cell death and differentiation Medium 29358671
2013 Hamartin (TSC1) is selectively induced by ischemia in resistant hippocampal CA3 neurons and by ischemic preconditioning in CA1 neurons; TSC1 shRNA knockdown increases neuronal vulnerability to ischemia in vitro and in vivo; hamartin overexpression increases resistance to OGD by inducing productive autophagy through an mTORC1-dependent mechanism. shRNA knockdown in vitro and in vivo (viral vectors), OGD model, overexpression, autophagy assay, mTORC1 activity assay Nature medicine Medium 23435171
2002 Hamartin and tuberin are multicompartmental proteins present in cytosolic, microsomal, and cytoskeletal compartments as a stable complex; in the microsomal fraction they behave as peripheral membrane proteins on the cytosolic leaflet; immunoisolation shows enrichment of Rap1, Rab5, and caveolin-1 in tuberin-bound vesicle fractions. Subcellular fractionation, co-immunoprecipitation, magnetic bead immunoisolation, carbonate extraction Archives of biochemistry and biophysics Medium 12147258
2003 Pam (a RING-zinc finger protein) associates with the tuberin-hamartin complex in the brain; the C-terminus of Pam (RING domain) binds tuberin; Pam co-localizes with tuberin and hamartin in neurites and growth cones. The Drosophila ortholog HIW genetically interacts with the Tsc1-Tsc2 complex and could negatively regulate its activity. Co-immunoprecipitation, co-localization (immunofluorescence), Drosophila genetic interaction The Journal of biological chemistry Low 14559897
2016 VPS34 forms a protein complex with PIKFYVE and TSC1 at the plasma membrane via PI3P; this disengages TSC2 from the TSC1/TSC2 heterodimer, leading to TSC2 ubiquitination and degradation, thereby activating RheB and mTORC1/S6K1. Co-immunoprecipitation, ubiquitination assay, lipid kinase assay, VPS34 kinase-dead mutant Oncotarget Medium 27409169

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science (New York, N.Y.) 1287 9242607
2008 The TSC1-TSC2 complex: a molecular switchboard controlling cell growth. The Biochemical journal 1001 18466115
2003 Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Current biology : CB 986 12906785
2000 Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs. American journal of human genetics 735 11112665
2012 Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice. Nature 692 22763451
2007 IKK beta suppression of TSC1 links inflammation and tumor angiogenesis via the mTOR pathway. Cell 545 17693255
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
1999 Comprehensive mutation analysis of TSC1 and TSC2-and phenotypic correlations in 150 families with tuberous sclerosis. American journal of human genetics 382 10205261
2001 TSC1 and TSC2 tumor suppressors antagonize insulin signaling in cell growth. Genes & development 380 11390358
2003 Rhebbing up mTOR: new insights on TSC1 and TSC2, and the pathogenesis of tuberous sclerosis. Cancer biology & therapy 271 14614311
2000 The TSC1 tumour suppressor hamartin regulates cell adhesion through ERM proteins and the GTPase Rho. Nature cell biology 269 10806479
2014 TSC1 controls macrophage polarization to prevent inflammatory disease. Nature communications 256 25175012
1998 Hamartin, the product of the tuberous sclerosis 1 (TSC1) gene, interacts with tuberin and appears to be localized to cytoplasmic vesicles. Cancer research 217 9809973
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
2013 Tsc1 (hamartin) confers neuroprotection against ischemia by inducing autophagy. Nature medicine 192 23435171
2006 TSC1 stabilizes TSC2 by inhibiting the interaction between TSC2 and the HERC1 ubiquitin ligase. The Journal of biological chemistry 186 16464865
2020 Gut epithelial TSC1/mTOR controls RIPK3-dependent necroptosis in intestinal inflammation and cancer. The Journal of clinical investigation 171 31961824
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
2011 Single-cell Tsc1 knockout during corticogenesis generates tuber-like lesions and reduces seizure threshold in mice. The Journal of clinical investigation 140 21403402
2011 Neuronal and glia abnormalities in Tsc1-deficient forebrain and partial rescue by rapamycin. Neurobiology of disease 140 21907282
2002 Mutation analysis of the TSC1 and TSC2 genes in Japanese patients with pulmonary lymphangioleiomyomatosis. Journal of human genetics 115 11829138
2013 TSC1 regulates the balance between effector and regulatory T cells. The Journal of clinical investigation 114 24270422
2017 TSC1 and TSC2 gene mutations and their implications for treatment in Tuberous Sclerosis Complex: a review. Genetics and molecular biology 111 28222202
2003 Tumour suppressors hamartin and tuberin: intracellular signalling. Cellular signalling 105 12781866
2000 The TSC1 gene product, hamartin, negatively regulates cell proliferation. Human molecular genetics 104 10915759
2011 GABAergic interneuron development and function is modulated by the Tsc1 gene. Cerebral cortex (New York, N.Y. : 1991) 103 22021912
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
2001 The spectrum of mutations in TSC1 and TSC2 in women with tuberous sclerosis and lymphangiomyomatosis. American journal of respiratory and critical care medicine 103 11208653
1999 Mutation of the 9q34 gene TSC1 in sporadic bladder cancer. Oncogene 97 10353610
2022 GPNMB expression identifies TSC1/2/mTOR-associated and MiT family translocation-driven renal neoplasms. The Journal of pathology 95 35072947
2004 TSC2 modulates actin cytoskeleton and focal adhesion through TSC1-binding domain and the Rac1 GTPase. The Journal of cell biology 93 15611338
2001 Pathological mutations in TSC1 and TSC2 disrupt the interaction between hamartin and tuberin. Human molecular genetics 92 11741833
2014 Neuronal Tsc1/2 complex controls autophagy through AMPK-dependent regulation of ULK1. Human molecular genetics 87 24599401
2011 TSC1/TSC2 signaling in the CNS. FEBS letters 87 21329690
2004 Tsc1+ and tsc2+ regulate arginine uptake and metabolism in Schizosaccharomyces pombe. The Journal of biological chemistry 86 14718525
2003 The tuberin-hamartin complex negatively regulates beta-catenin signaling activity. The Journal of biological chemistry 86 12511557
2005 Tuberin and hamartin are aberrantly expressed and linked to clinical outcome in human breast cancer: the role of promoter methylation of TSC genes. European journal of cancer (Oxford, England : 1990) 84 15951164
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
2011 Functional assessment of variants in the TSC1 and TSC2 genes identified in individuals with Tuberous Sclerosis Complex. Human mutation 80 21309039
2012 Altered LKB1/AMPK/TSC1/TSC2/mTOR signaling causes disruption of Sertoli cell polarity and spermatogenesis. Human molecular genetics 71 22791749
2011 Regulation of T-cell survival and mitochondrial homeostasis by TSC1. European journal of immunology 71 21805467
2008 Zebrafish Tsc1 reveals functional interactions between the cilium and the TOR pathway. Human molecular genetics 70 19008302
2003 Pam and its ortholog highwire interact with and may negatively regulate the TSC1.TSC2 complex. The Journal of biological chemistry 70 14559897
2005 Hamartin, the tuberous sclerosis complex 1 gene product, interacts with polo-like kinase 1 in a phosphorylation-dependent manner. Human molecular genetics 67 16339216
2005 Negative regulation of TSC1-TSC2 by mammalian D-type cyclins. Cancer research 66 16357142
2003 Cell cycle-regulated phosphorylation of hamartin, the product of the tuberous sclerosis complex 1 gene, by cyclin-dependent kinase 1/cyclin B. The Journal of biological chemistry 65 14551205
2006 Hamartin and tuberin: working together for tumour suppression. International journal of cancer 63 16206276
2009 TSC1 and TSC2 mutations in patients with lymphangioleiomyomatosis and tuberous sclerosis complex. Journal of medical genetics 60 19419980
1999 The expression of hamartin, the product of the TSC1 gene, in normal human tissues and in TSC1- and TSC2-linked angiomyolipomas. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 60 10349994
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
2012 Tumor suppressor TSC1 is critical for T-cell anergy. Proceedings of the National Academy of Sciences of the United States of America 56 22891340
2015 TSC1 activates TGF-β-Smad2/3 signaling in growth arrest and epithelial-to-mesenchymal transition. Developmental cell 55 25727005
2016 NK cell development requires Tsc1-dependent negative regulation of IL-15-triggered mTORC1 activation. Nature communications 53 27601261
2019 Tsc1-mTORC1 signaling controls striatal dopamine release and cognitive flexibility. Nature communications 51 31780742
2001 Hamartin and tuberin interaction with the G2/M cyclin-dependent kinase CDK1 and its regulatory cyclins A and B. Journal of neuropathology and experimental neurology 47 11444800
2021 TSC1 binding to lysosomal PIPs is required for TSC complex translocation and mTORC1 regulation. Molecular cell 45 33974911
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
2019 Tsc1 represses parvalbumin expression and fast-spiking properties in somatostatin lineage cortical interneurons. Nature communications 44 31676823
2000 Expression of the tuberous sclerosis complex gene products, hamartin and tuberin, in central nervous system tissues. Acta neuropathologica 41 10663963
2018 TSC1 and TSC2 regulate cilia length and canonical Hedgehog signaling via different mechanisms. Cellular and molecular life sciences : CMLS 39 29396625
2018 TSC1 regulates osteoclast podosome organization and bone resorption through mTORC1 and Rac1/Cdc42. Cell death and differentiation 37 29358671
2004 The mTOR/S6K signalling pathway: the role of the TSC1/2 tumour suppressor complex and the proto-oncogene Rheb. Novartis Foundation symposium 37 15562827
2022 Loss of TSC1/TSC2 sensitizes immune checkpoint blockade in non-small cell lung cancer. Science advances 36 35119931
2007 TSC1 sets the rate of ribosome export and protein synthesis through nucleophosmin translation. Cancer research 35 17308101
2005 TSC1-2 tumour suppressor and regulation of mTOR signalling: linking cell growth and proliferation? Current opinion in genetics & development 35 15661536
2019 Loss of FOXP3 and TSC1 Accelerates Prostate Cancer Progression through Synergistic Transcriptional and Posttranslational Regulation of c-MYC. Cancer research 34 30733194
2015 TSC1 controls IL-1β expression in macrophages via mTORC1-dependent C/EBPβ pathway. Cellular & molecular immunology 33 27593484
2002 Multicompartmental distribution of the tuberous sclerosis gene products, hamartin and tuberin. Archives of biochemistry and biophysics 33 12147258
2019 TSC1/mTOR-controlled metabolic-epigenetic cross talk underpins DC control of CD8+ T-cell homeostasis. PLoS biology 32 31433805
2006 Hypoxia-inducible factor-1alpha polymorphisms and TSC1/2 mutations are complementary in head and neck cancers. Molecular cancer 32 16412252
2000 Simultaneous loss of hamartin and tuberin from the cerebrum, kidney and heart with tuberous sclerosis. Acta neuropathologica 32 10805093
2000 Similarities and differences in the subcellular localization of hamartin and tuberin in the kidney. American journal of physiology. Renal physiology 31 10807585
2021 Role of TSC1 in physiology and diseases. Molecular and cellular biochemistry 30 33575875
2015 Tsc1 is a Critical Regulator of Macrophage Survival and Function. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 30 26159807
2005 Phosphorylation and binding partner analysis of the TSC1-TSC2 complex. Biochemical and biophysical research communications 30 15963462
2024 The mTOR pathway genes MTOR, Rheb, Depdc5, Pten, and Tsc1 have convergent and divergent impacts on cortical neuron development and function. eLife 29 38411613
2020 Long non-coding RNA OIP5-AS1 suppresses multiple myeloma progression by sponging miR-27a-3p to activate TSC1 expression. Cancer cell international 29 32410883
2017 Mutational analysis of TSC1 and TSC2 genes in Tuberous Sclerosis Complex patients from Greece. Scientific reports 27 29196670
2001 Pathogenesis of multifocal micronodular pneumocyte hyperplasia and lymphangioleiomyomatosis in tuberous sclerosis and association with tuberous sclerosis genes TSC1 and TSC2. Pathology international 27 11564212
2018 TSC1 and DEPDC5 regulate HIV-1 latency through the mTOR signaling pathway. Emerging microbes & infections 26 30087333
2010 Polymorphic variants in TSC1 and TSC2 and their association with breast cancer phenotypes. Breast cancer research and treatment 26 20658316
2016 VPS34 regulates TSC1/TSC2 heterodimer to mediate RheB and mTORC1/S6K1 activation and cellular transformation. Oncotarget 25 27409169
2015 Pharmacological inhibition of Polo-like kinase 1 (PLK1) by BI-2536 decreases the viability and survival of hamartin and tuberin deficient cells via induction of apoptosis and attenuation of autophagy. Cell cycle (Georgetown, Tex.) 25 25565629
2012 Cystogenesis and elongated primary cilia in Tsc1-deficient distal convoluted tubules. American journal of physiology. Renal physiology 25 22674026
2001 Developmental expression of the tuberous sclerosis proteins tuberin and hamartin. Acta neuropathologica 25 11307618
2016 Tuberous sclerosis complex: Hamartin and tuberin expression in renal cysts and its discordant expression in renal neoplasms. Pathology, research and practice 24 27640314
2021 TSC1 Affects the Process of Renal Ischemia-Reperfusion Injury by Controlling Macrophage Polarization. Frontiers in immunology 23 33767704
2019 PTEN expression and mutations in TSC1, TSC2 and MTOR are associated with response to rapalogs in patients with renal cell carcinoma. International journal of cancer 23 31335987
2013 Comparative analysis of Tsc1 and Tsc2 single and double radial glial cell mutants. The Journal of comparative neurology 23 23749404
2008 Expression of tuberin and hamartin in tuberous sclerosis complex-associated and sporadic cortical dysplasia of Taylor's balloon cell type. Folia neuropathologica 23 18368626
2004 Tuberin and hamartin expression is reduced in the majority of subependymal giant cell astrocytomas in tuberous sclerosis complex consistent with a two-hit model of pathogenesis. Journal of child neurology 23 15072102
2001 The chromosome 9q genes TGFBR1, TSC1, and ZNF189 are rarely mutated in bladder cancer. The Journal of pathology 22 11329144
2021 Tsc1 regulates tight junction independent of mTORC1. Proceedings of the National Academy of Sciences of the United States of America 21 34301883
2019 Osteocyte TSC1 promotes sclerostin secretion to restrain osteogenesis in mice. Open biology 21 31088250
2006 Hamartin and tuberin modulate gene transcription via beta-catenin. Journal of neuro-oncology 21 16552619

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