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Q64729

- TGFR1_MOUSE

UniProt

Q64729 - TGFR1_MOUSE

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Protein

TGF-beta receptor type-1

Gene

Tgfbr1

Organism
Mus musculus (Mouse)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein 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).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 sitei232 – 2321ATPPROSITE-ProRule annotation
Active sitei333 – 3331Proton acceptorPROSITE-ProRule annotation

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi211 – 2199ATPPROSITE-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. SMAD binding Source: BHF-UCL
  5. transforming growth factor beta-activated receptor activity Source: MGI
  6. transforming growth factor beta binding Source: MGI
  7. transforming growth factor beta receptor activity, type I Source: Ensembl

GO - Biological processi

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

BRENDAi2.7.10.2. 3474.
ReactomeiREACT_196549. TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition).
REACT_203510. TGF-beta receptor signaling activates SMADs.
REACT_215733. Downregulation of TGF-beta receptor signaling.
REACT_216792. SMAD2/3 MH2 Domain Mutants in Cancer.
REACT_217958. SMAD2/3 Phosphorylation Motif Mutants in Cancer.
REACT_224217. TGFBR1 LBD Mutants in Cancer.
REACT_224787. TGFBR2 Kinase Domain Mutants in Cancer.
REACT_224802. TGFBR1 KD Mutants in Cancer.

Names & Taxonomyi

Protein namesi
Recommended name:
TGF-beta receptor type-1 (EC:2.7.11.30)
Short name:
TGFR-1
Alternative name(s):
ESK2
Transforming growth factor-beta receptor type I
Short name:
TGF-beta receptor type I
Short name:
TbetaR-I
Gene namesi
Name:Tgfbr1
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
ProteomesiUP000000589: Chromosome 4

Organism-specific databases

MGIiMGI:98728. Tgfbr1.

Subcellular locationi

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

GO - Cellular componenti

  1. caveola Source: MGI
  2. endosome Source: UniProt
  3. integral component of membrane Source: UniProtKB-KW
  4. membrane raft Source: MGI
  5. receptor complex Source: Ensembl
  6. tight junction Source: UniProtKB-KW
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 – 2929By similarityAdd
BLAST
Chaini30 – 503474TGF-beta receptor type-1PRO_0000024424Add
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 residuei165 – 1651PhosphoserineBy similarity
Modified residuei185 – 1851Phosphothreonine; by TGFBR2By similarity
Modified residuei186 – 1861Phosphothreonine; by TGFBR2By similarity
Modified residuei187 – 1871Phosphoserine; by TGFBR2By similarity
Modified residuei189 – 1891Phosphoserine; by TGFBR2By similarity
Modified residuei191 – 1911Phosphoserine; by TGFBR2By similarity
Cross-linki391 – 391Glycyl 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

MaxQBiQ64729.
PRIDEiQ64729.

PTM databases

PhosphoSiteiQ64729.

Expressioni

Gene expression databases

BgeeiQ64729.
CleanExiMM_TGFBR1.
ExpressionAtlasiQ64729. baseline and differential.
GenevestigatoriQ64729.

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

Binary interactionsi

WithEntry#Exp.IntActNotes
Cdh5P552842EBI-2899393,EBI-7087433
DLG5Q8TDM63EBI-2899393,EBI-715138From a different organism.
Shc1P98083-23EBI-2899393,EBI-1019301

Protein-protein interaction databases

BioGridi204163. 9 interactions.
DIPiDIP-42262N.
IntActiQ64729. 9 interactions.
MINTiMINT-1341331.

Structurei

3D structure databases

ProteinModelPortaliQ64729.
SMRiQ64729. Positions 27-110, 175-500.
ModBaseiSearch...
MobiDBiSearch...

Topological domain

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Topological domaini30 – 12697ExtracellularSequence AnalysisAdd
BLAST
Topological domaini148 – 503356CytoplasmicSequence AnalysisAdd
BLAST

Transmembrane

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Transmembranei127 – 14721HelicalSequence AnalysisAdd
BLAST

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini175 – 20430GSPROSITE-ProRule annotationAdd
BLAST
Domaini205 – 495291Protein kinasePROSITE-ProRule annotationAdd
BLAST

Motif

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Motifi193 – 1942FKBP1A-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.
GeneTreeiENSGT00760000118876.
HOGENOMiHOG000230587.
HOVERGENiHBG054502.
InParanoidiQ64729.
KOiK04674.
OMAiLYICHNR.
OrthoDBiEOG7Q8CN3.
PhylomeDBiQ64729.
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]

Sequences (2)i

Sequence statusi: Complete.

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

This entry describes 2 isoformsi produced by alternative splicing. Align

Isoform 1 (identifier: Q64729) [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
MEAAAAAPRR PQLLIVLVAA ATLLPGAKAL QCFCHLCTKD NFTCETDGLC
60 70 80 90 100
FVSVTETTDK VIHNSMCIAE IDLIPRDRPF VCAPSSKTGA VTTTYCCNQD
110 120 130 140 150
HCNKIELPTT GPFSEKQSAG LGPVELAAVI AGPVCFVCIA LMLMVYICHN
160 170 180 190 200
RTVIHHRVPN EEDPSLDRPF ISEGTTLKDL IYDMTTSGSG SGLPLLVQRT
210 220 230 240 250
IARTIVLQES IGKGRFGEVW RGKWRGEEVA VKIFSSREER SWFREAEIYQ
260 270 280 290 300
TVMLRHENIL GFIAADNKDN GTWTQLWLVS DYHEHGSLFD YLNRYTVTVE
310 320 330 340 350
GMIKLALSTA SGLAHLHMEI VGTQGKPAIA HRDLKSKNIL VKKNGTCCIA
360 370 380 390 400
DLGLAVRHDS ATDTIDIAPN HRVGTKRYMA PEVLDDSINM KHFESFKRAD
410 420 430 440 450
IYAMGLVFWE IARRCSIGGI HEDYQLPYYD LVPSDPSVEE MRKVVCEQKL
460 470 480 490 500
RPNIPNRWQS CEALRVMAKI MRECWYANGA ARLTALRIKK TLSQLSQQEG

IKM
Length:503
Mass (Da):56,179
Last modified:November 1, 1996 - v1
Checksum:iBB8BB6D2261793AF
GO
Isoform 2 (identifier: Q64729-2) [UniParc]FASTAAdd to Basket

The sequence of this isoform differs from the canonical sequence as follows:
     111-114: Missing.

Note: May be due to a competing donnor splice site.

Show »
Length:499
Mass (Da):55,790
Checksum:i914DE6236B689C1C
GO

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei111 – 1144Missing in isoform 2. 1 PublicationVSP_021593

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
D28526 mRNA. Translation: BAA05878.1.
D25540 mRNA. Translation: BAA05023.1.
AL772232, AL772150 Genomic DNA. Translation: CAM13897.1.
AL772150, AL772232 Genomic DNA. Translation: CAM24923.1.
BC063260 mRNA. Translation: AAH63260.1.
CCDSiCCDS18160.1. [Q64729-1]
PIRiJC2061.
JC2062.
RefSeqiNP_033396.1. NM_009370.2. [Q64729-1]
UniGeneiMm.197552.

Genome annotation databases

EnsembliENSMUST00000007757; ENSMUSP00000007757; ENSMUSG00000007613. [Q64729-1]
ENSMUST00000044234; ENSMUSP00000048501; ENSMUSG00000007613. [Q64729-2]
GeneIDi21812.
KEGGimmu:21812.
UCSCiuc008sun.1. mouse. [Q64729-1]
uc008suo.1. mouse. [Q64729-2]

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
D28526 mRNA. Translation: BAA05878.1 .
D25540 mRNA. Translation: BAA05023.1 .
AL772232 , AL772150 Genomic DNA. Translation: CAM13897.1 .
AL772150 , AL772232 Genomic DNA. Translation: CAM24923.1 .
BC063260 mRNA. Translation: AAH63260.1 .
CCDSi CCDS18160.1. [Q64729-1 ]
PIRi JC2061.
JC2062.
RefSeqi NP_033396.1. NM_009370.2. [Q64729-1 ]
UniGenei Mm.197552.

3D structure databases

ProteinModelPortali Q64729.
SMRi Q64729. Positions 27-110, 175-500.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

BioGridi 204163. 9 interactions.
DIPi DIP-42262N.
IntActi Q64729. 9 interactions.
MINTi MINT-1341331.

Chemistry

ChEMBLi CHEMBL2021750.

PTM databases

PhosphoSitei Q64729.

Proteomic databases

MaxQBi Q64729.
PRIDEi Q64729.

Protocols and materials databases

Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENSMUST00000007757 ; ENSMUSP00000007757 ; ENSMUSG00000007613 . [Q64729-1 ]
ENSMUST00000044234 ; ENSMUSP00000048501 ; ENSMUSG00000007613 . [Q64729-2 ]
GeneIDi 21812.
KEGGi mmu:21812.
UCSCi uc008sun.1. mouse. [Q64729-1 ]
uc008suo.1. mouse. [Q64729-2 ]

Organism-specific databases

CTDi 7046.
MGIi MGI:98728. Tgfbr1.

Phylogenomic databases

eggNOGi COG0515.
GeneTreei ENSGT00760000118876.
HOGENOMi HOG000230587.
HOVERGENi HBG054502.
InParanoidi Q64729.
KOi K04674.
OMAi LYICHNR.
OrthoDBi EOG7Q8CN3.
PhylomeDBi Q64729.
TreeFami TF314724.

Enzyme and pathway databases

BRENDAi 2.7.10.2. 3474.
Reactomei REACT_196549. TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition).
REACT_203510. TGF-beta receptor signaling activates SMADs.
REACT_215733. Downregulation of TGF-beta receptor signaling.
REACT_216792. SMAD2/3 MH2 Domain Mutants in Cancer.
REACT_217958. SMAD2/3 Phosphorylation Motif Mutants in Cancer.
REACT_224217. TGFBR1 LBD Mutants in Cancer.
REACT_224787. TGFBR2 Kinase Domain Mutants in Cancer.
REACT_224802. TGFBR1 KD Mutants in Cancer.

Miscellaneous databases

ChiTaRSi TGFBR1. mouse.
NextBioi 301202.
PROi Q64729.
SOURCEi Search...

Gene expression databases

Bgeei Q64729.
CleanExi MM_TGFBR1.
ExpressionAtlasi Q64729. baseline and differential.
Genevestigatori Q64729.

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

« Hide 'large scale' publications
  1. "Molecular cloning of a mouse counterpart for human TGF-beta type I receptor."
    Tomoda T., Kudoh T., Noma T., Nakazawa A., Muramatsu M.-A., Arai K.
    Biochem. Biophys. Res. Commun. 198:1054-1062(1994) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
    Tissue: Brain and Testis.
  2. "A mouse TGF-beta type I receptor that requires type II receptor for ligand binding."
    Suzuki A., Shioda N., Maeda T., Tada M., Ueno N.
    Biochem. Biophys. Res. Commun. 198:1063-1069(1994) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
    Tissue: Brain.
  3. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
    Strain: C57BL/6J.
  4. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
    The MGC Project Team
    Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
    Strain: C57BL/6.
    Tissue: Brain.

Entry informationi

Entry nameiTGFR1_MOUSE
AccessioniPrimary (citable) accession number: Q64729
Secondary accession number(s): A2AJN0
Entry historyi
Integrated into UniProtKB/Swiss-Prot: July 15, 1999
Last sequence update: November 1, 1996
Last modified: October 29, 2014
This is version 145 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. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  3. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3