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Protein

TGF-beta receptor type-1

Gene

Tgfbr1

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: 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

Mg2+By similarity, Mn2+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)DescriptionActionsGraphical viewLength
Binding sitei232ATPPROSITE-ProRule annotation1
Active sitei333Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi211 – 219ATPPROSITE-ProRule annotation9

GO - Molecular functioni

GO - Biological processi

  • activation of MAPKK activity Source: MGI
  • activin receptor signaling pathway Source: AgBase
  • angiogenesis Source: MGI
  • angiogenesis involved in coronary vascular morphogenesis Source: BHF-UCL
  • anterior/posterior pattern specification Source: MGI
  • apoptotic process Source: UniProtKB-KW
  • artery morphogenesis Source: MGI
  • blastocyst development Source: MGI
  • cardiac epithelial to mesenchymal transition Source: AgBase
  • cell motility Source: MGI
  • cellular response to transforming growth factor beta stimulus Source: BHF-UCL
  • collagen fibril organization Source: MGI
  • coronary artery morphogenesis Source: BHF-UCL
  • embryonic cranial skeleton morphogenesis Source: MGI
  • endothelial cell activation Source: AgBase
  • endothelial cell migration Source: MGI
  • epicardium morphogenesis Source: BHF-UCL
  • epithelial to mesenchymal transition Source: MGI
  • germ cell migration Source: MGI
  • heart development Source: AgBase
  • intracellular signal transduction Source: AgBase
  • in utero embryonic development Source: MGI
  • kidney development Source: MGI
  • lens development in camera-type eye Source: MGI
  • male gonad development Source: MGI
  • mesenchymal cell differentiation Source: AgBase
  • negative regulation of apoptotic process Source: MGI
  • negative regulation of chondrocyte differentiation Source: BHF-UCL
  • negative regulation of endothelial cell proliferation Source: MGI
  • negative regulation of extrinsic apoptotic signaling pathway Source: MGI
  • neuron fate commitment Source: MGI
  • palate development Source: MGI
  • parathyroid gland development Source: MGI
  • pathway-restricted SMAD protein phosphorylation Source: MGI
  • peptidyl-serine phosphorylation Source: MGI
  • peptidyl-threonine phosphorylation Source: MGI
  • pharyngeal system development Source: MGI
  • positive regulation of apoptotic signaling pathway Source: MGI
  • positive regulation of cell growth Source: MGI
  • positive regulation of cell migration Source: MGI
  • positive regulation of cell proliferation Source: MGI
  • positive regulation of cellular component movement Source: MGI
  • positive regulation of endothelial cell proliferation Source: AgBase
  • positive regulation of epithelial to mesenchymal transition Source: BHF-UCL
  • positive regulation of epithelial to mesenchymal transition involved in endocardial cushion formation Source: BHF-UCL
  • positive regulation of filopodium assembly Source: MGI
  • positive regulation of gene expression Source: AgBase
  • positive regulation of occluding junction disassembly Source: BHF-UCL
  • positive regulation of pathway-restricted SMAD protein phosphorylation Source: MGI
  • positive regulation of protein kinase B signaling Source: MGI
  • positive regulation of SMAD protein import into nucleus Source: MGI
  • positive regulation of stress fiber assembly Source: BHF-UCL
  • positive regulation of transcription, DNA-templated Source: AgBase
  • post-embryonic development Source: MGI
  • protein phosphorylation Source: MGI
  • regulation of cardiac muscle cell proliferation Source: BHF-UCL
  • regulation of epithelial to mesenchymal transition Source: AgBase
  • regulation of gene expression Source: AgBase
  • regulation of protein binding Source: MGI
  • regulation of protein ubiquitination Source: MGI
  • regulation of transcription, DNA-templated Source: MGI
  • response to cholesterol Source: BHF-UCL
  • signal transduction Source: MGI
  • skeletal system development Source: MGI
  • skeletal system morphogenesis Source: MGI
  • thymus development Source: MGI
  • transforming growth factor beta receptor signaling pathway Source: BHF-UCL
  • ventricular compact myocardium morphogenesis Source: BHF-UCL
  • ventricular septum morphogenesis Source: BHF-UCL
  • ventricular trabecula myocardium morphogenesis Source: BHF-UCL
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.
ReactomeiR-MMU-2173788. Downregulation of TGF-beta receptor signaling.
R-MMU-2173789. TGF-beta receptor signaling activates SMADs.
R-MMU-2173791. TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition).
R-MMU-5689880. Ub-specific processing proteases.

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
Proteomesi
  • UP000000589 Componenti: 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
  • Membrane raft By similarity
  • Cell surface By similarity

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini30 – 126ExtracellularSequence analysisAdd BLAST97
Transmembranei127 – 147HelicalSequence analysisAdd BLAST21
Topological domaini148 – 503CytoplasmicSequence analysisAdd BLAST356

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Cell junction, Cell membrane, Membrane, Tight junction

Pathology & Biotechi

Chemistry databases

ChEMBLiCHEMBL2021750.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 29By similarityAdd BLAST29
ChainiPRO_000002442430 – 503TGF-beta receptor type-1Add BLAST474

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Disulfide bondi32 ↔ 50By similarity
Disulfide bondi34 ↔ 37By similarity
Glycosylationi41N-linked (GlcNAc...)Sequence analysis1
Disulfide bondi44 ↔ 67By similarity
Disulfide bondi82 ↔ 96By similarity
Disulfide bondi97 ↔ 102By similarity
Modified residuei165PhosphoserineBy similarity1
Modified residuei185Phosphothreonine; by TGFBR2By similarity1
Modified residuei186Phosphothreonine; by TGFBR2By similarity1
Modified residuei187Phosphoserine; by TGFBR2By similarity1
Modified residuei189Phosphoserine; by TGFBR2By similarity1
Modified residuei191Phosphoserine; by TGFBR2By similarity1
Cross-linki391Glycyl 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. Its ubiquitination and proteasome-mediated degradation is negatively regulated by SDCBP (By similarity).By similarity

Keywords - PTMi

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

Proteomic databases

PaxDbiQ64729.
PRIDEiQ64729.

PTM databases

iPTMnetiQ64729.
PhosphoSitePlusiQ64729.

Expressioni

Gene expression databases

BgeeiENSMUSG00000007613.
CleanExiMM_TGFBR1.
ExpressionAtlasiQ64729. baseline and differential.
GenevisibleiQ64729. MM.

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. Interacts with SDCBP (via C-terminus). Interacts with CAV1 and this interaction is impaired in the presence of SDCBP (By similarity).By similarity

Binary interactionsi

WithEntry#Exp.IntActNotes
Cd44P153794EBI-2899393,EBI-7565891
Cdh5P552842EBI-2899393,EBI-7087433
DLG5Q8TDM63EBI-2899393,EBI-715138From a different organism.
Shc1P98083-23EBI-2899393,EBI-1019301

GO - Molecular functioni

  • I-SMAD binding Source: MGI
  • receptor binding Source: UniProtKB
  • SMAD binding Source: BHF-UCL
  • transforming growth factor beta binding Source: MGI
  • type II transforming growth factor beta receptor binding Source: MGI

Protein-protein interaction databases

BioGridi204163. 25 interactors.
DIPiDIP-42262N.
IntActiQ64729. 25 interactors.
MINTiMINT-1341331.
STRINGi10090.ENSMUSP00000007757.

Chemistry databases

BindingDBiQ64729.

Structurei

3D structure databases

ProteinModelPortaliQ64729.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini175 – 204GSPROSITE-ProRule annotationAdd BLAST30
Domaini205 – 495Protein kinasePROSITE-ProRule annotationAdd BLAST291

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi193 – 194FKBP1A-binding2

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

eggNOGiKOG2052. Eukaryota.
ENOG410XQT0. LUCA.
GeneTreeiENSGT00760000118876.
HOGENOMiHOG000230587.
HOVERGENiHBG054502.
InParanoidiQ64729.
KOiK04674.
OMAiGATALQC.
OrthoDBiEOG091G0BIU.
PhylomeDBiQ64729.
TreeFamiTF314724.

Family and domain databases

InterProiIPR000472. Activin_recp.
IPR003605. GS_dom.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR008271. Ser/Thr_kinase_AS.
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.
SM00220. S_TKc. 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. AlignAdd to basket

Isoform 1 (identifier: Q64729-1) [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
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)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_021593111 – 114Missing in isoform 2. 1 Publication4

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
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_001299797.1. NM_001312868.1. [Q64729-2]
NP_001299798.1. NM_001312869.1.
NP_033396.1. NM_009370.3. [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:
EMBLi
GenBanki
DDBJi
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_001299797.1. NM_001312868.1. [Q64729-2]
NP_001299798.1. NM_001312869.1.
NP_033396.1. NM_009370.3. [Q64729-1]
UniGeneiMm.197552.

3D structure databases

ProteinModelPortaliQ64729.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi204163. 25 interactors.
DIPiDIP-42262N.
IntActiQ64729. 25 interactors.
MINTiMINT-1341331.
STRINGi10090.ENSMUSP00000007757.

Chemistry databases

BindingDBiQ64729.
ChEMBLiCHEMBL2021750.

PTM databases

iPTMnetiQ64729.
PhosphoSitePlusiQ64729.

Proteomic databases

PaxDbiQ64729.
PRIDEiQ64729.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

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]

Organism-specific databases

CTDi7046.
MGIiMGI:98728. Tgfbr1.

Phylogenomic databases

eggNOGiKOG2052. Eukaryota.
ENOG410XQT0. LUCA.
GeneTreeiENSGT00760000118876.
HOGENOMiHOG000230587.
HOVERGENiHBG054502.
InParanoidiQ64729.
KOiK04674.
OMAiGATALQC.
OrthoDBiEOG091G0BIU.
PhylomeDBiQ64729.
TreeFamiTF314724.

Enzyme and pathway databases

BRENDAi2.7.10.2. 3474.
ReactomeiR-MMU-2173788. Downregulation of TGF-beta receptor signaling.
R-MMU-2173789. TGF-beta receptor signaling activates SMADs.
R-MMU-2173791. TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition).
R-MMU-5689880. Ub-specific processing proteases.

Miscellaneous databases

ChiTaRSiTgfbr1. mouse.
PROiQ64729.
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000007613.
CleanExiMM_TGFBR1.
ExpressionAtlasiQ64729. baseline and differential.
GenevisibleiQ64729. MM.

Family and domain databases

InterProiIPR000472. Activin_recp.
IPR003605. GS_dom.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR008271. Ser/Thr_kinase_AS.
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.
SM00220. S_TKc. 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]
ProtoNetiSearch...

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: November 30, 2016
This is version 167 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

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.