TGFBR3 explained

Betaglycan also known as Transforming growth factor beta receptor III (TGFBR3), is a cell-surface chondroitin sulfate / heparan sulfate proteoglycan >300 kDa in molecular weight. Betaglycan binds to various members of the TGF-beta superfamily of ligands via its core protein, and bFGF via its heparan sulfate chains.^[1] TGFBR3 is the most widely expressed type of TGF-beta receptor. Its affinity towards all individual isoforms of TGF-beta is similarly high and therefore it plays an important role as a coreceptor mediating the binding of TGF-beta to its other receptors - specifically TGFBR2. The intrinsic kinase activity of this receptor has not yet been described. In regard of TGF-beta signalling it is generally considered a non-signaling receptor or a coreceptor.^{[2] [3]} By binding to various member of the TGF-beta superfamily at the cell surface it acts as a reservoir of TGF-beta.^[4]

Study of a mouse knock-out for the Tgfbr3 gene showed a fundamental effect on the correct development of organs and the overall viability of the animals used. Within the same study, no significant changes in Smad signalling (typical for TGF-beta cascade) were detected. This fact suggests that additional, as yet undescribed functions of betaglycan may be mediated by non-classical signalling pathways.^[2]

Domains and function

TGFBR3 is composed of an extracellular receptor domain consisting of 849 amino acids which is intracellularly connected to a short cytoplasmic domain. Betaglycan, being expressed by a whole range of various cell types within the organism, can be found in the form of a membrane-bound receptor, or as a soluble protein capable of interactions with the extracellular matrix (ECM).^{[2] [5]}

The formation of soluble betaglycan is mediated by metalloproteinases and other enzymes present in the ECM. Proteolytic cleavage releases an ectodomain containing two binding sites for TGF-beta. Due to high affinity to its ligand, free betaglycan is an important factor in the deposition and neutralization of this cytokine within the ECM. The ratio of membrane and soluble variant in the organism significantly affects the availability of TGF-beta and subsequent intracellular signalling.^[6]

The cytoplasmic domain mediates interactions with scaffold proteins inside the cell. These intracellular interactions do not affect the functionality of the ectodomain - nor its affinity to TGF-beta. However, they affect cell migration and the overall responsiveness of a given cell to the action of TGF-beta.^[7]

Re-release of the cytokine can occur due to the proteolytic activity of the pro-apoptotic serine protease - granzyme B.^[8] Plasmin - a serine protease present in the blood, activated as part of inflammatory reactions, then participates in the definitive degradation of betaglycan.

See also

• TGF beta receptors

Further reading

• Massagué J . Receptors for the TGF-beta family . Cell . 69 . 7 . 1067–70 . 1992 . 1319842 . 10.1016/0092-8674(92)90627-O . 54268875 .
• Border WA, Noble NA . Transforming growth factor beta in tissue fibrosis . N. Engl. J. Med. . 331 . 19 . 1286–92 . 1994 . 7935686 . 10.1056/NEJM199411103311907 .
• Morén A, Ichijo H, Miyazono K . Molecular cloning and characterization of the human and porcine transforming growth factor-beta type III receptors . Biochem. Biophys. Res. Commun. . 189 . 1 . 356–62 . 1992 . 1333192 . 10.1016/0006-291X(92)91566-9 .
• López-Casillas F, Cheifetz S, Doody J, etal . Structure and expression of the membrane proteoglycan betaglycan, a component of the TGF-beta receptor system . Cell . 67 . 4 . 785–95 . 1991 . 1657406 . 10.1016/0092-8674(91)90073-8 . 54304782 .
• Wang XF, Lin HY, Ng-Eaton E, etal . Expression cloning and characterization of the TGF-beta type III receptor . Cell . 67 . 4 . 797–805 . 1991 . 1657407 . 10.1016/0092-8674(91)90074-9 . 54258148 .
• Lin HY, Moustakas A, Knaus P, etal . The soluble exoplasmic domain of the type II transforming growth factor (TGF)-beta receptor. A heterogeneously glycosylated protein with high affinity and selectivity for TGF-beta ligands . J. Biol. Chem. . 270 . 6 . 2747–54 . 1995 . 7852346 . 10.1074/jbc.270.6.2747. free .
• López-Casillas F, Payne HM, Andres JL, Massagué J . Betaglycan can act as a dual modulator of TGF-beta access to signaling receptors: mapping of ligand binding and GAG attachment sites . J. Cell Biol. . 124 . 4 . 557–68 . 1994 . 8106553 . 10.1083/jcb.124.4.557 . 2119924 .
• Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides . Gene . 138 . 1–2 . 171–4 . 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .
• Johnson DW, Qumsiyeh M, Benkhalifa M, Marchuk DA . Assignment of human transforming growth factor-beta type I and type III receptor genes (TGFBR1 and TGFBR3) to 9q33-q34 and 1p32-p33, respectively . Genomics . 28 . 2 . 356–7 . 1996 . 8530052 . 10.1006/geno.1995.1157 .
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, etal . Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library . Gene . 200 . 1–2 . 149–56 . 1997 . 9373149 . 10.1016/S0378-1119(97)00411-3 .
• Brown CB, Boyer AS, Runyan RB, Barnett JV . Requirement of type III TGF-beta receptor for endocardial cell transformation in the heart . Science . 283 . 5410 . 2080–2 . 1999 . 10092230 . 10.1126/science.283.5410.2080 .
• Gao J, Symons AL, Bartold PM . Expression of transforming growth factor-beta receptors types II and III within various cells in the rat periodontium . Journal of Periodontal Research . 34 . 2 . 113–22 . 1999 . 10207840 . 10.1111/j.1600-0765.1999.tb02230.x .
• Lewis KA, Gray PC, Blount AL, etal . Betaglycan binds inhibin and can mediate functional antagonism of activin signalling . Nature . 404 . 6776 . 411–4 . 2000 . 10746731 . 10.1038/35006129 . 2000Natur.404..411L . 4393629 .
• Zippert R, Bässler A, Holmer SR, etal . Eleven single nucleotide polymorphisms and one triple nucleotide insertion of the human TGF-beta III receptor gene . J. Hum. Genet. . 45 . 4 . 250–3 . 2000 . 10944857 . 10.1007/s100380070035 . free .
• Rotzer D, Roth M, Lutz M, etal . Type III TGF-β receptor-independent signalling of TGF-β2 via TβRII-B, an alternatively spliced TGF-β type II receptor . EMBO J. . 20 . 3 . 480–90 . 2001 . 11157754 . 10.1093/emboj/20.3.480 . 133482 .
• Blobe GC, Schiemann WP, Pepin MC, etal . Functional roles for the cytoplasmic domain of the type III transforming growth factor beta receptor in regulating transforming growth factor beta signaling . J. Biol. Chem. . 276 . 27 . 24627–37 . 2001 . 11323414 . 10.1074/jbc.M100188200 . free .
• De Crescenzo G, Grothe S, Zwaagstra J, etal . Real-time monitoring of the interactions of transforming growth factor-beta (TGF-beta) isoforms with latency-associated protein and the ectodomains of the TGF-beta type II and III receptors reveals different kinetic models and stoichiometries of binding . J. Biol. Chem. . 276 . 32 . 29632–43 . 2001 . 11382746 . 10.1074/jbc.M009765200 . free .
• Blobe GC, Liu X, Fang SJ, etal . A novel mechanism for regulating transforming growth factor beta (TGF-beta) signaling. Functional modulation of type III TGF-beta receptor expression through interaction with the PDZ domain protein, GIPC . J. Biol. Chem. . 276 . 43 . 39608–17 . 2001 . 11546783 . 10.1074/jbc.M106831200 . free .

Notes and References

1. Andres JL, Stanley K, etal . 1989 . Membrane-anchored and soluble forms of betaglycan, a polymorphic proteoglycan that binds transforming growth factor-beta . J. Cell Biol. . 109 . 6 (Pt 1) . 3137–3145 . 10.1083/jcb.109.6.3137 . 2115961 . 2592419.
2. Vander Ark . Alexandra . Cao . Jingchen . Li . Xiaohong . 2018-12-01 . TGF-β receptors: In and beyond TGF-β signaling . Cellular Signalling . en . 52 . 112–120 . 10.1016/j.cellsig.2018.09.002 . 30184463 . 52164499 . 0898-6568. free .
3. Batlle . Eduard . Massagué . Joan . April 2019 . Transforming Growth Factor-β Signaling in Immunity and Cancer . Immunity . 50 . 4 . 924–940 . 10.1016/j.immuni.2019.03.024 . 1074-7613 . 7507121 . 30995507.
4. Andres JL, DeFalcis D, etal . Binding of two growth factor families to separate domains of the proteoglycan betaglycan . J. Biol. Chem. . 1992 . 267 . 9 . 5927–5930 . 10.1016/S0021-9258(18)42643-9 . 1556106. free .
5. Velasco-Loyden . Gabriela . Arribas . Joaquín . López-Casillas . Fernando . February 2004 . The Shedding of Betaglycan Is Regulated by Pervanadate and Mediated by Membrane Type Matrix Metalloprotease-1 . Journal of Biological Chemistry . 279 . 9 . 7721–7733 . 10.1074/jbc.m306499200 . 14672946 . 0021-9258. free .
6. Mendoza . Valentín . Vilchis-Landeros . M. Magdalena . Mendoza-Hernández . Guillermo . Huang . Tao . Villarreal . Maria M. . Hinck . Andrew P. . López-Casillas . Fernando . Montiel . Jose-Luis . 2009-12-15 . Betaglycan has Two Independent Domains Required for High Affinity TGF-β Binding: Proteolytic Cleavage Separates the Domains and Inactivates the Neutralizing Activity of the Soluble Receptor . Biochemistry . en . 48 . 49 . 11755–11765 . 10.1021/bi901528w . 0006-2960 . 2796082 . 19842711.
7. Chen . Yuhong . Di . Cuixia . Zhang . Xuetian . Wang . Jing . Wang . Fang . Yan . Jun‐fang . Xu . Caipeng . Zhang . Jinhua . Zhang . Qianjing . Li . Hongyan . Yang . Hongying . March 2020 . Transforming growth factor β signaling pathway: A promising therapeutic target for cancer . Journal of Cellular Physiology . en . 235 . 3 . 1903–1914 . 10.1002/jcp.29108 . 31332789 . 198172452 . 0021-9541.
8. Boivin . Wendy A. . Shackleford . Marlo . Hoek . Amanda Vanden . Zhao . Hongyan . Hackett . Tillie L. . Knight . Darryl A. . Granville . David J. . 2012-03-30 . Granzyme B Cleaves Decorin, Biglycan and Soluble Betaglycan, Releasing Active Transforming Growth Factor-β1 . PLOS ONE . en . 7 . 3 . e33163 . 10.1371/journal.pone.0033163 . 1932-6203 . 3316562 . 22479366. 2012PLoSO...733163B . free .