| Structural highlights
Function
TGFB1_MOUSE 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.[UniProtKB:P01137] 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).[UniProtKB:P01137][1] [2] 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 (By similarity) (PubMed:10025398). 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. Positively regulates odontoblastic differentiation in dental papilla cells, via promotion of IPO7-mediated translocation of phosphorylated SMAD2 to the nucleus and subsequent transcription of target genes (PubMed:33548622). Can induce epithelial-to-mesenchymal transition (EMT) and cell migration in various cell types (By similarity).[UniProtKB:P01137][3] [4] [5] [6] [7]
References
- ↑ Munger JS, Huang X, Kawakatsu H, Griffiths MJ, Dalton SL, Wu J, Pittet JF, Kaminski N, Garat C, Matthay MA, Rifkin DB, Sheppard D. The integrin alpha v beta 6 binds and activates latent TGF beta 1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell. 1999 Feb 5;96(3):319-28. PMID:10025398 doi:10.1016/s0092-8674(00)80545-0
- ↑ Qin Y, Garrison BS, Ma W, Wang R, Jiang A, Li J, Mistry M, Bronson RT, Santoro D, Franco C, Robinton DA, Stevens B, Rossi DJ, Lu C, Springer TA. A Milieu Molecule for TGF-β Required for Microglia Function in the Nervous System. Cell. 2018 Jun 28;174(1):156-171.e16. PMID:29909984 doi:10.1016/j.cell.2018.05.027
- ↑ Munger JS, Huang X, Kawakatsu H, Griffiths MJ, Dalton SL, Wu J, Pittet JF, Kaminski N, Garat C, Matthay MA, Rifkin DB, Sheppard D. The integrin alpha v beta 6 binds and activates latent TGF beta 1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell. 1999 Feb 5;96(3):319-28. PMID:10025398 doi:10.1016/s0092-8674(00)80545-0
- ↑ Zhou L, Lopes JE, Chong MM, Ivanov II, Min R, Victora GD, Shen Y, Du J, Rubtsov YP, Rudensky AY, Ziegler SF, Littman DR. TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature. 2008 May 8;453(7192):236-40. doi: 10.1038/nature06878. Epub 2008 Mar 26. PMID:18368049 doi:https://dx.doi.org/10.1038/nature06878
- ↑ Bruce DL, Macartney T, Yong W, Shou W, Sapkota GP. Protein phosphatase 5 modulates SMAD3 function in the transforming growth factor-β pathway. Cell Signal. 2012 Nov;24(11):1999-2006. PMID:22781750 doi:10.1016/j.cellsig.2012.07.003
- ↑ Qin Y, Garrison BS, Ma W, Wang R, Jiang A, Li J, Mistry M, Bronson RT, Santoro D, Franco C, Robinton DA, Stevens B, Rossi DJ, Lu C, Springer TA. A Milieu Molecule for TGF-β Required for Microglia Function in the Nervous System. Cell. 2018 Jun 28;174(1):156-171.e16. PMID:29909984 doi:10.1016/j.cell.2018.05.027
- ↑ Zhang Y, Zhang H, Yuan G, Yang G. Effects of transforming growth factor-β1 on odontoblastic differentiation in dental papilla cells is determined by IPO7 expression level. Biochem Biophys Res Commun. 2021 Mar 19;545:105-111. PMID:33548622 doi:10.1016/j.bbrc.2021.01.076
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