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Protein

TGF-beta receptor type-1

Gene

Tgfbr1

Organism
Rattus norvegicus (Rat)
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.1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei230ATPPROSITE-ProRule annotation1
Active sitei331Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi209 – 217ATPPROSITE-ProRule annotation9

GO - Molecular functioni

  • ATP binding Source: RGD
  • I-SMAD binding Source: RGD
  • metal ion binding Source: UniProtKB-KW
  • protein complex binding Source: RGD
  • protein heterodimerization activity Source: RGD
  • protein kinase activity Source: RGD
  • protein serine/threonine kinase activity Source: RGD
  • receptor binding Source: RGD
  • signal transducer, downstream of receptor, with serine/threonine kinase activity Source: RGD
  • signal transducer activity, downstream of receptor Source: AgBase
  • SMAD binding Source: RGD
  • transforming growth factor beta-activated receptor activity Source: RGD
  • transforming growth factor beta binding Source: RGD
  • transforming growth factor beta receptor activity, type I Source: RGD
  • type II transforming growth factor beta receptor binding Source: RGD
  • ubiquitin protein ligase binding Source: RGD

GO - Biological processi

Keywordsi

Molecular functionKinase, Receptor, Serine/threonine-protein kinase, Transferase
Biological processApoptosis, Differentiation, Growth regulation
LigandATP-binding, Magnesium, Manganese, Metal-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAi2.7.10.2. 5301.
2.7.11.30. 5301.

Names & Taxonomyi

Protein namesi
Recommended name:
TGF-beta receptor type-1 (EC:2.7.11.30)
Short name:
TGFR-1
Alternative name(s):
Serine/threonine-protein kinase receptor R4
Short name:
SKR4
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
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeRattus
Proteomesi
  • UP000002494 Componenti: Unplaced

Organism-specific databases

RGDi3852. Tgfbr1.

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini30 – 124ExtracellularSequence analysisAdd BLAST95
Transmembranei125 – 145HelicalSequence analysisAdd BLAST21
Topological domaini146 – 501CytoplasmicSequence analysisAdd BLAST356

Keywords - Cellular componenti

Cell junction, Cell membrane, Membrane, Tight junction

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 29By similarityAdd BLAST29
ChainiPRO_000002442530 – 501TGF-beta receptor type-1Add BLAST472

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Disulfide bondi32 ↔ 50By similarity
Disulfide bondi34 ↔ 37By similarity
Glycosylationi41N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi44 ↔ 67By similarity
Disulfide bondi82 ↔ 94By similarity
Disulfide bondi95 ↔ 100By similarity
Modified residuei163PhosphoserineBy similarity1
Modified residuei183Phosphothreonine; by TGFBR2By similarity1
Modified residuei184Phosphothreonine; by TGFBR2By similarity1
Modified residuei185Phosphoserine; by TGFBR2By similarity1
Modified residuei187Phosphoserine; by TGFBR2By similarity1
Modified residuei189Phosphoserine; by TGFBR2By similarity1
Cross-linki389Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO)

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

PaxDbiP80204.
PRIDEiP80204.

PTM databases

PhosphoSitePlusiP80204.

Expressioni

Tissue specificityi

Urogenital ridge, testis, ovary, brain and lungs.

Gene expression databases

GenevisibleiP80204. RN.

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 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). Interacts (unphosphorylated) with FKBP1A; prevents TGFBR1 phosphorylation by TGFBR2 and stabilizes it in the inactive conformation. Interacts with SDCBP (via C-terminus). Interacts with CAV1 and this interaction is impaired in the presence of SDCBP (By similarity).By similarity1 Publication

GO - Molecular functioni

  • I-SMAD binding Source: RGD
  • protein complex binding Source: RGD
  • protein heterodimerization activity Source: RGD
  • receptor binding Source: RGD
  • SMAD binding Source: RGD
  • transforming growth factor beta binding Source: RGD
  • type II transforming growth factor beta receptor binding Source: RGD
  • ubiquitin protein ligase binding Source: RGD

Protein-protein interaction databases

BioGridi248223. 2 interactors.
CORUMiP80204.
IntActiP80204. 4 interactors.
STRINGi10116.ENSRNOP00000009452.

Structurei

3D structure databases

ProteinModelPortaliP80204.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini173 – 202GSPROSITE-ProRule annotationAdd BLAST30
Domaini203 – 493Protein kinasePROSITE-ProRule annotationAdd BLAST291

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi191 – 192FKBP1A-binding2

Sequence similaritiesi

Keywords - Domaini

Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG2052. Eukaryota.
ENOG410XQT0. LUCA.
HOGENOMiHOG000230587.
HOVERGENiHBG054502.
InParanoidiP80204.
PhylomeDBiP80204.
TreeFamiTF314724.

Family and domain databases

InterProiView protein in InterPro
IPR000472. Activin_recp.
IPR003605. GS_dom.
IPR011009. Kinase-like_dom_sf.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR008271. Ser/Thr_kinase_AS.
IPR000333. TGFB_receptor.
PANTHERiPTHR23255. PTHR23255. 1 hit.
PfamiView protein in Pfam
PF01064. Activin_recp. 1 hit.
PF00069. Pkinase. 1 hit.
PF08515. TGF_beta_GS. 1 hit.
SMARTiView protein in SMART
SM00467. GS. 1 hit.
SM00220. S_TKc. 1 hit.
SUPFAMiSSF56112. SSF56112. 1 hit.
PROSITEiView protein in PROSITE
PS51256. GS. 1 hit.
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.

Sequencei

Sequence statusi: Complete.

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

P80204-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MEAASAALRR CLLLIVLVAA ATLLPGAKAL QCFCHLCTKD NFTCETDGLC
60 70 80 90 100
FVSVTETTDK VIHNSMCIAE IDLIPRDRPF VCAPSSKTGA VTYCCNQDHC
110 120 130 140 150
NKIELPTTGP FSEKQSAGLG PVELAAVIAG PVCFVCIALM LMVYICHNRT
160 170 180 190 200
VIHHRVPNEE DPSLDRPFIS EGTTLKDLIY DMTTSGSGSG LPLLVQRTIA
210 220 230 240 250
RTIVLQESIG KGRFGEVWRG KWRGEEVAVK IFSSREERSW FREAEIYQTV
260 270 280 290 300
MLRHENILGF IAADNKDNGT WTQLWLVSDY HEHGSLFDYL NRYTVTVEGM
310 320 330 340 350
IKLALSTASG LAHLHMEIVG TQGKPAIAHR DLKSKNILVK KNGTCCIADL
360 370 380 390 400
GLAVRHDSAT DTIDIAPNHR VGTKRYMAPE VLDDSINMKH FESFKRADIY
410 420 430 440 450
AMGLVFWEIA RRCSIGGIHE DYQLPYYDLV PSDPSVEEMR KVVCEQKLRP
460 470 480 490 500
NIPNRWQSCE ALRVMAKIMR ECWYANGAAR LTALRIKKTL SQLSQQEGIK

M
Length:501
Mass (Da):56,000
Last modified:October 1, 1993 - v1
Checksum:iEAD7F8D37E456102
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
L26110 mRNA. Translation: AAA83216.1.
RefSeqiXP_006238092.2. XM_006238030.3.
UniGeneiRn.44402.

Genome annotation databases

GeneIDi29591.
UCSCiRGD:3852. rat.

Similar proteinsi

Entry informationi

Entry nameiTGFR1_RAT
AccessioniPrimary (citable) accession number: P80204
Entry historyiIntegrated into UniProtKB/Swiss-Prot: October 1, 1993
Last sequence update: October 1, 1993
Last modified: November 22, 2017
This is version 163 of the entry and version 1 of the sequence. See 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