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P49816

- TSC2_RAT

UniProt

P49816 - TSC2_RAT

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Protein
Tuberin
Gene
Tsc2
Organism
Rattus norvegicus (Rat)
Status
Reviewed - Annotation score: 5 out of 5 - Experimental evidence at protein leveli

Functioni

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.

GO - Molecular functioni

  1. GTPase activator activity Source: RGD
  2. Rab GTPase activator activity Source: RGD
  3. phosphatase binding Source: UniProtKB
  4. protein binding Source: RGD
  5. protein heterodimerization activity Source: RGD

GO - Biological processi

  1. acute-phase response Source: RGD
  2. cell projection organization Source: MGI
  3. establishment of protein localization Source: RGD
  4. heart development Source: Ensembl
  5. insulin-like growth factor receptor signaling pathway Source: Ensembl
  6. negative regulation of MAP kinase activity Source: RGD
  7. negative regulation of TOR signaling Source: RGD
  8. negative regulation of Wnt signaling pathway Source: RGD
  9. negative regulation of cell proliferation Source: RGD
  10. negative regulation of cell size Source: MGI
  11. negative regulation of epithelial cell proliferation Source: RGD
  12. negative regulation of insulin receptor signaling pathway Source: RefGenome
  13. negative regulation of phosphatidylinositol 3-kinase signaling Source: Ensembl
  14. negative regulation of protein kinase B signaling Source: RefGenome
  15. neural tube closure Source: Ensembl
  16. phosphatidylinositol 3-kinase signaling Source: Ensembl
  17. positive chemotaxis Source: Ensembl
  18. positive regulation of Rab GTPase activity Source: GOC
  19. positive regulation of Ras GTPase activity Source: RefGenome
  20. protein heterooligomerization Source: RGD
  21. protein homooligomerization Source: RGD
  22. protein import into nucleus Source: Ensembl
  23. protein kinase B signaling Source: Ensembl
  24. regulation of cell cycle Source: RGD
  25. regulation of endocytosis Source: Ensembl
  26. response to hypoxia Source: Ensembl
  27. signal transduction Source: RGD
Complete GO annotation...

Keywords - Molecular functioni

GTPase activation

Enzyme and pathway databases

ReactomeiREACT_198729. Constitutive PI3K/AKT Signaling in Cancer.

Names & Taxonomyi

Protein namesi
Recommended name:
Tuberin
Alternative name(s):
Tuberous sclerosis 2 protein homolog
Gene namesi
Name:Tsc2
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus
ProteomesiUP000002494: Chromosome 10

Organism-specific databases

RGDi3908. Tsc2.

Subcellular locationi

GO - Cellular componenti

  1. Golgi apparatus Source: Ensembl
  2. TSC1-TSC2 complex Source: RefGenome
  3. caveola Source: RGD
  4. cytoskeleton Source: RGD
  5. cytosol Source: RGD
  6. dendrite Source: RGD
  7. growth cone Source: RGD
  8. intracellular membrane-bounded organelle Source: RGD
  9. membrane raft Source: RGD
  10. neuron projection Source: RGD
  11. neuronal cell body Source: RGD
  12. nucleus Source: Ensembl
  13. perinuclear region of cytoplasm Source: RGD
  14. protein complex Source: RGD
Complete GO annotation...

Pathology & Biotechi

Involvement in diseasei

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.

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi314 – 3141N → S in chemically induced renal carcinoma. 1 Publication
Mutagenesisi713 – 7131L → R in chemically induced renal carcinoma. 1 Publication

Keywords - Diseasei

Tumor suppressor

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 18091809Tuberin
PRO_0000065656Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei540 – 5401Phosphoserine By similarity
Modified residuei664 – 6641Phosphoserine By similarity
Modified residuei927 – 9271Phosphothreonine By similarity
Modified residuei939 – 9391Phosphoserine; by PKB/AKT1 By similarity
Modified residuei981 – 9811Phosphoserine By similarity
Modified residuei1132 – 11321Phosphoserine By similarity
Modified residuei1155 – 11551Phosphoserine By similarity
Modified residuei1340 – 13401Phosphoserine By similarity
Modified residuei1341 – 13411Phosphoserine By similarity
Modified residuei1349 – 13491Phosphoserine By similarity
Modified residuei1389 – 13891Phosphoserine By similarity
Modified residuei1413 – 14131Phosphoserine By similarity
Modified residuei1420 – 14201Phosphoserine By similarity
Modified residuei1422 – 14221Phosphoserine By similarity
Modified residuei1452 – 14521Phosphoserine; by AMPK By similarity
Modified residuei1456 – 14561Phosphoserine By similarity
Modified residuei1466 – 14661Phosphothreonine; by PKB/AKT1 By similarity
Modified residuei1800 – 18001Phosphoserine; by RPS6KA1 By similarity

Post-translational modificationi

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.

Keywords - PTMi

Phosphoprotein, Ubl conjugation

Proteomic databases

PaxDbiP49816.
PRIDEiP49816.

PTM databases

PhosphoSiteiP49816.

Expressioni

Tissue specificityi

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

Gene expression databases

GenevestigatoriP49816.

Interactioni

Subunit structurei

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.1 Publication

Protein-protein interaction databases

BioGridi246972. 8 interactions.
IntActiP49816. 4 interactions.
MINTiMINT-4783802.
STRINGi10116.ENSRNOP00000016221.

Structurei

3D structure databases

ProteinModelPortaliP49816.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini1533 – 1760228Rap-GAP
Add
BLAST

Sequence similaritiesi

Contains 1 Rap-GAP domain.

Phylogenomic databases

eggNOGiNOG290929.
GeneTreeiENSGT00390000017866.
HOGENOMiHOG000045987.
HOVERGENiHBG018005.
InParanoidiP49816.
KOiK07207.
OrthoDBiEOG7KM5S3.
PhylomeDBiP49816.
TreeFamiTF324484.

Family and domain databases

Gene3Di1.25.10.10. 3 hits.
InterProiIPR011989. ARM-like.
IPR016024. ARM-type_fold.
IPR000331. Rap_GAP_dom.
IPR003913. Tuberin.
IPR018515. Tuberin-type_domain.
IPR024584. Tuberin_N.
[Graphical view]
PANTHERiPTHR10063:SF1. PTHR10063:SF1. 1 hit.
PfamiPF11864. DUF3384. 1 hit.
PF02145. Rap_GAP. 1 hit.
PF03542. Tuberin. 1 hit.
[Graphical view]
PRINTSiPR01431. TUBERIN.
SUPFAMiSSF48371. SSF48371. 1 hit.
PROSITEiPS50085. RAPGAP. 1 hit.
[Graphical view]

Sequences (4)i

Sequence statusi: Complete.

This entry describes 4 isoformsi produced by alternative splicing. Align

Note: Additional isoforms seem to exist.

Isoform 1 (identifier: P49816-1) [UniParc]FASTAAdd to Basket

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.

« Hide

MAKPTSKDSG LKEKFKILLG LGTSRPNPRC AEGKQTEFII TAEILRELSG     50
ECGLNNRIRM IGQICDVAKT KKLEEHAVEA LWKAVSDLLQ PERPPEARHA 100
VLALLKAIVQ GQGDRLGVLR ALFFKVIKDY PSNEDLHERL EVFKALTDNG 150
RHITYLEEEL AEFVLQWMDV GLSSEFLLVL VNLVKFNSCY LDEYIAPMVH 200
MICLLCIRTV SSVDIEVSLQ VLDAVVCYNC LPAESLPLFI ITLCRTVNVK 250
ELCEPCWKLM RNLLGTHLGH SAIYNMCRIM ENRSYMEDAP LLRGAVFFVG 300
MALWGAHRLY SLKNSPTSVL PSFYEAMTCP NEVVSYEIVL SITRLIKKYR 350
KELQAVTWDI LLDIIERLLQ QLQNLDSPEL RTIVHDLLTT VEELCDQNEF 400
HGSQERYYEL VESYADQRPE SSLLNLITYR AQSIHPAKDG WIQNLQLLME 450
RFFRNECRSA VRIKVLDVLS FVLLINRQFY EEELINSVVI SQLSHIPEDK 500
DHQVRKLATQ LLVDLAEGCH THHFNSLLDI IEKVMARSLS PPLELEERDL 550
AVYSASLEDV KTAVLGLLVI LQTKLYTLPA SHATRVYETL ISHIQLHYKH 600
GYSLPIASSI RLQAFDFLLL LRADSLHRLG LPNKDGVVRF SPYCLCDCAE 650
LDRASEKKAS GPLSPPTGPP SPVPTGPAVR LGHLPYSLLF RVLLQCLKQE 700
TDWKVLKLVL SKLPESLRYK VLIFTSPCSV DQLSSALCSM LSAPKTLERL 750
RGTPEGFSRT DLHLAVVPVL TALISYHNYL DKTRQREMVY CLEQGLIYRC 800
ASQCVVALAI CSVEMPDIII KALPVLVVKL THISATASMA IPLLEFLSTL 850
ARLPHLYRNF AAEQYASVFA ISLPYTNPSK FNQYIVCLAH HVIAMWFIRC 900
RLPFRKDFVP YITKGLRSNV LLSFDDTPEK DKFRARSTSL NERPKSLRIA 950
RAPKQGLNNS PPVKEFKESC AAEAFRCRSI SVSEHVVRSR IQTSLTSASL 1000
GSADENSMAQ ADDNLKNLHL ELTETCLDMM ARYVFSNFTA VPKRSPVGEF 1050
LLAGGRTKTW LVGNKLVTVT TSVGTGTRSL LGLDSGDLQG GSASSSDPGT 1100
HVRQTKEAPA KLESQAGQQV SRGARDRVRS MSGGHGLRVG VLDTSAPYTP 1150
GGPASLGAQA APAARPEKPC AGAQLPAAEK ANLAAYVPLL TQGWAEILVR 1200
RPTGNTSWLM SLENPLSPFS SDINNMPLQE LSNALMAAER FKEHRDTALY 1250
KSLSVPAAGT AKPPTLPRSN TVASFSSLYQ PSCQGQLHRS VSWADSAVVL 1300
EEGSPGEAHV PVEPPELEDF EAALGTDRHC QRPDAYSRSS SASSQEEKSH 1350
LEELAAGGIP IERAISSEGA RPTVDLSFQP SQPLSKSSSS PELQTLQDIL 1400
GDLGDKTDIG RLSPEAKVRS QSGILDGEAA TWSAPGEESR ITVPPEGPLP 1450
SSSPRSPSGL RPRGYTISDS APSRRGKRVE RDNFKSRTAA SSAEKVPGIN 1500
PSFVFLQLYH SPFCGDESNK PILLPNESFE RSVQLLDQIP SYDTHKIAVL 1550
YVGEGQSSSE LAILSNEHGS YRYTEFLTGL GRLIELKDCQ PDKVYLGGLD 1600
VCGEDGQFTY CWHDDIMQAV FHIATLMPTK DVDKHRCDKK RHLGNDFVSI 1650
IYNDSGEDFK LGTIKGQFNF VHVIITPLDY KCNLLTLQCR KDMEGLVDTS 1700
VAKIVSDRNL SFVARQMALH ANMASQVHHR RSNPTDIYPS KWIARLRHIK 1750
RLRQRIREEV HYSNPSLPLM HPPAHTKVPA QAPTEATPTY ETGQRKRLIS 1800
SVDDFTEFV 1809
Length:1,809
Mass (Da):201,278
Last modified:October 1, 1996 - v1
Checksum:i6190BEFB45272664
GO
Isoform 2 (identifier: P49816-2) [UniParc]FASTAAdd to Basket

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

Show »
Length:1,766
Mass (Da):196,527
Checksum:i85B44025626BC659
GO
Isoform 3 (identifier: P49816-3) [UniParc]FASTAAdd to Basket

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

Show »
Length:1,786
Mass (Da):198,757
Checksum:i8D02C6EA34616F36
GO
Isoform 4 (identifier: P49816-4) [UniParc]FASTAAdd to Basket

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

Show »
Length:1,743
Mass (Da):194,006
Checksum:iF923B79ADBF45D10
GO

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei947 – 98943Missing in isoform 2 and isoform 4.
VSP_004481Add
BLAST
Alternative sequencei1272 – 129423Missing in isoform 3 and isoform 4.
VSP_004482Add
BLAST

Sequence conflict

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti932 – 9321K → S in BAA08914. 1 Publication
Sequence conflicti1514 – 15141C → F in BAA08914. 1 Publication
Sequence conflicti1730 – 17301R → S in BAA08914. 1 Publication

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
U24150 mRNA. Translation: AAC52289.1.
D50413 mRNA. Translation: BAA08914.1.
PIRiS57329.
RefSeqiNP_036812.2. NM_012680.3. [P49816-1]
UniGeneiRn.5875.

Genome annotation databases

EnsembliENSRNOT00000016221; ENSRNOP00000016221; ENSRNOG00000011375.
GeneIDi24855.
KEGGirno:24855.
UCSCiRGD:3908. rat. [P49816-1]

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
U24150 mRNA. Translation: AAC52289.1 .
D50413 mRNA. Translation: BAA08914.1 .
PIRi S57329.
RefSeqi NP_036812.2. NM_012680.3. [P49816-1 ]
UniGenei Rn.5875.

3D structure databases

ProteinModelPortali P49816.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

BioGridi 246972. 8 interactions.
IntActi P49816. 4 interactions.
MINTi MINT-4783802.
STRINGi 10116.ENSRNOP00000016221.

PTM databases

PhosphoSitei P49816.

Proteomic databases

PaxDbi P49816.
PRIDEi P49816.

Protocols and materials databases

Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENSRNOT00000016221 ; ENSRNOP00000016221 ; ENSRNOG00000011375 .
GeneIDi 24855.
KEGGi rno:24855.
UCSCi RGD:3908. rat. [P49816-1 ]

Organism-specific databases

CTDi 7249.
RGDi 3908. Tsc2.

Phylogenomic databases

eggNOGi NOG290929.
GeneTreei ENSGT00390000017866.
HOGENOMi HOG000045987.
HOVERGENi HBG018005.
InParanoidi P49816.
KOi K07207.
OrthoDBi EOG7KM5S3.
PhylomeDBi P49816.
TreeFami TF324484.

Enzyme and pathway databases

Reactomei REACT_198729. Constitutive PI3K/AKT Signaling in Cancer.

Miscellaneous databases

NextBioi 604654.
PROi P49816.

Gene expression databases

Genevestigatori P49816.

Family and domain databases

Gene3Di 1.25.10.10. 3 hits.
InterProi IPR011989. ARM-like.
IPR016024. ARM-type_fold.
IPR000331. Rap_GAP_dom.
IPR003913. Tuberin.
IPR018515. Tuberin-type_domain.
IPR024584. Tuberin_N.
[Graphical view ]
PANTHERi PTHR10063:SF1. PTHR10063:SF1. 1 hit.
Pfami PF11864. DUF3384. 1 hit.
PF02145. Rap_GAP. 1 hit.
PF03542. Tuberin. 1 hit.
[Graphical view ]
PRINTSi PR01431. TUBERIN.
SUPFAMi SSF48371. SSF48371. 1 hit.
PROSITEi PS50085. RAPGAP. 1 hit.
[Graphical view ]
ProtoNeti Search...

Publicationsi

  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.

Entry informationi

Entry nameiTSC2_RAT
AccessioniPrimary (citable) accession number: P49816
Entry historyi
Integrated into UniProtKB/Swiss-Prot: October 1, 1996
Last sequence update: October 1, 1996
Last modified: September 3, 2014
This is version 125 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

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