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Protein

Transforming growth factor beta-1

Gene

TGFB1

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Multifunctional protein that controls proliferation, differentiation and other functions in many cell types. Many cells synthesize TGFB1 and have specific receptors for it. It positively and negatively regulates many other growth factors. It plays an important role in bone remodeling as it is a potent stimulator of osteoblastic bone formation, causing chemotaxis, proliferation and differentiation in committed osteoblasts (By similarity). Stimulates sustained production of collagen through the activation of CREB3L1 by regulated intramembrane proteolysis (RIP) (PubMed:25310401). Can promote either T-helper 17 cells (Th17) or regulatory T-cells (Treg) lineage differentiation in a concentration-dependent manner. At high concentrations, leads to FOXP3-mediated suppression of RORC and down-regulation of IL-17 expression, favoring Treg cell development. At low concentrations in concert with IL-6 and IL-21, leads to expression of the IL-17 and IL-23 receptors, favoring differentiation to Th17 cells. Mediates SMAD2/3 activation by inducing its phosphorylation and subsequent translocation to the nucleus (PubMed:25893292). Can induce epithelial-to-mesenchymal transition (EMT) and cell migration in various cell types (PubMed:25893292).By similarity2 Publications

GO - Molecular functioni

  • antigen binding Source: UniProtKB
  • cytokine activity Source: AgBase
  • enzyme binding Source: BHF-UCL
  • glycoprotein binding Source: UniProtKB
  • growth factor activity Source: UniProtKB-KW
  • protein heterodimerization activity Source: Ensembl
  • protein homodimerization activity Source: Ensembl
  • protein N-terminus binding Source: Ensembl
  • protein serine/threonine kinase activator activity Source: Ensembl
  • transforming growth factor beta receptor binding Source: Reactome
  • type III transforming growth factor beta receptor binding Source: AgBase
  • type II transforming growth factor beta receptor binding Source: BHF-UCL
  • type I transforming growth factor beta receptor binding Source: AgBase

GO - Biological processi

Keywordsi

Molecular functionGrowth factor, Mitogen

Enzyme and pathway databases

ReactomeiR-HSA-114608. Platelet degranulation.
R-HSA-168277. Influenza Virus Induced Apoptosis.
R-HSA-202733. Cell surface interactions at the vascular wall.
R-HSA-2129379. Molecules associated with elastic fibres.
R-HSA-2173788. Downregulation of TGF-beta receptor signaling.
R-HSA-2173789. TGF-beta receptor signaling activates SMADs.
R-HSA-2173791. TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition).
R-HSA-3000170. Syndecan interactions.
R-HSA-3000178. ECM proteoglycans.
R-HSA-3304356. SMAD2/3 Phosphorylation Motif Mutants in Cancer.
R-HSA-3315487. SMAD2/3 MH2 Domain Mutants in Cancer.
R-HSA-3642279. TGFBR2 MSI Frameshift Mutants in Cancer.
R-HSA-3645790. TGFBR2 Kinase Domain Mutants in Cancer.
R-HSA-3656532. TGFBR1 KD Mutants in Cancer.
R-HSA-3656535. TGFBR1 LBD Mutants in Cancer.
R-HSA-381340. Transcriptional regulation of white adipocyte differentiation.
R-HSA-5689603. UCH proteinases.
R-HSA-6785807. Interleukin-4 and 13 signaling.
R-HSA-8941855. RUNX3 regulates CDKN1A transcription.
R-HSA-8941858. Regulation of RUNX3 expression and activity.
R-HSA-8951936. RUNX3 regulates p14-ARF.
SignaLinkiP01137.
SIGNORiP01137.

Names & Taxonomyi

Protein namesi
Recommended name:
Transforming growth factor beta-1
Short name:
TGF-beta-1
Cleaved into the following chain:
Gene namesi
Name:TGFB1
Synonyms:TGFB
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 19

Organism-specific databases

HGNCiHGNC:11766. TGFB1.

Subcellular locationi

GO - Cellular componenti

  • axon Source: Ensembl
  • blood microparticle Source: UniProtKB
  • cell surface Source: BHF-UCL
  • cytoplasm Source: BHF-UCL
  • extracellular matrix Source: BHF-UCL
  • extracellular region Source: Reactome
  • extracellular space Source: BHF-UCL
  • Golgi lumen Source: Reactome
  • neuronal cell body Source: Ensembl
  • nucleus Source: BHF-UCL
  • plasma membrane Source: Reactome
  • platelet alpha granule lumen Source: Reactome
  • proteinaceous extracellular matrix Source: UniProtKB

Keywords - Cellular componenti

Extracellular matrix, Secreted

Pathology & Biotechi

Involvement in diseasei

Camurati-Engelmann disease (CAEND)5 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionAn autosomal dominant disorder characterized by hyperostosis and sclerosis of the diaphyses of long bones. The disease typically presents in early childhood with pain, muscular weakness and waddling gait, and in some cases other features such as exophthalmos, facial paralysis, hearing difficulties and loss of vision.
See also OMIM:131300
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_01760781Y → H in CAEND; leads to TGF-beta-1 intracellular accumulation. 2 Publications1
Natural variantiVAR_017608218R → C in CAEND; higher levels of active TGF-beta-1 in the culture medium; enhances osteoclast formation in vitro. 4 Publications1
Natural variantiVAR_017609218R → H in CAEND. 1 Publication1
Natural variantiVAR_017610222H → D in CAEND; sporadic case; higher levels of active TGF-beta-1 in the culture medium. 1 Publication1
Natural variantiVAR_067303223C → G in CAEND. 1 Publication1
Natural variantiVAR_067304223C → R in CAEND. 1 Publication1
Natural variantiVAR_017611225C → R in CAEND; higher levels of active TGF-beta-1 in the culture medium. 3 Publications1

Keywords - Diseasei

Disease mutation

Organism-specific databases

DisGeNETi7040.
GeneReviewsiTGFB1.
MalaCardsiTGFB1.
MIMi131300. phenotype.
Orphaneti1328. Camurati-Engelmann disease.
586. Cystic fibrosis.
PharmGKBiPA350.

Chemistry databases

ChEMBLiCHEMBL1795178.
DrugBankiDB00070. Hyaluronidase.
DB06205. Hyaluronidase (Human Recombinant).

Polymorphism and mutation databases

BioMutaiTGFB1.
DMDMi135674.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 291 PublicationAdd BLAST29
ChainiPRO_000003376230 – 278Latency-associated peptideAdd BLAST249
ChainiPRO_0000033763279 – 390Transforming growth factor beta-1Add BLAST112

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Disulfide bondi33Interchain (with C-1359 or C-1384 in LTBP1); in inactive formBy similarity
Glycosylationi82N-linked (GlcNAc...) asparagine2 Publications1
Glycosylationi136N-linked (GlcNAc...) asparagineBy similarity1
Glycosylationi176N-linked (GlcNAc...) asparagineBy similarity1
Disulfide bondi223Interchain (with C-225)By similarity
Disulfide bondi225Interchain (with C-223)By similarity
Disulfide bondi285 ↔ 294
Disulfide bondi293 ↔ 356
Disulfide bondi322 ↔ 387
Disulfide bondi326 ↔ 389
Disulfide bondi355Interchain

Post-translational modificationi

Glycosylated.2 Publications
The precursor is cleaved into mature TGF-beta-1 and LAP, which remains non-covalently linked to mature TGF-beta-1 rendering it inactive.

Keywords - PTMi

Cleavage on pair of basic residues, Disulfide bond, Glycoprotein

Proteomic databases

EPDiP01137.
MaxQBiP01137.
PaxDbiP01137.
PeptideAtlasiP01137.
PRIDEiP01137.

2D gel databases

OGPiP01137.

PTM databases

iPTMnetiP01137.
PhosphoSitePlusiP01137.

Expressioni

Tissue specificityi

Highly expressed in bone. Abundantly expressed in articular cartilage and chondrocytes and is increased in osteoarthritis (OA). Colocalizes with ASPN in chondrocytes within OA lesions of articular cartilage.2 Publications

Inductioni

Activated in vitro at pH below 3.5 and over 12.5.

Gene expression databases

BgeeiENSG00000105329.
CleanExiHS_TGFB1.
ExpressionAtlasiP01137. baseline and differential.
GenevisibleiP01137. HS.

Organism-specific databases

HPAiCAB000361.
CAB073543.

Interactioni

Subunit structurei

Homodimer; disulfide-linked, or heterodimer with TGFB2 (By similarity). Secreted and stored as a biologically inactive form in the extracellular matrix in a 290 kDa complex (large latent TGF-beta1 complex) containing the TGFB1 homodimer, the latency-associated peptide (LAP), and the latent TGFB1 binding protein-1 (LTBP1). The complex without LTBP1 is known as the'small latent TGF-beta1 complex'. Dissociation of the TGFB1 from LAP is required for growth factor activation and biological activity. Release of the large latent TGF-beta1 complex from the extracellular matrix is carried out by the matrix metalloproteinase MMP3 (By similarity). May interact with THSD4; this interaction may lead to sequestration by FBN1 microfibril assembly and attenuation of TGFB signaling. Interacts with the serine proteases, HTRA1 and HTRA3: the interaction with either inhibits TGFB1-mediated signaling. The HTRA protease activity is required for this inhibition (By similarity). Latency-associated peptide interacts with NREP; the interaction results in a decrease in TGFB1 autoinduction (By similarity). Interacts with CD109, DPT and ASPN. Interacts (via processed form (LAP)) with HSP90AB1; inhibits latent TGFB1 activation (PubMed:20599762).By similarity4 Publications

Binary interactionsi

Show more details

GO - Molecular functioni

  • cytokine activity Source: AgBase
  • enzyme binding Source: BHF-UCL
  • glycoprotein binding Source: UniProtKB
  • growth factor activity Source: UniProtKB-KW
  • protein heterodimerization activity Source: Ensembl
  • protein homodimerization activity Source: Ensembl
  • protein N-terminus binding Source: Ensembl
  • transforming growth factor beta receptor binding Source: Reactome
  • type III transforming growth factor beta receptor binding Source: AgBase
  • type II transforming growth factor beta receptor binding Source: BHF-UCL
  • type I transforming growth factor beta receptor binding Source: AgBase

Protein-protein interaction databases

BioGridi112898. 69 interactors.
DIPiDIP-5934N.
IntActiP01137. 76 interactors.
MINTiMINT-6806111.
STRINGi9606.ENSP00000221930.

Chemistry databases

BindingDBiP01137.

Structurei

Secondary structure

1390
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi38 – 56Combined sources19
Beta strandi70 – 72Combined sources3
Helixi75 – 84Combined sources10
Beta strandi106 – 112Combined sources7
Turni118 – 123Combined sources6
Beta strandi131 – 136Combined sources6
Helixi137 – 143Combined sources7
Beta strandi144 – 146Combined sources3
Turni147 – 149Combined sources3
Beta strandi150 – 156Combined sources7
Beta strandi167 – 174Combined sources8
Turni175 – 177Combined sources3
Beta strandi178 – 186Combined sources9
Beta strandi197 – 199Combined sources3
Helixi201 – 209Combined sources9
Beta strandi213 – 221Combined sources9
Beta strandi242 – 244Combined sources3
Turni245 – 247Combined sources3
Beta strandi257 – 262Combined sources6
Helixi265 – 268Combined sources4
Helixi282 – 285Combined sources4
Beta strandi291 – 296Combined sources6
Beta strandi299 – 301Combined sources3
Helixi302 – 306Combined sources5
Beta strandi311 – 313Combined sources3
Beta strandi315 – 318Combined sources4
Beta strandi321 – 324Combined sources4
Beta strandi330 – 332Combined sources3
Helixi335 – 346Combined sources12
Beta strandi347 – 349Combined sources3
Beta strandi350 – 353Combined sources4
Beta strandi356 – 370Combined sources15
Beta strandi373 – 389Combined sources17

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1KLANMR-A/B279-390[»]
1KLCNMR-A/B279-390[»]
1KLDNMR-A/B279-390[»]
3KFDX-ray3.00A/B/C/D279-390[»]
4KV5X-ray3.00A/B/C/D279-390[»]
5FFOX-ray3.49C/D/G/H34-390[»]
ProteinModelPortaliP01137.
SMRiP01137.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP01137.

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni30 – 74Straightjacket domainBy similarityAdd BLAST45
Regioni75 – 271Arm domainBy similarityAdd BLAST197

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi244 – 246Cell attachment siteSequence analysis3

Domaini

The 'straitjacket' and 'arm' domains encircle the growth factor monomers and are fastened together by strong bonding between Lys-56 and Tyr-103/Tyr-104. Activation of TGF-beta1 requires the binding of integrin alpha-V to an RGD sequence in the prodomain and exertion of force on this domain, which is held in the extracellular matrix by latent TGF-beta binding proteins. The sheer physical force unfastens the straitjacket and releases the active growth factor dimer (By similarity).By similarity

Sequence similaritiesi

Belongs to the TGF-beta family.Curated

Keywords - Domaini

Signal

Phylogenomic databases

eggNOGiKOG3900. Eukaryota.
ENOG410XT8Z. LUCA.
HOGENOMiHOG000290198.
HOVERGENiHBG074115.
InParanoidiP01137.
KOiK13375.
OrthoDBiEOG091G0BMM.
PhylomeDBiP01137.
TreeFamiTF318514.

Family and domain databases

Gene3Di2.10.90.10. 1 hit.
InterProiView protein in InterPro
IPR029034. Cystine-knot_cytokine.
IPR001839. TGF-b_C.
IPR001111. TGF-b_propeptide.
IPR016319. TGF-beta.
IPR015615. TGF-beta-rel.
IPR003939. TGFb1.
IPR017948. TGFb_CS.
PANTHERiPTHR11848. PTHR11848. 1 hit.
PfamiView protein in Pfam
PF00019. TGF_beta. 1 hit.
PF00688. TGFb_propeptide. 1 hit.
PIRSFiPIRSF001787. TGF-beta. 1 hit.
PRINTSiPR01423. TGFBETA.
PR01424. TGFBETA1.
SMARTiView protein in SMART
SM00204. TGFB. 1 hit.
SUPFAMiSSF57501. SSF57501. 1 hit.
PROSITEiView protein in PROSITE
PS00250. TGF_BETA_1. 1 hit.
PS51362. TGF_BETA_2. 1 hit.

Sequencei

Sequence statusi: Complete.

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

P01137-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MPPSGLRLLL LLLPLLWLLV LTPGRPAAGL STCKTIDMEL VKRKRIEAIR
60 70 80 90 100
GQILSKLRLA SPPSQGEVPP GPLPEAVLAL YNSTRDRVAG ESAEPEPEPE
110 120 130 140 150
ADYYAKEVTR VLMVETHNEI YDKFKQSTHS IYMFFNTSEL REAVPEPVLL
160 170 180 190 200
SRAELRLLRL KLKVEQHVEL YQKYSNNSWR YLSNRLLAPS DSPEWLSFDV
210 220 230 240 250
TGVVRQWLSR GGEIEGFRLS AHCSCDSRDN TLQVDINGFT TGRRGDLATI
260 270 280 290 300
HGMNRPFLLL MATPLERAQH LQSSRHRRAL DTNYCFSSTE KNCCVRQLYI
310 320 330 340 350
DFRKDLGWKW IHEPKGYHAN FCLGPCPYIW SLDTQYSKVL ALYNQHNPGA
360 370 380 390
SAAPCCVPQA LEPLPIVYYV GRKPKVEQLS NMIVRSCKCS
Length:390
Mass (Da):44,341
Last modified:February 1, 1991 - v2
Checksum:i75391614250288FE
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti159R → RR in CAA26580 (PubMed:3861940).Curated1

Polymorphismi

In post-menopausal Japanese women, the frequency of Leu-10 is higher in subjects with osteoporosis than in controls.1 Publication

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_01617110L → P Associated with higher bone mineral density and lower frequency of vertebral fractures in Japanese post-menopausal women. 3 PublicationsCorresponds to variant dbSNP:rs1800470Ensembl.1
Natural variantiVAR_01617225R → P1 PublicationCorresponds to variant dbSNP:rs1800471Ensembl.1
Natural variantiVAR_01760781Y → H in CAEND; leads to TGF-beta-1 intracellular accumulation. 2 Publications1
Natural variantiVAR_017608218R → C in CAEND; higher levels of active TGF-beta-1 in the culture medium; enhances osteoclast formation in vitro. 4 Publications1
Natural variantiVAR_017609218R → H in CAEND. 1 Publication1
Natural variantiVAR_017610222H → D in CAEND; sporadic case; higher levels of active TGF-beta-1 in the culture medium. 1 Publication1
Natural variantiVAR_067303223C → G in CAEND. 1 Publication1
Natural variantiVAR_067304223C → R in CAEND. 1 Publication1
Natural variantiVAR_017611225C → R in CAEND; higher levels of active TGF-beta-1 in the culture medium. 3 Publications1
Natural variantiVAR_016173263T → I. Corresponds to variant dbSNP:rs1800472Ensembl.1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X05839
, X05840, X05843, X05844, X05849, X05850 Genomic DNA. Translation: CAA29283.1.
X02812 mRNA. Translation: CAA26580.1.
BT007245 mRNA. Translation: AAP35909.1.
AK291907 mRNA. Translation: BAF84596.1.
CH471126 Genomic DNA. Translation: EAW57032.1.
BC001180 mRNA. Translation: AAH01180.1.
BC000125 mRNA. Translation: AAH00125.1.
BC022242 mRNA. Translation: AAH22242.1.
M38449 mRNA. Translation: AAA36735.1.
CCDSiCCDS33031.1.
PIRiA27513. WFHU2.
RefSeqiNP_000651.3. NM_000660.6.
UniGeneiHs.645227.

Genome annotation databases

EnsembliENST00000221930; ENSP00000221930; ENSG00000105329.
GeneIDi7040.
KEGGihsa:7040.
UCSCiuc002oqh.4. human.

Keywords - Coding sequence diversityi

Polymorphism

Similar proteinsi

Entry informationi

Entry nameiTGFB1_HUMAN
AccessioniPrimary (citable) accession number: P01137
Secondary accession number(s): A8K792, Q9UCG4
Entry historyiIntegrated into UniProtKB/Swiss-Prot: July 21, 1986
Last sequence update: February 1, 1991
Last modified: August 30, 2017
This is version 229 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. Human chromosome 19
    Human chromosome 19: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. SIMILARITY comments
    Index of protein domains and families