Q64729 (TGFR1_MOUSE) 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):
ESK2
Transforming growth factor-beta receptor type I
Short name=TGF-beta receptor type I
Short name=TbetaR-I

Gene names

Name:

Tgfbr1

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [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 › Mus › Mus

Protein attributes

Sequence length	503 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at transcript 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 By similarity.
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 (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.
Subcellular location	Cell membrane; Single-pass type I membrane protein By similarity. Cell junction › tight junction By similarity.
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
Coding sequence diversity	Alternative splicing
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	activation of MAPKK activity Inferred from electronic annotation. Source: Compara angiogenesis Inferred from mutant phenotype PubMed 11285230. Source: MGI anterior/posterior pattern specification Inferred from genetic interaction PubMed 16845371. Source: MGI apoptotic process Inferred from electronic annotation. Source: UniProtKB-KW artery morphogenesis Inferred from mutant phenotype PubMed 17078885. Source: MGI blastocyst development Inferred from direct assay PubMed 9921650. Source: MGI collagen fibril organization Inferred from mutant phenotype PubMed 15993878. Source: MGI embryonic cranial skeleton morphogenesis Inferred from mutant phenotype PubMed 16806156. Source: MGI endothelial cell migration Inferred from mutant phenotype PubMed 11285230. Source: MGI epithelial to mesenchymal transition Inferred from electronic annotation. Source: Compara germ cell migration Inferred from mutant phenotype PubMed 15993878. Source: MGI heart development Inferred from mutant phenotype PubMed 17078885. Source: MGI induction of apoptosis Inferred from mutant phenotype PubMed 16806156. Source: MGI kidney development Inferred from genetic interaction PubMed 16845371. Source: MGI lens development in camera-type eye Inferred from mutant phenotype PubMed 11641223. Source: MGI negative regulation of apoptotic process Inferred from mutant phenotype PubMed 17078885. Source: MGI negative regulation of chondrocyte differentiation Inferred from mutant phenotype PubMed 19494318. Source: BHF-UCL negative regulation of endothelial cell proliferation Inferred from genetic interaction PubMed 21832243. Source: MGI neuron fate commitment Inferred from mutant phenotype PubMed 15744664. Source: MGI palate development Inferred from mutant phenotype PubMed 16806156. Source: MGI parathyroid gland development Inferred from mutant phenotype PubMed 17078885. Source: MGI pathway-restricted SMAD protein phosphorylation Inferred from electronic annotation. Source: Compara peptidyl-serine phosphorylation Inferred from electronic annotation. Source: Compara peptidyl-threonine phosphorylation Inferred from electronic annotation. Source: Compara pharyngeal system development Inferred from mutant phenotype PubMed 17078885. Source: MGI positive regulation of SMAD protein import into nucleus Inferred from electronic annotation. Source: Compara positive regulation of cell growth Inferred from electronic annotation. Source: Compara positive regulation of cell proliferation Inferred from electronic annotation. Source: Compara positive regulation of cellular component movement Inferred from electronic annotation. Source: Compara positive regulation of filopodium assembly Inferred from mutant phenotype PubMed 16806156. Source: MGI positive regulation of pathway-restricted SMAD protein phosphorylation Inferred from electronic annotation. Source: Compara positive regulation of protein kinase B signaling cascade Inferred from electronic annotation. Source: Compara positive regulation of transcription, DNA-dependent Inferred from electronic annotation. Source: Compara post-embryonic development Inferred from mutant phenotype PubMed 16806156. Source: MGI regulation of gene expression Inferred from mutant phenotype PubMed 16806156. Source: MGI regulation of protein binding Inferred from mutant phenotype PubMed 16601693. Source: MGI regulation of protein ubiquitination Inferred from electronic annotation. Source: Compara response to cholesterol Inferred from direct assay PubMed 17878231. Source: BHF-UCL thymus development Inferred from mutant phenotype PubMed 17078885. Source: MGI transforming growth factor beta receptor signaling pathway Inferred from direct assay PubMed 14580334PubMed 15820682. Source: MGI
Cellular_component	caveola Inferred from sequence orthology PubMed 17878231. Source: MGI integral to membrane Inferred from electronic annotation. Source: UniProtKB-KW receptor complex Inferred from electronic annotation. Source: Compara tight junction Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW SMAD binding Inferred from direct assay PubMed 12773577. Source: BHF-UCL metal ion binding Inferred from electronic annotation. Source: UniProtKB-KW transforming growth factor beta-activated receptor activity Inferred from direct assay PubMed 15820682. Source: MGI
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q64729-1)

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.

Isoform 2 (identifier: Q64729-2)

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.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Signal peptide	1 – 29	29	By similarity
	Chain	30 – 503	474	TGF-beta receptor type-1		PRO_0000024424
Regions
	Topological domain	30 – 126	97	Extracellular Potential
	Transmembrane	127 – 147	21	Helical; Potential
	Topological domain	148 – 503	356	Cytoplasmic Potential
	Domain	175 – 204	30	GS
	Domain	205 – 495	291	Protein kinase
	Nucleotide binding	211 – 219	9	ATP By similarity
	Motif	193 – 194	2	FKBP1A-binding
Sites
	Active site	333	1	Proton acceptor By similarity
	Binding site	232	1	ATP By similarity
Amino acid modifications
	Modified residue	165	1	Phosphoserine By similarity
	Modified residue	185	1	Phosphothreonine; by TGFBR2 By similarity
	Modified residue	186	1	Phosphothreonine; by TGFBR2 By similarity
	Modified residue	187	1	Phosphoserine; by TGFBR2 By similarity
	Modified residue	189	1	Phosphoserine; by TGFBR2 By similarity
	Modified residue	191	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 ↔ 96		By similarity
	Disulfide bond	97 ↔ 102		By similarity
	Cross-link	391		Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO) By similarity
Natural variations
	Alternative sequence	111 – 114	4	Missing in isoform 2.		VSP_021593

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified November 1, 1996. Version 1. Checksum: BB8BB6D2261793AF	FASTA	503	56,179
	10 20 30 40 50 60 MEAAAAAPRR PQLLIVLVAA ATLLPGAKAL QCFCHLCTKD NFTCETDGLC FVSVTETTDK 70 80 90 100 110 120 VIHNSMCIAE IDLIPRDRPF VCAPSSKTGA VTTTYCCNQD HCNKIELPTT GPFSEKQSAG 130 140 150 160 170 180 LGPVELAAVI AGPVCFVCIA LMLMVYICHN RTVIHHRVPN EEDPSLDRPF ISEGTTLKDL 190 200 210 220 230 240 IYDMTTSGSG SGLPLLVQRT IARTIVLQES IGKGRFGEVW RGKWRGEEVA VKIFSSREER 250 260 270 280 290 300 SWFREAEIYQ TVMLRHENIL GFIAADNKDN GTWTQLWLVS DYHEHGSLFD YLNRYTVTVE 310 320 330 340 350 360 GMIKLALSTA SGLAHLHMEI VGTQGKPAIA HRDLKSKNIL VKKNGTCCIA DLGLAVRHDS 370 380 390 400 410 420 ATDTIDIAPN HRVGTKRYMA PEVLDDSINM KHFESFKRAD IYAMGLVFWE IARRCSIGGI 430 440 450 460 470 480 HEDYQLPYYD LVPSDPSVEE MRKVVCEQKL RPNIPNRWQS CEALRVMAKI MRECWYANGA 490 500 ARLTALRIKK TLSQLSQQEG IKM
	Isoform 2 [UniParc]. Checksum: 914DE6236B689C1C	FASTA	499	55,790
	10 20 30 40 50 60 MEAAAAAPRR PQLLIVLVAA ATLLPGAKAL QCFCHLCTKD NFTCETDGLC FVSVTETTDK 70 80 90 100 110 120 VIHNSMCIAE IDLIPRDRPF VCAPSSKTGA VTTTYCCNQD HCNKIELPTT EKQSAGLGPV 130 140 150 160 170 180 ELAAVIAGPV CFVCIALMLM VYICHNRTVI HHRVPNEEDP SLDRPFISEG TTLKDLIYDM 190 200 210 220 230 240 TTSGSGSGLP LLVQRTIART IVLQESIGKG RFGEVWRGKW RGEEVAVKIF SSREERSWFR 250 260 270 280 290 300 EAEIYQTVML RHENILGFIA ADNKDNGTWT QLWLVSDYHE HGSLFDYLNR YTVTVEGMIK 310 320 330 340 350 360 LALSTASGLA HLHMEIVGTQ GKPAIAHRDL KSKNILVKKN GTCCIADLGL AVRHDSATDT 370 380 390 400 410 420 IDIAPNHRVG TKRYMAPEVL DDSINMKHFE SFKRADIYAM GLVFWEIARR CSIGGIHEDY 430 440 450 460 470 480 QLPYYDLVPS DPSVEEMRKV VCEQKLRPNI PNRWQSCEAL RVMAKIMREC WYANGAARLT 490 ALRIKKTLSQ LSQQEGIKM

References

	« Hide 'large scale' referencesShow 'large scale' references »
[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]	"Lineage-specific biology revealed by a finished genome assembly of the mouse." Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X., Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y., Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S. , Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R., Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K., Eichler E.E., Ponting C.P. PLoS Biol. 7:E1000112-E1000112(2009) [PubMed] [Europe PMC] [Abstract] 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.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	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.
IPI	IPI00137994. IPI00649475.
PIR	JC2061. JC2062.
RefSeq	NP_033396.1. NM_009370.2.
UniGene	Mm.197552.
3D structure databases
ProteinModelPortal	Q64729.
SMR	Q64729. Positions 27-110, 175-500.
ModBase	Search...
Protein-protein interaction databases
DIP	DIP-42262N.
IntAct	Q64729. 4 interactions.
MINT	MINT-1341331.
PTM databases
PhosphoSite	Q64729.
Proteomic databases
PRIDE	Q64729.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000007757; ENSMUSP00000007757; ENSMUSG00000007613. ENSMUST00000044234; ENSMUSP00000048501; ENSMUSG00000007613.
GeneID	21812.
KEGG	mmu:21812.
UCSC	uc008suo.1. mouse.
Organism-specific databases
CTD	7046.
MGI	MGI:98728. Tgfbr1.
Phylogenomic databases
eggNOG	COG0515.
GeneTree	ENSGT00560000076615.
HOGENOM	HOG000230587.
HOVERGEN	HBG054502.
InParanoid	Q64729.
KO	K04674.
OMA	CISLMLI.
OrthoDB	EOG4JQ3XG.
Enzyme and pathway databases
BRENDA	2.7.10.2. 3474.
Gene expression databases
ArrayExpress	Q64729.
Bgee	Q64729.
CleanEx	MM_TGFBR1.
Genevestigator	Q64729.
GermOnline	ENSMUSG00000007613. Mus musculus.
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...
Other
ChiTaRS	TGFBR1. mouse.
NextBio	301202.
SOURCE	Search...

Entry information

Entry name

TGFR1_MOUSE

Accession

Primary (citable) accession number: Q64729
Secondary accession number(s): A2AJN0

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 15, 1999
Last sequence update:	November 1, 1996
Last modified:	May 1, 2013
This is version 128 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program