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P49816 (TSC2_RAT) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 121. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (1) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Tuberin
Alternative name(s):
Tuberous sclerosis 2 protein homolog
Gene names
Name:Tsc2
OrganismRattus norvegicus (Rat) [Reference proteome]
Taxonomic identifier10116 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus

Protein attributes

Sequence length1809 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

In complex with TSC1, inhibits the nutrient-mediated or growth factor-stimulated phosphorylation of S6K1 and EIF4EBP1 by negatively regulating mTORC1 signaling. Acts as a GTPase-activating protein (GAP) for the small GTPase RHEB, a direct activator of the protein kinase activity of mTORC1 By similarity. Implicated as a tumor suppressor. Involved in microtubule-mediated protein transport, but this seems to be due to unregulated mTOR signaling By similarity. 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.

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. Interacts with HSPA1 and HSPA8 By similarity. Interacts with DAPK1 By similarity. Ref.3

Tissue specificity

CNS, uterus, heart, skeletal muscle, kidney and spleen.

Post-translational modification

Phosphorylation at Ser-1388, Ser-1420 or Ser-1422 does not affect interaction with TSC1. Phosphorylation at Ser-939 and Thr-1466 by PKB/AKT1 is induced by growth factor stimulation. Phosphorylation by AMPK activates it and leads to negatively regulates the mTORC1 complex. Phosphorylated at Ser-1800 by RPS6KA1; phosphorylation inhibits TSC2 ability to suppress mTORC1 signaling By similarity. Phosphorylated by DAPK1 By similarity.

Ubiquitinated by the DCX(FBXW5) E3 ubiquitin-protein ligase complex, leading to its subsequent degradation. Ubiquitinated by MYCBP2 inependently of its phosphorylation status leading to subsequent degradation; association with TSC1 protects from ubiquitination By similarity.

Involvement in disease

A germline insertion in Tsc2 is the cause of the Eker rat model of inherited cancer susceptibility. Gives rise to a spectrum of epithelial and nonepithelial neoplasms.

Sequence similarities

Contains 1 Rap-GAP domain.

Ontologies

Keywords
   Coding sequence diversityAlternative splicing
   DiseaseTumor suppressor
   Molecular functionGTPase activation
   PTMPhosphoprotein
Ubl conjugation
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processacute-phase response

Inferred from mutant phenotype Ref.2. Source: RGD

cell projection organization

Inferred from mutant phenotype PubMed 16286931. Source: MGI

establishment of protein localization

Inferred from mutant phenotype PubMed 15093748. Source: RGD

heart development

Inferred from electronic annotation. Source: Ensembl

insulin-like growth factor receptor signaling pathway

Inferred from Biological aspect of Ancestor. Source: RefGenome

negative regulation of MAP kinase activity

Inferred from mutant phenotype PubMed 14612383. Source: RGD

negative regulation of TOR signaling

Inferred from direct assay PubMed 12869586. Source: RGD

negative regulation of Wnt signaling pathway

Inferred from direct assay PubMed 12511557. Source: RGD

negative regulation of cell proliferation

Inferred from mutant phenotype Ref.2. Source: RGD

negative regulation of cell size

Inferred from mutant phenotype PubMed 16286931. Source: MGI

negative regulation of epithelial cell proliferation

Inferred from direct assay PubMed 14612383. Source: RGD

negative regulation of phosphatidylinositol 3-kinase signaling

Inferred from electronic annotation. Source: Ensembl

negative regulation of protein kinase B signaling

Inferred from electronic annotation. Source: Ensembl

neural tube closure

Inferred from electronic annotation. Source: Ensembl

phosphatidylinositol 3-kinase signaling

Inferred from electronic annotation. Source: Ensembl

positive chemotaxis

Inferred from electronic annotation. Source: Ensembl

positive regulation of Rab GTPase activity

Traceable author statement PubMed 12045200. Source: GOC

protein heterooligomerization

Inferred from direct assay PubMed 17379185. Source: RGD

protein homooligomerization

Inferred from direct assay PubMed 17379185. Source: RGD

protein import into nucleus

Inferred from electronic annotation. Source: Ensembl

protein kinase B signaling

Inferred from Biological aspect of Ancestor. Source: RefGenome

regulation of cell cycle

Inferred from mutant phenotype Ref.2. Source: RGD

regulation of endocytosis

Inferred from electronic annotation. Source: Ensembl

regulation of insulin receptor signaling pathway

Inferred from Biological aspect of Ancestor. Source: RefGenome

response to hypoxia

Inferred from electronic annotation. Source: Ensembl

signal transduction

Inferred from direct assay PubMed 12045200. Source: RGD

   Cellular_componentGolgi apparatus

Inferred from electronic annotation. Source: Ensembl

TSC1-TSC2 complex

Inferred from Biological aspect of Ancestor. Source: RefGenome

caveola

Inferred from direct assay PubMed 15093748. Source: RGD

cytoskeleton

Inferred from direct assay PubMed 12147258. Source: RGD

cytosol

Inferred from direct assay PubMed 12147258. Source: RGD

dendrite

Inferred from direct assay PubMed 15525761. Source: RGD

growth cone

Inferred from direct assay PubMed 14559897. Source: RGD

intracellular membrane-bounded organelle

Inferred from direct assay PubMed 12147258PubMed 15093748. Source: RGD

membrane raft

Inferred from direct assay PubMed 15093748. Source: RGD

neuron projection

Inferred from direct assay PubMed 14559897. Source: RGD

neuronal cell body

Inferred from direct assay PubMed 15525761. Source: RGD

nucleus

Inferred from Biological aspect of Ancestor. Source: RefGenome

perinuclear region of cytoplasm

Inferred from direct assay PubMed 14559897. Source: RGD

protein complex

Inferred from direct assay PubMed 17379185. Source: RGD

   Molecular_functionGTPase activator activity

Inferred from direct assay PubMed 12869586. Source: RGD

Rab GTPase activator activity

Traceable author statement PubMed 12045200. Source: RGD

phosphatase binding

Inferred from sequence or structural similarity. Source: UniProtKB

protein heterodimerization activity

Inferred from physical interaction PubMed 15093748. Source: RGD

Complete GO annotation...

Alternative products

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

Note: Additional isoforms seem to exist.
Isoform 1 (identifier: P49816-1)

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: P49816-2)

The sequence of this isoform differs from the canonical sequence as follows:
     947-989: Missing.
Isoform 3 (identifier: P49816-3)

The sequence of this isoform differs from the canonical sequence as follows:
     1272-1294: Missing.
Isoform 4 (identifier: P49816-4)

The sequence of this isoform differs from the canonical sequence as follows:
     947-989: Missing.
     1272-1294: Missing.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 18091809Tuberin
PRO_0000065656

Regions

Domain1533 – 1760228Rap-GAP

Amino acid modifications

Modified residue5401Phosphoserine By similarity
Modified residue6641Phosphoserine By similarity
Modified residue9271Phosphothreonine By similarity
Modified residue9391Phosphoserine; by PKB/AKT1 By similarity
Modified residue9811Phosphoserine By similarity
Modified residue11321Phosphoserine By similarity
Modified residue11551Phosphoserine By similarity
Modified residue13401Phosphoserine By similarity
Modified residue13411Phosphoserine By similarity
Modified residue13491Phosphoserine By similarity
Modified residue13891Phosphoserine By similarity
Modified residue14131Phosphoserine By similarity
Modified residue14201Phosphoserine By similarity
Modified residue14221Phosphoserine By similarity
Modified residue14521Phosphoserine; by AMPK By similarity
Modified residue14561Phosphoserine By similarity
Modified residue14661Phosphothreonine; by PKB/AKT1 By similarity
Modified residue18001Phosphoserine; by RPS6KA1 By similarity

Natural variations

Alternative sequence947 – 98943Missing in isoform 2 and isoform 4.
VSP_004481
Alternative sequence1272 – 129423Missing in isoform 3 and isoform 4.
VSP_004482

Experimental info

Mutagenesis3141N → S in chemically induced renal carcinoma. Ref.4
Mutagenesis7131L → R in chemically induced renal carcinoma. Ref.4
Sequence conflict9321K → S in BAA08914. Ref.2
Sequence conflict15141C → F in BAA08914. Ref.2
Sequence conflict17301R → S in BAA08914. Ref.2

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified October 1, 1996. Version 1.
Checksum: 6190BEFB45272664

FASTA1,809201,278
        10         20         30         40         50         60 
MAKPTSKDSG LKEKFKILLG LGTSRPNPRC AEGKQTEFII TAEILRELSG ECGLNNRIRM 

        70         80         90        100        110        120 
IGQICDVAKT KKLEEHAVEA LWKAVSDLLQ PERPPEARHA VLALLKAIVQ GQGDRLGVLR 

       130        140        150        160        170        180 
ALFFKVIKDY PSNEDLHERL EVFKALTDNG RHITYLEEEL AEFVLQWMDV GLSSEFLLVL 

       190        200        210        220        230        240 
VNLVKFNSCY LDEYIAPMVH MICLLCIRTV SSVDIEVSLQ VLDAVVCYNC LPAESLPLFI 

       250        260        270        280        290        300 
ITLCRTVNVK ELCEPCWKLM RNLLGTHLGH SAIYNMCRIM ENRSYMEDAP LLRGAVFFVG 

       310        320        330        340        350        360 
MALWGAHRLY SLKNSPTSVL PSFYEAMTCP NEVVSYEIVL SITRLIKKYR KELQAVTWDI 

       370        380        390        400        410        420 
LLDIIERLLQ QLQNLDSPEL RTIVHDLLTT VEELCDQNEF HGSQERYYEL VESYADQRPE 

       430        440        450        460        470        480 
SSLLNLITYR AQSIHPAKDG WIQNLQLLME RFFRNECRSA VRIKVLDVLS FVLLINRQFY 

       490        500        510        520        530        540 
EEELINSVVI SQLSHIPEDK DHQVRKLATQ LLVDLAEGCH THHFNSLLDI IEKVMARSLS 

       550        560        570        580        590        600 
PPLELEERDL AVYSASLEDV KTAVLGLLVI LQTKLYTLPA SHATRVYETL ISHIQLHYKH 

       610        620        630        640        650        660 
GYSLPIASSI RLQAFDFLLL LRADSLHRLG LPNKDGVVRF SPYCLCDCAE LDRASEKKAS 

       670        680        690        700        710        720 
GPLSPPTGPP SPVPTGPAVR LGHLPYSLLF RVLLQCLKQE TDWKVLKLVL SKLPESLRYK 

       730        740        750        760        770        780 
VLIFTSPCSV DQLSSALCSM LSAPKTLERL RGTPEGFSRT DLHLAVVPVL TALISYHNYL 

       790        800        810        820        830        840 
DKTRQREMVY CLEQGLIYRC ASQCVVALAI CSVEMPDIII KALPVLVVKL THISATASMA 

       850        860        870        880        890        900 
IPLLEFLSTL ARLPHLYRNF AAEQYASVFA ISLPYTNPSK FNQYIVCLAH HVIAMWFIRC 

       910        920        930        940        950        960 
RLPFRKDFVP YITKGLRSNV LLSFDDTPEK DKFRARSTSL NERPKSLRIA RAPKQGLNNS 

       970        980        990       1000       1010       1020 
PPVKEFKESC AAEAFRCRSI SVSEHVVRSR IQTSLTSASL GSADENSMAQ ADDNLKNLHL 

      1030       1040       1050       1060       1070       1080 
ELTETCLDMM ARYVFSNFTA VPKRSPVGEF LLAGGRTKTW LVGNKLVTVT TSVGTGTRSL 

      1090       1100       1110       1120       1130       1140 
LGLDSGDLQG GSASSSDPGT HVRQTKEAPA KLESQAGQQV SRGARDRVRS MSGGHGLRVG 

      1150       1160       1170       1180       1190       1200 
VLDTSAPYTP GGPASLGAQA APAARPEKPC AGAQLPAAEK ANLAAYVPLL TQGWAEILVR 

      1210       1220       1230       1240       1250       1260 
RPTGNTSWLM SLENPLSPFS SDINNMPLQE LSNALMAAER FKEHRDTALY KSLSVPAAGT 

      1270       1280       1290       1300       1310       1320 
AKPPTLPRSN TVASFSSLYQ PSCQGQLHRS VSWADSAVVL EEGSPGEAHV PVEPPELEDF 

      1330       1340       1350       1360       1370       1380 
EAALGTDRHC QRPDAYSRSS SASSQEEKSH LEELAAGGIP IERAISSEGA RPTVDLSFQP 

      1390       1400       1410       1420       1430       1440 
SQPLSKSSSS PELQTLQDIL GDLGDKTDIG RLSPEAKVRS QSGILDGEAA TWSAPGEESR 

      1450       1460       1470       1480       1490       1500 
ITVPPEGPLP SSSPRSPSGL RPRGYTISDS APSRRGKRVE RDNFKSRTAA SSAEKVPGIN 

      1510       1520       1530       1540       1550       1560 
PSFVFLQLYH SPFCGDESNK PILLPNESFE RSVQLLDQIP SYDTHKIAVL YVGEGQSSSE 

      1570       1580       1590       1600       1610       1620 
LAILSNEHGS YRYTEFLTGL GRLIELKDCQ PDKVYLGGLD VCGEDGQFTY CWHDDIMQAV 

      1630       1640       1650       1660       1670       1680 
FHIATLMPTK DVDKHRCDKK RHLGNDFVSI IYNDSGEDFK LGTIKGQFNF VHVIITPLDY 

      1690       1700       1710       1720       1730       1740 
KCNLLTLQCR KDMEGLVDTS VAKIVSDRNL SFVARQMALH ANMASQVHHR RSNPTDIYPS 

      1750       1760       1770       1780       1790       1800 
KWIARLRHIK RLRQRIREEV HYSNPSLPLM HPPAHTKVPA QAPTEATPTY ETGQRKRLIS 


SVDDFTEFV 

« Hide

Isoform 2 [UniParc].

Checksum: 85B44025626BC659
Show »

FASTA1,766196,527
Isoform 3 [UniParc].

Checksum: 8D02C6EA34616F36
Show »

FASTA1,786198,757
Isoform 4 [UniParc].

Checksum: F923B79ADBF45D10
Show »

FASTA1,743194,006

References

[1]"Identification of tuberous sclerosis 2 messenger RNA splice variants that are conserved and differentially expressed in rat and human tissues."
Xiao G.-H., Jin F., Yeung R.S.
Cell Growth Differ. 6:1185-1191(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2; 3 AND 4).
Strain: Wistar.
Tissue: Kidney.
[2]"cDNA structure, alternative splicing and exon-intron organization of the predisposing tuberous sclerosis (Tsc2) gene of the Eker rat model."
Kobayashi T., Nishizawa M., Hirayama Y., Kobayashi E., Hino O.
Nucleic Acids Res. 23:2608-2613(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
Strain: Long Evans.
Tissue: Brain and Kidney.
[3]"The tuberous sclerosis 2 gene product, tuberin, functions as a Rab5 GTPase activating protein (GAP) in modulating endocytosis."
Xiao G.-H., Shoarinejad F., Jin F., Golemis E.A., Yeung R.S.
J. Biol. Chem. 272:6097-6100(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH RAB5.
[4]"Isolation and characterization of a rat homologue of the human tuberous sclerosis 1 gene (Tsc1) and analysis of its mutations in rat renal carcinomas."
Satake N., Kobayashi T., Kobayashi E., Izumi K., Hino O.
Cancer Res. 59:849-855(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: MUTAGENESIS OF ASN-314 AND LEU-713.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
U24150 mRNA. Translation: AAC52289.1.
D50413 mRNA. Translation: BAA08914.1.
PIRS57329.
RefSeqNP_036812.2. NM_012680.3.
UniGeneRn.5875.

3D structure databases

ProteinModelPortalP49816.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid246972. 8 interactions.
IntActP49816. 4 interactions.
MINTMINT-4783802.
STRING10116.ENSRNOP00000016221.

PTM databases

PhosphoSiteP49816.

Proteomic databases

PaxDbP49816.
PRIDEP49816.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSRNOT00000016221; ENSRNOP00000016221; ENSRNOG00000011375.
GeneID24855.
KEGGrno:24855.
UCSCRGD:3908. rat. [P49816-1]

Organism-specific databases

CTD7249.
RGD3908. Tsc2.

Phylogenomic databases

eggNOGNOG290929.
GeneTreeENSGT00390000017866.
HOGENOMHOG000045987.
HOVERGENHBG018005.
InParanoidP49816.
KOK07207.
OrthoDBEOG7KM5S3.
PhylomeDBP49816.
TreeFamTF324484.

Gene expression databases

GenevestigatorP49816.

Family and domain databases

Gene3D1.25.10.10. 3 hits.
InterProIPR011989. ARM-like.
IPR016024. ARM-type_fold.
IPR000331. Rap_GAP_dom.
IPR003913. Tuberin.
IPR018515. Tuberin-type_domain.
IPR027107. Tuberin/Ral-act_asu.
IPR024584. Tuberin_N.
[Graphical view]
PANTHERPTHR10063. PTHR10063. 1 hit.
PTHR10063:SF1. PTHR10063:SF1. 1 hit.
PfamPF11864. DUF3384. 1 hit.
PF02145. Rap_GAP. 1 hit.
PF03542. Tuberin. 1 hit.
[Graphical view]
PRINTSPR01431. TUBERIN.
SUPFAMSSF48371. SSF48371. 1 hit.
PROSITEPS50085. RAPGAP. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

NextBio604654.
PROP49816.

Entry information

Entry nameTSC2_RAT
AccessionPrimary (citable) accession number: P49816
Entry history
Integrated into UniProtKB/Swiss-Prot: October 1, 1996
Last sequence update: October 1, 1996
Last modified: April 16, 2014
This is version 121 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families