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FLASH GENE

Symbol

TSC2

contributors: mct/pgu/shn - updated : 30-07-2014

HGNC name	tuberous sclerosis 2
HGNC id	12363

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_000548 42 - 5675 NP_000539 180 1807 - 1995 7558029 NM_021056 - splicing 5411 NP_066400 - 1763 widely 1995 7558029 exon 26 NM_001077183 40 - 5474 NP_001070651 - 1740 - 1995 7581393 variant 4 NM_001114382 41 - 5577 NP_001107854 - 1784 - 1995 7581393 variant 5

EXPRESSION

Type

widely

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Digestive mouth tongue     highly Lymphoid/Immune thymus       highly Nervous brain         Respiratory respiratory tract larynx     highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Nervous central       Nervous peripherous

cells

System Cell Pubmed Species Stage Rna symbol Nervous astrocyte Nervous neuron

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)

Type Gene Modification Chromosome rearrangement Protein expression Protein 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
	System Type Disorder Pubmed 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 (