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O46680

- TGFR1_BOVIN

UniProt

O46680 - TGFR1_BOVIN

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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

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.

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.

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei228 – 2281ATP By similarity
Active sitei329 – 3291Proton acceptor By similarity

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi207 – 2159ATP By similarity

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 SMAD protein import into nucleus Source: Ensembl
  28. positive regulation of apoptotic signaling pathway Source: Ensembl
  29. positive regulation of cell growth Source: Ensembl
  30. positive regulation of cell proliferation Source: Ensembl
  31. positive regulation of cellular component movement Source: Ensembl
  32. positive regulation of filopodium assembly Source: Ensembl
  33. positive regulation of pathway-restricted SMAD protein phosphorylation Source: Ensembl
  34. positive regulation of protein kinase B signaling 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
Complete GO annotation...

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

Topology

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Topological domaini30 – 12293Extracellular Reviewed prediction
Add
BLAST
Transmembranei123 – 14321Helical; Reviewed prediction
Add
BLAST
Topological domaini144 – 499356Cytoplasmic Reviewed prediction
Add
BLAST

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
Complete GO annotation...

Keywords - Cellular componenti

Cell junction, Cell membrane, Membrane, Tight junction

PTM / Processingi

Molecule processing

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

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Disulfide bondi32 ↔ 50 By similarity
Disulfide bondi34 ↔ 37 By similarity
Glycosylationi41 – 411N-linked (GlcNAc...) Reviewed prediction
Disulfide bondi44 ↔ 67 By similarity
Disulfide bondi82 ↔ 96 By similarity
Disulfide bondi97 ↔ 102 By similarity
Modified residuei161 – 1611Phosphoserine By similarity
Modified residuei181 – 1811Phosphothreonine; by TGFBR2 By similarity
Modified residuei182 – 1821Phosphothreonine; by TGFBR2 By similarity
Modified residuei183 – 1831Phosphoserine; by TGFBR2 By similarity
Modified residuei185 – 1851Phosphoserine; by TGFBR2 By similarity
Modified residuei187 – 1871Phosphoserine; by TGFBR2 By 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.
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.

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.

Protein-protein interaction databases

STRINGi9913.ENSBTAP00000024010.

Structurei

3D structure databases

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

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini171 – 20030GS
Add
BLAST
Domaini201 – 491291Protein kinase
Add
BLAST

Motif

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

Sequence similaritiesi

Contains 1 GS domain.

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

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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: September 3, 2014
This is version 114 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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