P80204 (TGFR1_RAT) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
TGF-beta receptor type-1
Short name=TGFR-1
EC=2.7.11.30

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 names

Name:

Tgfbr1

Organism

Rattus norvegicus (Rat) [Reference proteome]

Taxonomic identifier

10116 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Rattus

Protein attributes

Sequence length	501 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	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 activity	ATP + [receptor-protein] = ADP + [receptor-protein] phosphate.
Cofactor	Magnesium or manganese By similarity.
Enzyme regulation	Kept in an inactive conformation by FKBP1A preventing receptor activation in absence of ligand. CD109 is another inhibitor of the receptor. Ref.2
Subunit structure	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. Ref.2
Subcellular location	Cell membrane; Single-pass type I membrane protein By similarity. Cell junction › tight junction By similarity.
Tissue specificity	Urogenital ridge, testis, ovary, brain and lungs.
Post-translational modification	Phosphorylated at basal levels in the absence of ligand. Activated upon phosphorylation by TGFBR2, mainly in the GS domain. Phosphorylation in the GS domain abbrogates 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.
Sequence similarities	Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. TGFB receptor subfamily. Contains 1 GS domain. Contains 1 protein kinase domain.

Ontologies

Keywords
Biological process	Apoptosis Differentiation Growth regulation
Cellular component	Cell junction Cell membrane Membrane Tight junction
Domain	Signal Transmembrane Transmembrane helix
Ligand	ATP-binding Magnesium Manganese Metal-binding Nucleotide-binding
Molecular function	Kinase Receptor Serine/threonine-protein kinase Transferase
PTM	Disulfide bond Glycoprotein Isopeptide bond Phosphoprotein Ubl conjugation
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	aging Inferred from expression pattern PubMed 12051734. Source: RGD apoptotic process Inferred from electronic annotation. Source: UniProtKB-KW cell differentiation Inferred from electronic annotation. Source: UniProtKB-KW digestive tract development Inferred from expression pattern PubMed 12815632. Source: RGD embryo development Inferred from expression pattern PubMed 17428384. Source: RGD embryo implantation Inferred from expression pattern PubMed 16426643. Source: RGD lung development Inferred from expression pattern PubMed 10835329. Source: RGD negative regulation of endothelial cell differentiation Inferred from mutant phenotype PubMed 17450384. Source: RGD organ regeneration Inferred from expression pattern PubMed 9699514. Source: RGD protein autophosphorylation Inferred from mutant phenotype PubMed 8272871. Source: RGD regulation of growth Inferred from electronic annotation. Source: UniProtKB-KW response to electrical stimulus Inferred from expression pattern PubMed 16682418. Source: RGD response to estrogen stimulus Inferred from direct assay PubMed 12097811. Source: RGD response to hypoxia Inferred from expression pattern PubMed 18760335. Source: RGD response to prostaglandin E stimulus Inferred from expression pattern PubMed 12890451. Source: RGD response to toxic substance Inferred from expression pattern PubMed 16682418. Source: RGD transforming growth factor beta receptor signaling pathway Inferred from mutant phenotype PubMed 17505012PubMed 18684975PubMed 8272871. Source: RGD
Cellular_component	apical plasma membrane Inferred from direct assay PubMed 10590020. Source: RGD basolateral plasma membrane Inferred from direct assay PubMed 10590020. Source: RGD caveola Inferred from direct assay PubMed 17878231. Source: MGI tight junction Inferred from electronic annotation. Source: UniProtKB-SubCell transforming growth factor beta receptor homodimeric complex Inferred by curator PubMed 18684975. Source: RGD
Molecular_function	ATP binding Inferred from mutant phenotype PubMed 17505012. Source: RGD metal ion binding Inferred from electronic annotation. Source: UniProtKB-KW protein heterodimerization activity Inferred from mutant phenotype PubMed 8272871. Source: RGD transforming growth factor beta binding Inferred from direct assay PubMed 8272871. Source: RGD transforming growth factor beta receptor activity, type I Inferred from mutant phenotype PubMed 17505012PubMed 18684975PubMed 8272871. Source: RGD
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Signal peptide	1 – 29	29	By similarity
	Chain	30 – 501	472	TGF-beta receptor type-1		PRO_0000024425
Regions
	Topological domain	30 – 124	95	Extracellular Potential
	Transmembrane	125 – 145	21	Helical; Potential
	Topological domain	146 – 501	356	Cytoplasmic Potential
	Domain	173 – 202	30	GS
	Domain	203 – 493	291	Protein kinase
	Nucleotide binding	209 – 217	9	ATP By similarity
	Motif	191 – 192	2	FKBP1A-binding
Sites
	Active site	331	1	Proton acceptor By similarity
	Binding site	230	1	ATP By similarity
Amino acid modifications
	Modified residue	163	1	Phosphoserine By similarity
	Modified residue	183	1	Phosphothreonine; by TGFBR2 By similarity
	Modified residue	184	1	Phosphothreonine; by TGFBR2 By similarity
	Modified residue	185	1	Phosphoserine; by TGFBR2 By similarity
	Modified residue	187	1	Phosphoserine; by TGFBR2 By similarity
	Modified residue	189	1	Phosphoserine; by TGFBR2 By similarity
	Glycosylation	41	1	N-linked (GlcNAc...) Potential
	Disulfide bond	32 ↔ 50		By similarity
	Disulfide bond	34 ↔ 37		By similarity
	Disulfide bond	44 ↔ 67		By similarity
	Disulfide bond	82 ↔ 94		By similarity
	Disulfide bond	95 ↔ 100		By similarity
	Cross-link	389		Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO) Ref.3

Sequences

	Sequence		Length	Mass (Da)
	P80204 [UniParc]. Last modified October 1, 1993. Version 1. Checksum: EAD7F8D37E456102	FASTA	501	56,000
	10 20 30 40 50 60 MEAASAALRR CLLLIVLVAA ATLLPGAKAL QCFCHLCTKD NFTCETDGLC FVSVTETTDK 70 80 90 100 110 120 VIHNSMCIAE IDLIPRDRPF VCAPSSKTGA VTYCCNQDHC NKIELPTTGP FSEKQSAGLG 130 140 150 160 170 180 PVELAAVIAG PVCFVCIALM LMVYICHNRT VIHHRVPNEE DPSLDRPFIS EGTTLKDLIY 190 200 210 220 230 240 DMTTSGSGSG LPLLVQRTIA RTIVLQESIG KGRFGEVWRG KWRGEEVAVK IFSSREERSW 250 260 270 280 290 300 FREAEIYQTV MLRHENILGF IAADNKDNGT WTQLWLVSDY HEHGSLFDYL NRYTVTVEGM 310 320 330 340 350 360 IKLALSTASG LAHLHMEIVG TQGKPAIAHR DLKSKNILVK KNGTCCIADL GLAVRHDSAT 370 380 390 400 410 420 DTIDIAPNHR VGTKRYMAPE VLDDSINMKH FESFKRADIY AMGLVFWEIA RRCSIGGIHE 430 440 450 460 470 480 DYQLPYYDLV PSDPSVEEMR KVVCEQKLRP NIPNRWQSCE ALRVMAKIMR ECWYANGAAR 490 500 LTALRIKKTL SQLSQQEGIK M

References

[1]	"Developmental expression of four novel serine/threonine kinase receptors homologous to the activin/transforming growth factor-beta type II receptor family." He W.-W., Gustafson M.L., Hirobe S., Donahoe P.K. Dev. Dyn. 196:133-142(1993) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Strain: Sprague-Dawley. Tissue: Urogenital ridge.
[2]	"The immunophilin FKBP12 functions as a common inhibitor of the TGF beta family type I receptors." Wang T., Li B.Y., Danielson P.D., Shah P.C., Rockwell S., Lechleider R.J., Martin J., Manganaro T., Donahoe P.K. Cell 86:435-444(1996) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH FKBP1A, ENZYME REGULATION.
[3]	"The type I TGF-beta receptor is covalently modified and regulated by sumoylation." Kang J.S., Saunier E.F., Akhurst R.J., Derynck R. Nat. Cell Biol. 10:654-664(2008) [PubMed] [Europe PMC] [Abstract] Cited for: SUMOYLATION AT LYS-389.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	L26110 mRNA. Translation: AAA83216.1.
IPI	IPI00195461.
UniGene	Rn.44402.
3D structure databases
ProteinModelPortal	P80204.
SMR	P80204. Positions 29-105, 169-498.
ModBase	Search...
Protein-protein interaction databases
IntAct	P80204. 3 interactions.
STRING	10116.ENSRNOP00000009452.
Proteomic databases
PaxDb	P80204.
PRIDE	P80204.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSRNOT00000009452; ENSRNOP00000009452; ENSRNOG00000007036.
UCSC	RGD:3852. rat.
Organism-specific databases
RGD	3852. Tgfbr1.
Phylogenomic databases
eggNOG	COG0515.
GeneTree	ENSGT00560000076615.
HOGENOM	HOG000230587.
HOVERGEN	HBG054502.
InParanoid	P80204.
OrthoDB	EOG4JQ3XG.
Enzyme and pathway databases
BRENDA	2.7.10.2. 5301.
Gene expression databases
ArrayExpress	P80204.
Genevestigator	P80204.
GermOnline	ENSRNOG00000007036. Rattus norvegicus.
Family and domain databases
InterPro	IPR000472. Activin_rcpt. IPR011009. Kinase-like_dom. IPR000719. Prot_kinase_cat_dom. IPR017441. Protein_kinase_ATP_BS. IPR008271. Ser/Thr_kinase_AS. IPR003605. TGF_beta_rcpt_GS. [Graphical view]
Pfam	PF01064. Activin_recp. 1 hit. PF00069. Pkinase. 1 hit. PF08515. TGF_beta_GS. 1 hit. [Graphical view]
SMART	SM00467. GS. 1 hit. [Graphical view]
SUPFAM	SSF56112. Kinase_like. 1 hit.
PROSITE	PS51256. GS. 1 hit. PS00107. PROTEIN_KINASE_ATP. 1 hit. PS50011. PROTEIN_KINASE_DOM. 1 hit. PS00108. PROTEIN_KINASE_ST. 1 hit. [Graphical view]
ProtoNet	Search...

Entry information

Entry name

TGFR1_RAT

Accession

Primary (citable) accession number: P80204

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1993
Last sequence update:	October 1, 1993
Last modified:	May 29, 2013
This is version 123 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program