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Reviewed, UniProtKB/Swiss-Prot P49815 (TSC2_HUMAN)

Last modified November 25, 2008. Version 97. Feed History...

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Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Binary interactions · Alternative products · Sequence annotation (Features) · Sequences · References · Web resources · Cross-references · Entry information · Relevant documents

Names and origin

Protein namesRecommended name:
    Tuberin
Alternative name(s):
    Tuberous sclerosis 2 protein
Gene names
Name: TSC2
Synonyms: TSC4
OrganismHomo sapiens (Human)
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length1807 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is not processed.
Protein existenceEvidence at protein level.

General annotation (Comments)

Function

Implicated as a tumor suppressor. May have a function in vesicular transport, but may also play a role in the regulation of cell growth arrest and in the regulation of transcription mediated by steroid receptors. Interaction between TSC1 and TSC2 may facilitate vesicular docking. Specifically stimulates the intrinsic GTPase activity of the Ras-related protein RAP1A and RAB5. Suggesting a possible mechanism for its role in regulating cellular growth. Mutations in TSC2 leads to constitutive activation of RAP1A in tumors.

Subunit structure

Interacts with TSC1 and HERC1; the interaction with TSC1 stabilizes TSC2 and prevents the interaction with HERC1. May also interact with the adapter molecule RABEP1. The final complex contains TSC2 and RABEP1 linked to RAB5 Probable. Interacts with HSPA1 and HSPA8.

Subcellular location

Cytoplasm. Membrane; Peripheral membrane protein. Note= At steady state found in association with membranes.

Tissue specificity

Liver, brain, heart, lymphocytes, fibroblasts, biliary epithelium, pancreas, skeletal muscle, kidney, lung and placenta.

Post-translational modification

Phosphorylation at Ser-1387, Ser-1418 or Ser-1420 does not affect interaction with TSC1.

Involvement in disease

Defects in TSC2 are the cause of tuberous sclerosis complex (TSC) [MIM:191100]. The molecular basis of TSC is a functional impairment of the tuberin-hamartin complex. TSC is an autosomal dominant multi-system disorder that affects especially the brain, kidneys, heart, and skin. TSC is characterized by hamartomas (benign overgrowths predominantly of a cell or tissue type that occurs normally in the organ) and hamartias (developmental abnormalities of tissue combination). Clinical symptoms can range from benign hypopigmented macules of the skin to profound mental retardation with intractable seizures to premature death from a variety of disease-associated causes.

Defects in TSC2 are a cause of lymphangioleiomyomatosis (LAM) [MIM:606690]. LAM is a progressive and often fatal lung disease characterized by a diffuse proliferation of abnormal smooth muscle cells in the lungs. It affects almost exclusively young women and can occur as an isolated disorder or in association with tuberous sclerosis complex.

Sequence similarities

Contains 1 Rap-GAP domain.

Ontologies

Keywords

   Biological processCell cycle
   Cellular componentCytoplasm
Membrane
   Coding sequence diversityAlternative splicing
Polymorphism
   DiseaseDisease mutation
   Molecular functionAnti-oncogene
GTPase activation
   PTMPhosphoprotein

Gene Ontology (GO)

   Biological processheart development

Inferred from sequence or structural similarity. Source: UniProtKB

insulin-like growth factor receptor signaling pathway

Inferred from sequence or structural similarity. Source: UniProtKB

negative regulation of cell cycle

Inferred from electronic annotation. Source: UniProtKB-KW

negative regulation of cell proliferation

Inferred from sequence or structural similarity. Source: UniProtKB

negative regulation of phosphoinositide 3-kinase cascade

Inferred from sequence or structural similarity. Source: UniProtKB

negative regulation of protein kinase B signaling cascade

Inferred from sequence or structural similarity. Source: UniProtKB

negative regulation of protein kinase activity

Inferred from sequence or structural similarity. Source: UniProtKB

neural tube closure

Inferred from sequence or structural similarity. Source: UniProtKB

positive chemotaxis

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of GTPase activity

Inferred from electronic annotation. Source: InterPro

protein import into nucleus

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of endocytosis

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of insulin receptor signaling pathway

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of small GTPase mediated signal transduction

Inferred from electronic annotation. Source: InterPro

   Cellular componentGolgi apparatus Ref.9

Inferred from direct assay. Source: UniProtKB

TSC1-TSC2 complex Ref.8

Inferred from direct assay. Source: UniProtKB

membrane

Inferred from electronic annotation. Source: UniProtKB-KW

membrane fraction

Inferred from direct assay. Source: UniProtKB

nucleus

Inferred from direct assay. Source: UniProtKB

perinuclear region of cytoplasm

Inferred from direct assay. Source: UniProtKB

   Molecular functionGTPase activator activity Ref.7

Inferred from direct assay. Source: UniProtKB

protein homodimerization activity Ref.9

Inferred from physical interaction. Source: UniProtKB

Complete GO annotation...

Binary interactions

Alternative products

This entry describes 4 isoforms produced by alternative splicing. [Align] [Select]

Notes: Additional isoforms seem to exist. Experimental confirmation may be lacking for some isoforms.
Isoform 1 (identifier: P49815-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
Isoform 2 (identifier: P49815-2)

The sequence of this isoform differs from the canonical sequence as follows:
     946-988: Missing.
Isoform 3 (identifier: P49815-3)

The sequence of this isoform differs from the canonical sequence as follows:
     946-989: Missing.
Isoform 4 (identifier: P49815-4)

The sequence of this isoform differs from the canonical sequence as follows:
     1272-1294: Missing.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 18071807Tuberin
PRO_0000065654

Regions

Domain1531 – 1758228Rap-GAP

Amino acid modifications

Modified residue9271Phosphothreonine
Modified residue9811Phosphoserine
Modified residue10971Phosphoserine
Modified residue11321Phosphoserine
Modified residue11551Phosphoserine
Modified residue13341Phosphoserine
Modified residue13371Phosphoserine
Modified residue13381Phosphoserine
Modified residue13411Phosphoserine
Modified residue13641Phosphoserine By similarity
Modified residue13871Phosphoserine
Modified residue14111Phosphoserine
Modified residue14181Phosphoserine
Modified residue14201Phosphoserine
Modified residue14491Phosphoserine
Modified residue14521Phosphoserine
Modified residue17981Phosphoserine

Natural variations

Alternative sequence946 – 98944Missing in isoform 3.
VSP_004471
Alternative sequence946 – 98843Missing in isoform 2.
VSP_004470
Alternative sequence1272 – 129423Missing in isoform 4.
VSP_004472
Natural variant941T → P
VAR_008019
Natural variant1371H → R in TSC; could be a polymorphism.
VAR_009415
Natural variant1601L → V
VAR_009416
Natural variant2271C → Y in TSC.
VAR_008020
Natural variant2581K → N in TSC.
VAR_009417
Natural variant2611R → P in TSC.
VAR_009418
Natural variant2611R → W
VAR_009419
Natural variant2861M → T
VAR_009420
Natural variant2861M → V: dbSNP rs1800748.
VAR_009421
Natural variant2921L → P in TSC.
VAR_005646
Natural variant2941G → E in TSC.
VAR_009422
Natural variant3041W → WGMALW in TSC.
VAR_009423
Natural variant3091L → Q
VAR_009424
Natural variant3201F → L in TSC; could be a polymorphism characteristic to the Asian population.
VAR_009425
Natural variant3311N → K in TSC.
VAR_008021
Natural variant3611L → P in TSC.
VAR_009426
Natural variant3651Missing in TSC.
VAR_009427
Natural variant3671R → Q: dbSNP rs1800725.
VAR_009428
Natural variant3781P → L
VAR_009429
Natural variant4071Y → D in TSC.
VAR_005647
Natural variant4401G → S
VAR_009430
Natural variant4491M → I in TSC.
VAR_005648
Natural variant4631I → V
VAR_009431
Natural variant4861N → I in TSC.
VAR_008022
Natural variant4901I → V
VAR_008023
Natural variant5251N → S in TSC.
VAR_009432
Natural variant5361A → V
VAR_008024
Natural variant5831A → T: dbSNP rs1800729.
VAR_009433
Natural variant5931H → R
VAR_009434
Natural variant5991K → M in TSC.
VAR_009435
Natural variant6071A → T
VAR_005649
Natural variant6111R → Q in TSC and LAM; impairs phosphorylation at S-1387, S-1418 and S-1420.
VAR_005650
Natural variant6111R → W in TSC; impairs phosphorylation at S-1387, S-1418 and S-1420.
VAR_005651
Natural variant6141A → D in TSC.
VAR_009436
Natural variant6151F → S
VAR_008025
Natural variant6471D → N in TSC; could be a polymorphism.
VAR_009437
Natural variant6941Missing in TSC.
VAR_009438
Natural variant6961C → Y in TSC.
VAR_009439
Natural variant7171L → R in TSC.
VAR_009440
Natural variant7691V → E in TSC; could be a polymorphism.
VAR_009441
Natural variant8161P → L in TSC.
VAR_008026
Natural variant8261L → M in TSC.
VAR_005652
Natural variant8621A → V
VAR_018600
Natural variant8951M → V in TSC.
VAR_009442
Natural variant9051R → Q in TSC.
VAR_005653
Natural variant9051R → W in TSC.
VAR_005654
Natural variant9631V → M in TSC; could be a polymorphism.
VAR_009443
Natural variant10271L → P in TSC.
VAR_022919
Natural variant10841D → E in TSC.
VAR_005655
Natural variant11441V → M in TSC.
VAR_008027
Natural variant12001R → W in TSC.
VAR_005656
Natural variant12271P → L in TSC.
VAR_005657
Natural variant12401R → W in TSC.
VAR_005658
Natural variant12821S → G
VAR_009444
Natural variant12951D → V in TSC.
VAR_005659
Natural variant13151P → S in TSC.
VAR_008028
Natural variant13291R → H in TSC.
VAR_008029
Natural variant13411S → R
VAR_022920
Natural variant14291A → S
VAR_018601
Natural variant14501P → R
VAR_018602
Natural variant14971P → R in TSC.
VAR_009445