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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.By similarity

GO - Molecular functioni

  1. GTPase activator activity Source: RGD
  2. phosphatase binding Source: UniProtKB
  3. protein heterodimerization activity Source: RGD
  4. Rab GTPase activator 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 cell proliferation Source: RGD
  7. negative regulation of cell size Source: MGI
  8. negative regulation of epithelial cell proliferation Source: RGD
  9. negative regulation of insulin receptor signaling pathway Source: RefGenome
  10. negative regulation of MAP kinase activity Source: RGD
  11. negative regulation of phosphatidylinositol 3-kinase signaling Source: Ensembl
  12. negative regulation of protein kinase B signaling Source: RefGenome
  13. negative regulation of TOR signaling Source: RGD
  14. negative regulation of Wnt signaling pathway Source: RGD
  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. caveola Source: RGD
  2. cytoskeleton Source: RGD
  3. cytosol Source: RGD
  4. dendrite Source: RGD
  5. Golgi apparatus Source: Ensembl
  6. growth cone Source: RGD
  7. intracellular membrane-bounded organelle Source: RGD
  8. membrane raft Source: RGD
  9. neuronal cell body Source: RGD
  10. neuron projection Source: RGD
  11. nucleus Source: Ensembl
  12. perinuclear region of cytoplasm Source: RGD
  13. protein complex Source: RGD
  14. TSC1-TSC2 complex Source: RefGenome
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 – 18091809TuberinPRO_0000065656Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei540 – 5401PhosphoserineBy similarity
Modified residuei664 – 6641PhosphoserineBy similarity
Modified residuei927 – 9271PhosphothreonineBy similarity
Modified residuei939 – 9391Phosphoserine; by PKB/AKT1By similarity
Modified residuei981 – 9811PhosphoserineBy similarity
Modified residuei1132 – 11321PhosphoserineBy similarity
Modified residuei1155 – 11551PhosphoserineBy similarity
Modified residuei1340 – 13401PhosphoserineBy similarity
Modified residuei1341 – 13411PhosphoserineBy similarity
Modified residuei1349 – 13491PhosphoserineBy similarity
Modified residuei1389 – 13891PhosphoserineBy similarity
Modified residuei1413 – 14131PhosphoserineBy similarity
Modified residuei1420 – 14201PhosphoserineBy similarity
Modified residuei1422 – 14221PhosphoserineBy similarity
Modified residuei1452 – 14521Phosphoserine; by AMPKBy similarity
Modified residuei1456 – 14561PhosphoserineBy similarity
Modified residuei1466 – 14661Phosphothreonine; by PKB/AKT1By similarity
Modified residuei1800 – 18001Phosphoserine; by RPS6KA1By 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).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).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

ExpressionAtlasiP49816. baseline.
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).By similarity

Protein-protein interaction databases

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

Structurei

3D structure databases

ProteinModelPortaliP49816.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini1533 – 1760228Rap-GAPPROSITE-ProRule annotationAdd
BLAST

Sequence similaritiesi

Contains 1 Rap-GAP domain.PROSITE-ProRule annotation

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

        10         20         30         40         50
MAKPTSKDSG LKEKFKILLG LGTSRPNPRC AEGKQTEFII TAEILRELSG
60 70 80 90 100
ECGLNNRIRM IGQICDVAKT KKLEEHAVEA LWKAVSDLLQ PERPPEARHA
110 120 130 140 150
VLALLKAIVQ GQGDRLGVLR ALFFKVIKDY PSNEDLHERL EVFKALTDNG
160 170 180 190 200
RHITYLEEEL AEFVLQWMDV GLSSEFLLVL VNLVKFNSCY LDEYIAPMVH
210 220 230 240 250
MICLLCIRTV SSVDIEVSLQ VLDAVVCYNC LPAESLPLFI ITLCRTVNVK
260 270 280 290 300
ELCEPCWKLM RNLLGTHLGH SAIYNMCRIM ENRSYMEDAP LLRGAVFFVG
310 320 330 340 350
MALWGAHRLY SLKNSPTSVL PSFYEAMTCP NEVVSYEIVL SITRLIKKYR
360 370 380 390 400
KELQAVTWDI LLDIIERLLQ QLQNLDSPEL RTIVHDLLTT VEELCDQNEF
410 420 430 440 450
HGSQERYYEL VESYADQRPE SSLLNLITYR AQSIHPAKDG WIQNLQLLME
460 470 480 490 500
RFFRNECRSA VRIKVLDVLS FVLLINRQFY EEELINSVVI SQLSHIPEDK
510 520 530 540 550
DHQVRKLATQ LLVDLAEGCH THHFNSLLDI IEKVMARSLS PPLELEERDL
560 570 580 590 600
AVYSASLEDV KTAVLGLLVI LQTKLYTLPA SHATRVYETL ISHIQLHYKH
610 620 630 640 650
GYSLPIASSI RLQAFDFLLL LRADSLHRLG LPNKDGVVRF SPYCLCDCAE
660 670 680 690 700
LDRASEKKAS GPLSPPTGPP SPVPTGPAVR LGHLPYSLLF RVLLQCLKQE
710 720 730 740 750
TDWKVLKLVL SKLPESLRYK VLIFTSPCSV DQLSSALCSM LSAPKTLERL
760 770 780 790 800
RGTPEGFSRT DLHLAVVPVL TALISYHNYL DKTRQREMVY CLEQGLIYRC
810 820 830 840 850
ASQCVVALAI CSVEMPDIII KALPVLVVKL THISATASMA IPLLEFLSTL
860 870 880 890 900
ARLPHLYRNF AAEQYASVFA ISLPYTNPSK FNQYIVCLAH HVIAMWFIRC
910 920 930 940 950
RLPFRKDFVP YITKGLRSNV LLSFDDTPEK DKFRARSTSL NERPKSLRIA
960 970 980 990 1000
RAPKQGLNNS PPVKEFKESC AAEAFRCRSI SVSEHVVRSR IQTSLTSASL
1010 1020 1030 1040 1050
GSADENSMAQ ADDNLKNLHL ELTETCLDMM ARYVFSNFTA VPKRSPVGEF
1060 1070 1080 1090 1100
LLAGGRTKTW LVGNKLVTVT TSVGTGTRSL LGLDSGDLQG GSASSSDPGT
1110 1120 1130 1140 1150
HVRQTKEAPA KLESQAGQQV SRGARDRVRS MSGGHGLRVG VLDTSAPYTP
1160 1170 1180 1190 1200
GGPASLGAQA APAARPEKPC AGAQLPAAEK ANLAAYVPLL TQGWAEILVR
1210 1220 1230 1240 1250
RPTGNTSWLM SLENPLSPFS SDINNMPLQE LSNALMAAER FKEHRDTALY
1260 1270 1280 1290 1300
KSLSVPAAGT AKPPTLPRSN TVASFSSLYQ PSCQGQLHRS VSWADSAVVL
1310 1320 1330 1340 1350
EEGSPGEAHV PVEPPELEDF EAALGTDRHC QRPDAYSRSS SASSQEEKSH
1360 1370 1380 1390 1400
LEELAAGGIP IERAISSEGA RPTVDLSFQP SQPLSKSSSS PELQTLQDIL
1410 1420 1430 1440 1450
GDLGDKTDIG RLSPEAKVRS QSGILDGEAA TWSAPGEESR ITVPPEGPLP
1460 1470 1480 1490 1500
SSSPRSPSGL RPRGYTISDS APSRRGKRVE RDNFKSRTAA SSAEKVPGIN
1510 1520 1530 1540 1550
PSFVFLQLYH SPFCGDESNK PILLPNESFE RSVQLLDQIP SYDTHKIAVL
1560 1570 1580 1590 1600
YVGEGQSSSE LAILSNEHGS YRYTEFLTGL GRLIELKDCQ PDKVYLGGLD
1610 1620 1630 1640 1650
VCGEDGQFTY CWHDDIMQAV FHIATLMPTK DVDKHRCDKK RHLGNDFVSI
1660 1670 1680 1690 1700
IYNDSGEDFK LGTIKGQFNF VHVIITPLDY KCNLLTLQCR KDMEGLVDTS
1710 1720 1730 1740 1750
VAKIVSDRNL SFVARQMALH ANMASQVHHR RSNPTDIYPS KWIARLRHIK
1760 1770 1780 1790 1800
RLRQRIREEV HYSNPSLPLM HPPAHTKVPA QAPTEATPTY ETGQRKRLIS

SVDDFTEFV
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

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti932 – 9321K → S in BAA08914. (PubMed:7651821)Curated
Sequence conflicti1514 – 15141C → F in BAA08914. (PubMed:7651821)Curated
Sequence conflicti1730 – 17301R → S in BAA08914. (PubMed:7651821)Curated

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei947 – 98943Missing in isoform 2 and isoform 4. 1 PublicationVSP_004481Add
BLAST
Alternative sequencei1272 – 129423Missing in isoform 3 and isoform 4. 1 PublicationVSP_004482Add
BLAST

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

ExpressionAtlasi P49816. baseline.
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: October 29, 2014
This is version 127 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