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P49816

- TSC2_RAT

UniProt

P49816 - TSC2_RAT

Protein

Tuberin

Gene

Tsc2

Organism
Rattus norvegicus (Rat)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 126 (01 Oct 2014)
      Sequence version 1 (01 Oct 1996)
      Previous versions | rss
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    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 binding Source: RGD
    4. protein heterodimerization activity Source: RGD
    5. 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

    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

    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

    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

    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

    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

    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 1, 2014
    This is version 126 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