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Protein

Transforming growth factor beta-1 proprotein

Gene

Tgfb1

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Transforming growth factor beta-1 proprotein: Precursor of the Latency-associated peptide (LAP) and Transforming growth factor beta-1 (TGF-beta-1) chains, which constitute the regulatory and active subunit of TGF-beta-1, respectively.By similarity
Latency-associated peptide: Required to maintain the Transforming growth factor beta-1 (TGF-beta-1) chain in a latent state during storage in extracellular matrix (PubMed:29909984). Associates non-covalently with TGF-beta-1 and regulates its activation via interaction with 'milieu molecules', such as LTBP1, LRRC32/GARP and LRRC33/NRROS, that control activation of TGF-beta-1 (PubMed:29909984). Interaction with LRRC33/NRROS regulates activation of TGF-beta-1 in macrophages and microglia (PubMed:29909984). Interaction with LRRC32/GARP controls activation of TGF-beta-1 on the surface of activated regulatory T-cells (Tregs) (By similarity). Interaction with integrins (ITGAV:ITGB6 or ITGAV:ITGB8) results in distortion of the Latency-associated peptide chain and subsequent release of the active TGF-beta-1 (PubMed:10025398).By similarity2 Publications
Transforming growth factor beta-1: Multifunctional protein that regulates the growth and differentiation of various cell types and is involved in various processes, such as normal development, immune function, microglia function and responses to neurodegeneration (PubMed:22781750, PubMed:29909984). Activation into mature form follows different steps: following cleavage of the proprotein in the Golgi apparatus, Latency-associated peptide (LAP) and Transforming growth factor beta-1 (TGF-beta-1) chains remain non-covalently linked rendering TGF-beta-1 inactive during storage in extracellular matrix (By similarity). At the same time, LAP chain interacts with 'milieu molecules', such as LTBP1, LRRC32/GARP and LRRC33/NRROS that control activation of TGF-beta-1 and maintain it in a latent state during storage in extracellular milieus (PubMed:29909984). TGF-beta-1 is released from LAP by integrins (ITGAV:ITGB6 or ITGAV:ITGB8): integrin-binding to LAP stabilizes an alternative conformation of the LAP bowtie tail and results in distortion of the LAP chain and subsequent release of the active TGF-beta-1 (PubMed:10025398) (By similarity). Once activated following release of LAP, TGF-beta-1 acts by binding to TGF-beta receptors (TGFBR1 and TGFBR2), which transduce signal (By similarity). While expressed by many cells types, TGF-beta-1 only has a very localized range of action within cell environment thanks to fine regulation of its activation by Latency-associated peptide chain (LAP) and 'milieu molecules' (PubMed:29909984). Plays an important role in bone remodeling: acts as a potent stimulator of osteoblastic bone formation, causing chemotaxis, proliferation and differentiation in committed osteoblasts (PubMed:22781750). Can promote either T-helper 17 cells (Th17) or regulatory T-cells (Treg) lineage differentiation in a concentration-dependent manner (PubMed:18368049). At high concentrations, leads to FOXP3-mediated suppression of RORC and down-regulation of IL-17 expression, favoring Treg cell development (PubMed:18368049). 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 (PubMed:18368049). Stimulates sustained production of collagen through the activation of CREB3L1 by regulated intramembrane proteolysis (RIP) (By similarity). Mediates SMAD2/3 activation by inducing its phosphorylation and subsequent translocation to the nucleus. Can induce epithelial-to-mesenchymal transition (EMT) and cell migration in various cell types (By similarity).By similarity4 Publications

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionGrowth factor, Mitogen

Enzyme and pathway databases

ReactomeiR-MMU-114608 Platelet degranulation
R-MMU-202733 Cell surface interactions at the vascular wall
R-MMU-2129379 Molecules associated with elastic fibres
R-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-3000170 Syndecan interactions
R-MMU-8941855 RUNX3 regulates CDKN1A transcription
R-MMU-8941858 Regulation of RUNX3 expression and activity
R-MMU-8951936 RUNX3 regulates p14-ARF

Names & Taxonomyi

Protein namesi
Recommended name:
Transforming growth factor beta-1 proprotein
Cleaved into the following 2 chains:
Latency-associated peptideBy similarity
Short name:
LAP
Transforming growth factor beta-1By similarity
Short name:
TGF-beta-1
Gene namesi
Name:Tgfb1Imported
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 7

Organism-specific databases

MGIiMGI:98725 Tgfb1

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

Keywords - Cellular componenti

Extracellular matrix, Secreted

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 29By similarityAdd BLAST29
ChainiPRO_000003376630 – 278Latency-associated peptideBy similarityAdd BLAST249
ChainiPRO_0000033767279 – 390Transforming growth factor beta-1By similarityAdd 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...) asparagineSequence analysis1
Glycosylationi136N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi176N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi223Interchain (with C-225)By similarity
Disulfide bondi225Interchain (with C-223)By similarity
Disulfide bondi285 ↔ 294By similarity
Disulfide bondi293 ↔ 356By similarity
Disulfide bondi322 ↔ 387By similarity
Disulfide bondi326 ↔ 389By similarity
Disulfide bondi355InterchainBy similarity

Post-translational modificationi

Transforming growth factor beta-1 proprotein: The precursor proprotein is cleaved in the Golgi apparatus by FURIN to form Transforming growth factor beta-1 (TGF-beta-1) and Latency-associated peptide (LAP) chains, which remain non-covalently linked, rendering TGF-beta-1 inactive.By similarity
Latency-associated peptide: N-glycosylated. Deglycosylation leads to activation of Transforming growth factor beta-1 (TGF-beta-1); mechanisms triggering deglycosylation-driven activation of TGF-beta-1 are however unclear.By similarity

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei278 – 279Cleavage; by FURINBy similarity2

Keywords - PTMi

Cleavage on pair of basic residues, Disulfide bond, Glycoprotein

Proteomic databases

EPDiP04202
PaxDbiP04202
PeptideAtlasiP04202
PRIDEiP04202

PTM databases

iPTMnetiP04202
PhosphoSitePlusiP04202

Miscellaneous databases

PMAP-CutDBiP04202

Expressioni

Gene expression databases

BgeeiENSMUSG00000002603 Expressed in 223 organ(s), highest expression level in bone marrow
CleanExiMM_TGFB1
ExpressionAtlasiP04202 baseline and differential
GenevisibleiP04202 MM

Interactioni

Subunit structurei

Homodimer; disulfide-linked (By similarity). 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 (PubMed:14973287, PubMed:15206957). May interact with THSD4; this interaction may lead to sequestration by FBN1 microfibril assembly and attenuation of TGFB signaling (PubMed:21880733). Interacts with CD109, DPT and ASPN. Latency-associated peptide: Homodimer; disulfide-linked (By similarity). Latency-associated peptide: Interacts with Transforming growth factor beta-1 (TGF-beta-1) chain; interaction is non-covalent and maintains (TGF-beta-1) in a latent state; each Latency-associated peptide (LAP) monomer interacts with TGF-beta-1 in the other monomer (By similarity). Latency-associated peptide: Interacts with LTBP1; leading to regulate activation of TGF-beta-1 (By similarity). Latency-associated peptide: Interacts with LRRC32/GARP; leading to regulate activation of TGF-beta-1 on the surface of activated regulatory T-cells (Tregs) (By similarity). Latency-associated peptide: Interacts with LRRC33/NRROS; leading to regulate activation of TGF-beta-1 in macrophages and microglia (PubMed:29909984). Latency-associated peptide: Interacts (via cell attachment site) with integrins ITGAV and ITGB6 (ITGAV:ITGB6), leading to release of the active TGF-beta-1 (PubMed:10025398). Latency-associated peptide: Interacts with NREP; the interaction results in a decrease in TGFB1 autoinduction (PubMed:14985127). Latency-associated peptide: Interacts with HSP90AB1; inhibits latent TGFB1 activation. Transforming growth factor beta-1: Homodimer; disulfide-linked. Transforming growth factor beta-1: Interacts with TGF-beta receptors (TGFBR1 and TGFBR2), leading to signal transduction (By similarity).By similarity6 Publications

GO - Molecular functioni

Protein-protein interaction databases

BioGridi204157, 4 interactors
ComplexPortaliCPX-821 TGF-beta-1 complex
CPX-823 TGF-beta-1-TGFR complex
DIPiDIP-48640N
IntActiP04202, 1 interactor
STRINGi10090.ENSMUSP00000002678

Structurei

3D structure databases

ProteinModelPortaliP04202
SMRiP04202
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni30 – 74Straightjacket domainBy similarityAdd BLAST45
Regioni75 – 271Arm domainBy similarityAdd BLAST197
Regioni226 – 252Bowtie tailBy similarityAdd BLAST27

Motif

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

Domaini

Latency-associated peptide: The 'straitjacket' and 'arm' domains encircle the Transforming growth factor beta-1 (TGF-beta-1) monomers and are fastened together by strong bonding between Lys-56 and Tyr-103/Tyr-104.By similarity
Latency-associated peptide: The cell attachment site motif mediates binding to integrins (ITGAV:ITGB6 or ITGAV:ITGB8). The motif locates to a long loop in the arm domain called the bowtie tail. Integrin-binding stabilizes an alternative conformation of the bowtie tail. Activation by integrin requires force application by the actin cytoskeleton, which is resisted by the 'milieu molecules' (such as LTBP1, LRRC32/GARP and/or LRRC33/NRROS), resulting in distortion of the prodomain and release of the active TGF-beta-1.By similarity

Sequence similaritiesi

Belongs to the TGF-beta family.Curated

Keywords - Domaini

Signal

Phylogenomic databases

eggNOGiKOG3900 Eukaryota
ENOG410XT8Z LUCA
GeneTreeiENSGT00910000143982
HOGENOMiHOG000290198
HOVERGENiHBG074115
InParanoidiP04202
KOiK13375
OMAiFSAHCSC
OrthoDBiEOG091G0BMM
PhylomeDBiP04202
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

Sequence (1+)i

Sequence statusi: Complete.

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

This entry has 1 described isoform and 1 potential isoform that is computationally mapped.Show allAlign All

P04202-1 [UniParc]FASTAAdd to basket
« Hide
        10         20         30         40         50
MPPSGLRLLP LLLPLPWLLV LTPGRPAAGL STCKTIDMEL VKRKRIEAIR
60 70 80 90 100
GQILSKLRLA SPPSQGEVPP GPLPEAVLAL YNSTRDRVAG ESADPEPEPE
110 120 130 140 150
ADYYAKEVTR VLMVDRNNAI YEKTKDISHS IYMFFNTSDI REAVPEPPLL
160 170 180 190 200
SRAELRLQRL KSSVEQHVEL YQKYSNNSWR YLGNRLLTPT DTPEWLSFDV
210 220 230 240 250
TGVVRQWLNQ GDGIQGFRFS AHCSCDSKDN KLHVEINGIS PKRRGDLGTI
260 270 280 290 300
HDMNRPFLLL MATPLERAQH LHSSRHRRAL DTNYCFSSTE KNCCVRQLYI
310 320 330 340 350
DFRKDLGWKW IHEPKGYHAN FCLGPCPYIW SLDTQYSKVL ALYNQHNPGA
360 370 380 390
SASPCCVPQA LEPLPIVYYV GRKPKVEQLS NMIVRSCKCS
Length:390
Mass (Da):44,310
Last modified:March 20, 1987 - v1
Checksum:i4381A51B711D689E
GO

Computationally mapped potential isoform sequencesi

There is 1 potential isoform mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
E9Q6I6E9Q6I6_MOUSE
Transforming growth factor beta-1 p...
Tgfb1
49Annotation score:

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M13177 mRNA Translation: AAA40423.1
L42462
, L42456, L42457, L42458, L42459, L42460, L42461 Genomic DNA Translation: AAB00138.1
AJ009862 mRNA Translation: CAA08900.1
BC013738 mRNA Translation: AAH13738.1
CCDSiCCDS20993.1
PIRiA01396 WFMS2
RefSeqiNP_035707.1, NM_011577.2
UniGeneiMm.248380

Genome annotation databases

EnsembliENSMUST00000002678; ENSMUSP00000002678; ENSMUSG00000002603
GeneIDi21803
KEGGimmu:21803
UCSCiuc009ftq.1 mouse

Similar proteinsi

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M13177 mRNA Translation: AAA40423.1
L42462
, L42456, L42457, L42458, L42459, L42460, L42461 Genomic DNA Translation: AAB00138.1
AJ009862 mRNA Translation: CAA08900.1
BC013738 mRNA Translation: AAH13738.1
CCDSiCCDS20993.1
PIRiA01396 WFMS2
RefSeqiNP_035707.1, NM_011577.2
UniGeneiMm.248380

3D structure databases

ProteinModelPortaliP04202
SMRiP04202
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi204157, 4 interactors
ComplexPortaliCPX-821 TGF-beta-1 complex
CPX-823 TGF-beta-1-TGFR complex
DIPiDIP-48640N
IntActiP04202, 1 interactor
STRINGi10090.ENSMUSP00000002678

PTM databases

iPTMnetiP04202
PhosphoSitePlusiP04202

Proteomic databases

EPDiP04202
PaxDbiP04202
PeptideAtlasiP04202
PRIDEiP04202

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000002678; ENSMUSP00000002678; ENSMUSG00000002603
GeneIDi21803
KEGGimmu:21803
UCSCiuc009ftq.1 mouse

Organism-specific databases

CTDi7040
MGIiMGI:98725 Tgfb1

Phylogenomic databases

eggNOGiKOG3900 Eukaryota
ENOG410XT8Z LUCA
GeneTreeiENSGT00910000143982
HOGENOMiHOG000290198
HOVERGENiHBG074115
InParanoidiP04202
KOiK13375
OMAiFSAHCSC
OrthoDBiEOG091G0BMM
PhylomeDBiP04202
TreeFamiTF318514

Enzyme and pathway databases

ReactomeiR-MMU-114608 Platelet degranulation
R-MMU-202733 Cell surface interactions at the vascular wall
R-MMU-2129379 Molecules associated with elastic fibres
R-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-3000170 Syndecan interactions
R-MMU-8941855 RUNX3 regulates CDKN1A transcription
R-MMU-8941858 Regulation of RUNX3 expression and activity
R-MMU-8951936 RUNX3 regulates p14-ARF

Miscellaneous databases

PMAP-CutDBiP04202
PROiPR:P04202
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000002603 Expressed in 223 organ(s), highest expression level in bone marrow
CleanExiMM_TGFB1
ExpressionAtlasiP04202 baseline and differential
GenevisibleiP04202 MM

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
ProtoNetiSearch...

Entry informationi

Entry nameiTGFB1_MOUSE
AccessioniPrimary (citable) accession number: P04202
Entry historyiIntegrated into UniProtKB/Swiss-Prot: March 20, 1987
Last sequence update: March 20, 1987
Last modified: November 7, 2018
This is version 205 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
  2. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
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