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FLASH GENE
Symbol TSC2 contributors: mct/pgu/shn - updated : 30-07-2014
HGNC name tuberous sclerosis 2
HGNC id 12363
Corresponding disease
FCDBC3 focal cortical dysplasia of Taylor balloon cell type 3
TSC2 tuberous sclerosis 2
Location 16p13.3      Physical location : 2.097.989 - 2.138.712
Synonym name
  • tuberin
  • tuberous sclerosis 2 protein
    • Synonym symbol(s) TBR, TSC4, LAM, FLJ43106
    DNA
    TYPE functioning gene
    STRUCTURE 40.72 kb     42 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked Y status confirmed
    Map pter - D16S3024 - D16S3395 - TSC2 TSC2 - D16S3124 - D16S3070 - cen
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    42 - 5675 180 1807 - 1995 7558029
    - splicing 5411 - 1763 widely 1995 7558029
    exon 26
    40 - 5474 - 1740 - 1995 7581393
    variant 4
    41 - 5577 - 1784 - 1995 7581393
    variant 5
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestivemouthtongue  highly
    Lymphoid/Immunethymus   highly
    Nervousbrain    
    Respiratoryrespiratory tractlarynx  highly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Nervouscentral   
    Nervousperipherous   
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Nervousastrocyte
    Nervousneuron
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a relatively hydrophobic N terminal region
  • a putative leucine-zipper
  • four potential tyrosine-kinase phosphorylation sites
  • two putative small coiled-coil domains
  • a calmodulin-binding site
  • a conserved C terminal domain homolog to RAP1A, RAP1B, and RAB5B, GTPase activating protein
  • GAP domain
    • HOMOLOGY
    interspecies ortholog to Tsc2, Mus musculus
    ortholog to Tsc2, Rattus norvegicus
    ortholog to tsc2, Danio rerio
    ortholog to TSC2, Pan troglodytes
    Homologene
    FAMILY
    CATEGORY chaperone/stress , regulatory
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,organelle,Golgi
    intracellular,cytoplasm,cytosolic
    basic FUNCTION
  • functioning as a growth suppressor (in sporadic astrocytomas) through the inhibition of S6K via its RHEB GAP activity
  • regulating Rho activation, cell adhesion and migration
  • likely involved in endocytosis pathway
  • participating in normal brain development, restricts tissue growth and reducing cell size and cell proliferation
  • chaperone for hamartin
  • required to mediate the cellular energy response
  • playing a critical role in late stage myeloid cell differentiation
  • regulates CDKN1B nuclear/cytoplasmic localization MTOR activity, and negatively regulates the interaction of 14-3-3 and CDKN1B
  • activates the proapoptotic molecule BAD
  • key roles of TSC1/TSC2 in neuronal polarity, suggest a common pathway regulating polarization/growth in neurons and cell size in other tissues
  • TSC1-TSC2 complex inhibits MTORC1 and activates MTORC2, which through different mechanisms promotes Akt activation
  • with TSC2 function as a heterodimer to inhibit the activity of the mammalian target of rapamycin complex 1 (TORC1) TSC2
  • with TSC1, function as a heterodimer to inhibit the activity of the mammalian target of rapamycin complex 1 (MTORC1)
  • regulate formation of the primary cilium via a rapamycin-insensitive and polycystin 1-independent pathway
  • central player in negatively controlling cell proliferation and protein translation through suppressing the activity of MTOR
  • plays a critical role in the control of cell spreading, polarity, and migration
  • plays a role in controlling cell polarity and migration by regulating CDC42 and RAC1 activation
  • plays a positive role in maintaining the balance of small GTPases to ensure coordinated cell migration
  • important role in unfolded protein response and cell survival (
  • plays a role in regulating the cellular localization of cyclin B1
  • TSC2 and AKT1S1 are potent anti-apoptotic gatekeepers in early mammalian stem-cell differentiation, inhibiting embryoid bodies (EBs) degradation during early amniotic fluid stem (AFS) cell differentiation
  • TSC2 and AKT1S1 are major anti-apoptotic regulators during early AFS cell differentiation due to their potential to control the rapamycin-insensitive functions of MTOR
  • role of TSC2 as a transcription factor and of TSC2 binding to the promoter of any gene
  • TSC1 and TSC2 regulate the activity of small GTPases RHOA and RAC1, stress fiber formation and cell adhesion in a reciprocal manner
  • TSC1 and TSC2 differentially regulate actin stress fiber formation and cell migration, but only TSC2 loss promotes MTOR- and CTRC2-dependent pro-migratory cell phenotype
    • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS development
    PATHWAY
    metabolism
    signaling sensory transduction/vision
    PI3K pathway
    a component
  • heterodimerizing with TSC1
  • TSC1/2 complex has been found to play a crucial role in an evolutionarily-conserved signaling pathway that regulates cell growth: the MTOR pathway
  • TSC1-TSC2-TBC1D7 (TSC-TBC) complex is the functional complex that senses specific cellular growth conditions and possesses Rheb-GAP activity
    • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • heterodimerizing with TSC2 (
  • G2/M cyclin-dependent kinase CDK1 and cyclins A and B (
  • Akt/PKB (
  • 14-3-3zeta (
  • peptidylglycine alpha-amidating monooxygenase, PAM (
  • MTOR
  • GTP-bound RHEB
  • SMAD2 and SMAD3
  • CDKN1B
  • dedicator of cytokinesis 7, DOCK7
  • focal adhesion kinase, FAK (
  • forkhead box O1, FoxO1 (
  • TBC1 domain family, member 7, TBC7 (
  • inhibits MTORC1 via the Ras homologue RHEB, which is a key target of TSC2 highly conserved GTPase activating protein domain
  • F-box and WD repeat domain containing 5, FBXW5
  • binds and regulates the G 2/M cyclin, cyclin B1
  • PCTP bound to tuberous sclerosis complex 2 (TSC2) and stabilized the components of the TSC1-TSC2 complex, which functions to inhibit MTOR
  • TSC1, TSC2, negatively regulates the mammalian target of rapamycin complex 1 (MTOR) a master regulator of protein synthesis, cell growth and autophagy
  • TSC2 binds to the EREG promoter between -352 bp and -303 bp and negatively regulates its expression
  • FBXW5 is a TSC2 binding receptor within CUL4 E3 ligase complex, and it promotes proteasomal degradation of TSC2
    • cell & other
    REGULATION
    activated by AMPK-dependent phosphorylation, preparing protection from cell death
    Other phosphorylated by GSK3, thereby inhibiting the mTOR pathway
    ASSOCIATED DISORDERS
    corresponding disease(s) TSC2 , FCDBC3
    related resource TSC Variation database
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral   LOH    
    in hamartoma and angiomyolipoma
    tumoral germinal mutation      
    in pulmonary lymphangioleiomyomatosis
    tumoral       loss of function
    in hamartoma and kidney tumor
    tumoral somatic mutation     loss of function
    two-hit mechanism of biallelic inactivation of TSC1 or TSC2, leading to activation of FRAP1 and to subependymal giant cell
    constitutional        
    cells lacking TSC2 have cilia that are on average 1727 p100 longer than wild-type cells, which indicates a defect in normal ciliogenesis
    tumoral       loss of function
    inactivating mutations in TSC2 and PIK3R1 in urothelial carcinoma
    Susceptibility to medulloblastoma
    Variant & Polymorphism other allele A2 increase susceptibility to medulloblastoma
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    cancer  
    targeting TSC1/2 is a strategy for boosting antitumor immune therapy
    ANIMAL & CELL MODELS
  • homozygous state of Tsc2(Ek/Ek) mutation Eker rat model is lethal in mid-gestation displaying dysraphia and papillary overgrowth of the neuroepithelium (
  • Rats with a germline inactivation of one allele of the Tsc2 tumor suppressor gene developed early onset severe bilateral polycystic kidney disease (
  • mutations in the Drosophila Tsc2 cause a phenotype characterized by enhanced growth and increased cell size with no change in ploidy (
  • mice with a heterozygous, inactivating mutation in the Tsc2 gene (Tsc2(+/-) mice) show deficits in learning and memory (
  • mouse selectively deleted for the Tsc2 gene from radial glial progenitor cells in the developing cerebral cortex and hippocampus are severely runted, develop post-natal megalencephaly and die between 3 and 4 weeks of age with cortical and hippocampal lamination defects, hippocampal heterotopias, enlarged dysplastic neurons and glia, abnormal myelination and an astrocytosis (
  • Embryos homozygous for the del3 allele survive until E13.5, 2 days longer than Tsc2 null embryos (die from underdevelopment of the liver, deficient hematopoiesis, aberrant vascular development and hemorrhage. Mice heterozygous for the del3 allele have a markedly reduced kidney tumor burden in comparison with conventional Tsc2+/
    • mice
  • cells with mutation in TSC2 are hypersensitive to endoplasmic reticulum stress and undergo apoptosis (