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O46680

- TGFR1_BOVIN

UniProt

O46680 - TGFR1_BOVIN

Protein

TGF-beta receptor type-1

Gene

TGFBR1

Organism
Bos taurus (Bovine)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at transcript leveli
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    • History
      Entry version 115 (01 Oct 2014)
      Sequence version 1 (01 Jun 1998)
      Previous versions | rss
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    Functioni

    Transmembrane serine/threonine kinase forming with the TGF-beta type II serine/threonine kinase receptor, TGFBR2, the non-promiscuous receptor for the TGF-beta cytokines TGFB1, TGFB2 and TGFB3. Transduces the TGFB1, TGFB2 and TGFB3 signal from the cell surface to the cytoplasm and is thus regulating a plethora of physiological and pathological processes including cell cycle arrest in epithelial and hematopoietic cells, control of mesenchymal cell proliferation and differentiation, wound healing, extracellular matrix production, immunosuppression and carcinogenesis. The formation of the receptor complex composed of 2 TGFBR1 and 2 TGFBR2 molecules symmetrically bound to the cytokine dimer results in the phosphorylation and the activation of TGFBR1 by the constitutively active TGFBR2. Activated TGFBR1 phosphorylates SMAD2 which dissociates from the receptor and interacts with SMAD4. The SMAD2-SMAD4 complex is subsequently translocated to the nucleus where it modulates the transcription of the TGF-beta-regulated genes. This constitutes the canonical SMAD-dependent TGF-beta signaling cascade. Also involved in non-canonical, SMAD-independent TGF-beta signaling pathways. For instance, TGFBR1 induces TRAF6 autoubiquitination which in turn results in MAP3K7 ubiquitination and activation to trigger apoptosis. Also regulates epithelial to mesenchymal transition through a SMAD-independent signaling pathway through PARD6A phosphorylation and activation By similarity.By similarity

    Catalytic activityi

    ATP + [receptor-protein] = ADP + [receptor-protein] phosphate.

    Cofactori

    Magnesium or manganese.By similarity

    Enzyme regulationi

    Kept in an inactive conformation by FKBP1A preventing receptor activation in absence of ligand. CD109 is another inhibitor of the receptor By similarity.By similarity

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Binding sitei228 – 2281ATPPROSITE-ProRule annotation
    Active sitei329 – 3291Proton acceptorPROSITE-ProRule annotation

    Regions

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Nucleotide bindingi207 – 2159ATPPROSITE-ProRule annotation

    GO - Molecular functioni

    1. ATP binding Source: UniProtKB-KW
    2. metal ion binding Source: UniProtKB-KW
    3. receptor signaling protein serine/threonine kinase activity Source: InterPro
    4. transforming growth factor beta receptor activity, type I Source: AgBase

    GO - Biological processi

    1. activation of MAPKK activity Source: Ensembl
    2. angiogenesis Source: Ensembl
    3. anterior/posterior pattern specification Source: Ensembl
    4. apoptotic process Source: UniProtKB-KW
    5. artery morphogenesis Source: Ensembl
    6. blastocyst development Source: Ensembl
    7. cellular response to transforming growth factor beta stimulus Source: BHF-UCL
    8. collagen fibril organization Source: Ensembl
    9. embryonic cranial skeleton morphogenesis Source: Ensembl
    10. endothelial cell migration Source: Ensembl
    11. epithelial to mesenchymal transition Source: Ensembl
    12. germ cell migration Source: Ensembl
    13. heart development Source: Ensembl
    14. kidney development Source: Ensembl
    15. lens development in camera-type eye Source: Ensembl
    16. negative regulation of apoptotic process Source: Ensembl
    17. negative regulation of chondrocyte differentiation Source: Ensembl
    18. negative regulation of endothelial cell proliferation Source: Ensembl
    19. negative regulation of extrinsic apoptotic signaling pathway Source: Ensembl
    20. neuron fate commitment Source: Ensembl
    21. palate development Source: Ensembl
    22. parathyroid gland development Source: Ensembl
    23. pathway-restricted SMAD protein phosphorylation Source: Ensembl
    24. peptidyl-serine phosphorylation Source: Ensembl
    25. peptidyl-threonine phosphorylation Source: Ensembl
    26. pharyngeal system development Source: Ensembl
    27. positive regulation of apoptotic signaling pathway Source: Ensembl
    28. positive regulation of cell growth Source: Ensembl
    29. positive regulation of cell proliferation Source: Ensembl
    30. positive regulation of cellular component movement Source: Ensembl
    31. positive regulation of filopodium assembly Source: Ensembl
    32. positive regulation of pathway-restricted SMAD protein phosphorylation Source: Ensembl
    33. positive regulation of protein kinase B signaling Source: Ensembl
    34. positive regulation of SMAD protein import into nucleus Source: Ensembl
    35. positive regulation of transcription, DNA-templated Source: Ensembl
    36. post-embryonic development Source: Ensembl
    37. regulation of protein binding Source: Ensembl
    38. regulation of protein ubiquitination Source: Ensembl
    39. response to cholesterol Source: Ensembl
    40. thymus development Source: Ensembl
    41. transforming growth factor beta receptor signaling pathway Source: AgBase

    Keywords - Molecular functioni

    Kinase, Receptor, Serine/threonine-protein kinase, Transferase

    Keywords - Biological processi

    Apoptosis, Differentiation, Growth regulation

    Keywords - Ligandi

    ATP-binding, Magnesium, Manganese, Metal-binding, Nucleotide-binding

    Enzyme and pathway databases

    ReactomeiREACT_209664. SMAD2/3 Phosphorylation Motif Mutants in Cancer.
    REACT_211897. TGFBR2 Kinase Domain Mutants in Cancer.
    REACT_217890. TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition).
    REACT_220430. TGF-beta receptor signaling activates SMADs.
    REACT_220609. SMAD2/3 MH2 Domain Mutants in Cancer.
    REACT_220643. TGFBR1 LBD Mutants in Cancer.
    REACT_223905. TGFBR1 KD Mutants in Cancer.
    REACT_225632. Downregulation of TGF-beta receptor signaling.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    TGF-beta receptor type-1 (EC:2.7.11.30)
    Short name:
    TGFR-1
    Alternative name(s):
    TGF-beta type I receptor
    Transforming growth factor-beta receptor type I
    Short name:
    TGF-beta receptor type I
    Short name:
    TbetaR-I
    Gene namesi
    Name:TGFBR1
    OrganismiBos taurus (Bovine)
    Taxonomic identifieri9913 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaLaurasiatheriaCetartiodactylaRuminantiaPecoraBovidaeBovinaeBos
    ProteomesiUP000009136: Chromosome 8

    Subcellular locationi

    Cell membrane By similarity; Single-pass type I membrane protein By similarity. Cell junctiontight junction By similarity

    GO - Cellular componenti

    1. integral component of membrane Source: UniProtKB-KW
    2. plasma membrane Source: UniProtKB-SubCell
    3. receptor complex Source: Ensembl
    4. tight junction Source: UniProtKB-SubCell

    Keywords - Cellular componenti

    Cell junction, Cell membrane, Membrane, Tight junction

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Signal peptidei1 – 2929By similarityAdd
    BLAST
    Chaini30 – 499470TGF-beta receptor type-1PRO_0000254657Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Disulfide bondi32 ↔ 50By similarity
    Disulfide bondi34 ↔ 37By similarity
    Glycosylationi41 – 411N-linked (GlcNAc...)Sequence Analysis
    Disulfide bondi44 ↔ 67By similarity
    Disulfide bondi82 ↔ 96By similarity
    Disulfide bondi97 ↔ 102By similarity
    Modified residuei161 – 1611PhosphoserineBy similarity
    Modified residuei181 – 1811Phosphothreonine; by TGFBR2By similarity
    Modified residuei182 – 1821Phosphothreonine; by TGFBR2By similarity
    Modified residuei183 – 1831Phosphoserine; by TGFBR2By similarity
    Modified residuei185 – 1851Phosphoserine; by TGFBR2By similarity
    Modified residuei187 – 1871Phosphoserine; by TGFBR2By similarity
    Cross-linki387 – 387Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO)By similarity

    Post-translational modificationi

    Phosphorylated at basal levels in the absence of ligand. Activated upon phosphorylation by TGFBR2, mainly in the GS domain. Phosphorylation in the GS domain abrogates FKBP1A-binding By similarity.By similarity
    N-Glycosylated.By similarity
    Ubiquitinated; undergoes ubiquitination catalyzed by several E3 ubiquitin ligases including SMURF1, SMURF2 and NEDD4L2. Results in the proteasomal and/or lysosomal degradation of the receptor thereby negatively regulating its activity. Deubiquitinated by USP15, leading to stabilization of the protein and enhanced TGF-beta signal By similarity.By similarity

    Keywords - PTMi

    Disulfide bond, Glycoprotein, Isopeptide bond, Phosphoprotein, Ubl conjugation

    Proteomic databases

    PRIDEiO46680.

    Interactioni

    Subunit structurei

    Homodimer; in the endoplasmic reticulum but also at the cell membrane. Heterohexamer; TGFB1, TGFB2 and TGFB3 homodimeric ligands assemble a functional receptor composed of two TGFBR1 and TGFBR2 heterodimers to form a ligand-receptor heterohexamer. The respective affinity of TGBRB1 and TGFBR2 for the ligands may modulate the kinetics of assembly of the receptor and may explain the different biological activities of TGFB1, TGFB2 and TGFB3. Interacts with CD109; inhibits TGF-beta receptor activation in keratinocytes. Interacts with RBPMS. Interacts (unphosphorylated) with FKBP1A; prevents TGFBR1 phosphorylation by TGFBR2 and stabilizes it in the inactive conformation. Interacts with SMAD2, SMAD3 and ZFYVE9; ZFYVE9 recruits SMAD2 and SMAD3 to the TGF-beta receptor. Interacts with TRAF6 and MAP3K7; induces MAP3K7 activation by TRAF6. Interacts with PARD6A; involved in TGF-beta induced epithelial to mesenchymal transition. Interacts with SMAD7, NEDD4L, SMURF1 and SMURF2; SMAD7 recruits NEDD4L, SMURF1 and SMURF2 to the TGF-beta receptor By similarity. Interacts with USP15 and VPS39 By similarity.By similarity

    Protein-protein interaction databases

    STRINGi9913.ENSBTAP00000024010.

    Structurei

    3D structure databases

    ProteinModelPortaliO46680.
    SMRiO46680. Positions 30-107, 167-496.
    ModBaseiSearch...
    MobiDBiSearch...

    Topological domain

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Topological domaini30 – 12293ExtracellularSequence AnalysisAdd
    BLAST
    Topological domaini144 – 499356CytoplasmicSequence AnalysisAdd
    BLAST

    Transmembrane

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Transmembranei123 – 14321HelicalSequence AnalysisAdd
    BLAST

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini171 – 20030GSPROSITE-ProRule annotationAdd
    BLAST
    Domaini201 – 491291Protein kinasePROSITE-ProRule annotationAdd
    BLAST

    Motif

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Motifi189 – 1902FKBP1A-binding

    Sequence similaritiesi

    Contains 1 GS domain.PROSITE-ProRule annotation
    Contains 1 protein kinase domain.PROSITE-ProRule annotation

    Keywords - Domaini

    Signal, Transmembrane, Transmembrane helix

    Phylogenomic databases

    eggNOGiCOG0515.
    GeneTreeiENSGT00730000110337.
    HOGENOMiHOG000230587.
    HOVERGENiHBG054502.
    InParanoidiO46680.
    KOiK04674.
    OMAiLYICHNR.
    OrthoDBiEOG7Q8CN3.
    TreeFamiTF314724.

    Family and domain databases

    InterProiIPR000472. Activin_rcpt.
    IPR011009. Kinase-like_dom.
    IPR000719. Prot_kinase_dom.
    IPR017441. Protein_kinase_ATP_BS.
    IPR008271. Ser/Thr_kinase_AS.
    IPR003605. TGF_beta_rcpt_GS.
    IPR000333. TGFB_receptor.
    [Graphical view]
    PANTHERiPTHR23255. PTHR23255. 1 hit.
    PfamiPF01064. Activin_recp. 1 hit.
    PF00069. Pkinase. 1 hit.
    PF08515. TGF_beta_GS. 1 hit.
    [Graphical view]
    SMARTiSM00467. GS. 1 hit.
    [Graphical view]
    SUPFAMiSSF56112. SSF56112. 1 hit.
    PROSITEiPS51256. GS. 1 hit.
    PS00107. PROTEIN_KINASE_ATP. 1 hit.
    PS50011. PROTEIN_KINASE_DOM. 1 hit.
    PS00108. PROTEIN_KINASE_ST. 1 hit.
    [Graphical view]

    Sequencei

    Sequence statusi: Complete.

    Sequence processingi: The displayed sequence is further processed into a mature form.

    O46680-1 [UniParc]FASTAAdd to Basket

    « Hide

    MEAAAATPRP RLFLLMLAAA ATLVPEATPL QCFCHLCTKD NFTCVTDGLC    50
    FVSVTETTDK VIHNSMCIAE IDLIPRDRPF VCAPSSKTGS ITTTYCCNQD 100
    HCNKIELPTV GKPSSGLGPV ELAAVIAGPV CFVCISLMLM VYICHNRTVI 150
    HHRVPNEEDP SLDRPFISEG TTLKDLIYDM TTSGSGSGLP LLVQRTIART 200
    IVLQESIGKG RFGEVWRGKW RGEEVAVKIF SSREERSWFR EAEIYQTVML 250
    RHENILGFIA ADNKDNGTWT QLWLVSDYHE HGSLFDYLNR YTVTVEGMIK 300
    LALSTASGLA HLHMEIVGTQ GKPAIAHRDL KSKNILVKKN GTCCIADLGL 350
    AVRHDSATDT IDIAPNHRVG TKRYMAPEVL DDSINMKHFE SFKRADIYAM 400
    GLVFWEVARR CSIGGIHEDY QLPYYDLVPS DPSVEEMRKV VCEQKLRPNI 450
    PNRWQSCEAL RVMAKIMREC WYANGAARLT ALRIKKTLSQ LSQQEGIKM 499
    Length:499
    Mass (Da):55,814
    Last modified:June 1, 1998 - v1
    Checksum:i7FA311693CA938CD
    GO

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    U97485 mRNA. Translation: AAC02717.1.
    RefSeqiNP_777046.1. NM_174621.2.
    UniGeneiBt.91785.

    Genome annotation databases

    EnsembliENSBTAT00000024010; ENSBTAP00000024010; ENSBTAG00000018035.
    GeneIDi282382.
    KEGGibta:282382.

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    U97485 mRNA. Translation: AAC02717.1 .
    RefSeqi NP_777046.1. NM_174621.2.
    UniGenei Bt.91785.

    3D structure databases

    ProteinModelPortali O46680.
    SMRi O46680. Positions 30-107, 167-496.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    STRINGi 9913.ENSBTAP00000024010.

    Proteomic databases

    PRIDEi O46680.

    Protocols and materials databases

    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENSBTAT00000024010 ; ENSBTAP00000024010 ; ENSBTAG00000018035 .
    GeneIDi 282382.
    KEGGi bta:282382.

    Organism-specific databases

    CTDi 7046.

    Phylogenomic databases

    eggNOGi COG0515.
    GeneTreei ENSGT00730000110337.
    HOGENOMi HOG000230587.
    HOVERGENi HBG054502.
    InParanoidi O46680.
    KOi K04674.
    OMAi LYICHNR.
    OrthoDBi EOG7Q8CN3.
    TreeFami TF314724.

    Enzyme and pathway databases

    Reactomei REACT_209664. SMAD2/3 Phosphorylation Motif Mutants in Cancer.
    REACT_211897. TGFBR2 Kinase Domain Mutants in Cancer.
    REACT_217890. TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition).
    REACT_220430. TGF-beta receptor signaling activates SMADs.
    REACT_220609. SMAD2/3 MH2 Domain Mutants in Cancer.
    REACT_220643. TGFBR1 LBD Mutants in Cancer.
    REACT_223905. TGFBR1 KD Mutants in Cancer.
    REACT_225632. Downregulation of TGF-beta receptor signaling.

    Miscellaneous databases

    NextBioi 20806171.

    Family and domain databases

    InterProi IPR000472. Activin_rcpt.
    IPR011009. Kinase-like_dom.
    IPR000719. Prot_kinase_dom.
    IPR017441. Protein_kinase_ATP_BS.
    IPR008271. Ser/Thr_kinase_AS.
    IPR003605. TGF_beta_rcpt_GS.
    IPR000333. TGFB_receptor.
    [Graphical view ]
    PANTHERi PTHR23255. PTHR23255. 1 hit.
    Pfami PF01064. Activin_recp. 1 hit.
    PF00069. Pkinase. 1 hit.
    PF08515. TGF_beta_GS. 1 hit.
    [Graphical view ]
    SMARTi SM00467. GS. 1 hit.
    [Graphical view ]
    SUPFAMi SSF56112. SSF56112. 1 hit.
    PROSITEi PS51256. GS. 1 hit.
    PS00107. PROTEIN_KINASE_ATP. 1 hit.
    PS50011. PROTEIN_KINASE_DOM. 1 hit.
    PS00108. PROTEIN_KINASE_ST. 1 hit.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    1. "Molecular cloning, genetic mapping, and developmental expression of a bovine transforming growth factor beta (TGF-beta) type I receptor."
      Roelen B.A.J., Van Eijk M.J.T., Van Rooijen M.A., Bevers M.M., Larson J.H., Lewin H.A., Mummery C.L.
      Mol. Reprod. Dev. 49:1-9(1998) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA].
      Tissue: Placenta.

    Entry informationi

    Entry nameiTGFR1_BOVIN
    AccessioniPrimary (citable) accession number: O46680
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: October 31, 2006
    Last sequence update: June 1, 1998
    Last modified: October 1, 2014
    This is version 115 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