TGFBR3

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.^[5][6] 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.^[7][8] By binding to various member of the TGF-beta superfamily at the cell surface it acts as a reservoir of TGF-beta.^[6]

TGFBR3
Identifiers
Aliases	TGFBR3, BGCAN, betaglycan, transforming growth factor beta receptor 3
External IDs	OMIM: 600742; MGI: 104637; HomoloGene: 2436; GeneCards: TGFBR3; OMA:TGFBR3 - orthologs
Gene location (Human) Chr. Chromosome 1 (human)[1] Band 1p22.1 Start 91,680,343 bp[1] End 91,906,335 bp[1]
Gene location (Mouse) Chr. Chromosome 5 (mouse)[2] Band 5|5 E5 Start 107,254,436 bp[2] End 107,437,495 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in glomerulus metanephric glomerulus synovial joint Achilles tendon lactiferous duct tibia seminal vesicula tendon of biceps brachii nipple urethra Top expressed in ciliary body vestibular membrane of cochlear duct Epithelium of choroid plexus iris stroma of bone marrow gastrula conjunctival fornix retinal pigment epithelium carotid body decidua More reference expression data BioGPS More reference expression data
Gene ontology Molecular function transforming growth factor beta receptor binding heparin binding activin binding transforming growth factor beta receptor activity, type III transforming growth factor beta-activated receptor activity SMAD binding PDZ domain binding coreceptor activity fibroblast growth factor binding type II transforming growth factor beta receptor binding protein binding glycosaminoglycan binding transforming growth factor beta binding Cellular component extracellular exosome extracellular region cytoplasm integral component of membrane inhibin-betaglycan-ActRII complex integral component of plasma membrane membrane cell surface receptor complex plasma membrane external side of plasma membrane extracellular space extracellular matrix Biological process response to hypoxia heart trabecula formation intracellular signal transduction liver development animal organ regeneration definitive erythrocyte differentiation BMP signaling pathway positive regulation of transforming growth factor beta receptor signaling pathway regulation of protein binding heart morphogenesis transforming growth factor beta receptor complex assembly cardiac epithelial to mesenchymal transition pathway-restricted SMAD protein phosphorylation response to follicle-stimulating hormone ventricular cardiac muscle tissue morphogenesis roof of mouth development cardiac muscle cell proliferation response to prostaglandin E negative regulation of transforming growth factor beta receptor signaling pathway negative regulation of epithelial cell proliferation cell migration definitive hemopoiesis epithelial to mesenchymal transition response to luteinizing hormone immune response transforming growth factor beta receptor signaling pathway epicardium-derived cardiac fibroblast cell development ventricular septum morphogenesis regulation of ERK1 and ERK2 cascade ventricular compact myocardium morphogenesis heart trabecula morphogenesis positive regulation of cardiac muscle cell proliferation regulation of JNK cascade muscular septum morphogenesis vasculogenesis involved in coronary vascular morphogenesis outflow tract morphogenesis secondary palate development protein-containing complex assembly Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 7049 21814 Ensembl ENSG00000069702 ENSMUSG00000029287 UniProt Q03167 O88393 RefSeq (mRNA) NM_001195683 NM_001195684 NM_003243 NM_011578 RefSeq (protein) NP_001182612 NP_001182613 NP_003234 NP_035708 Location (UCSC) Chr 1: 91.68 – 91.91 Mb Chr 5: 107.25 – 107.44 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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.^[7]

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).^[7][9]

The formation of soluble betaglycan is mediated by metalloproteinases and other enzymes present in the ECM.^[9] 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.^[10]

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][11]

Re-release of the cytokine can occur due to the proteolytic activity of the pro-apoptotic serine protease - granzyme B.^[12] Plasmin - a serine protease present in the blood, activated as part of inflammatory reactions, then participates in the definitive degradation of betaglycan.^[10]

See also

• TGF beta receptors

References

1. GRCh38: Ensembl release 89: ENSG00000069702 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000029287 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Andres JL, Stanley K, et al. (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. doi:10.1083/jcb.109.6.3137. PMC 2115961. PMID 2592419.
6. Andres JL, DeFalcis D, et al. (1992). "Binding of two growth factor families to separate domains of the proteoglycan betaglycan". J. Biol. Chem. 267 (9): 5927–5930. doi:10.1016/S0021-9258(18)42643-9. PMID 1556106.
7. Vander Ark, Alexandra; Cao, Jingchen; Li, Xiaohong (2018-12-01). "TGF-β receptors: In and beyond TGF-β signaling". Cellular Signalling. 52: 112–120. doi:10.1016/j.cellsig.2018.09.002. ISSN 0898-6568. PMID 30184463. S2CID 52164499.
8. Batlle, Eduard; Massagué, Joan (April 2019). "Transforming Growth Factor-β Signaling in Immunity and Cancer". Immunity. 50 (4): 924–940. doi:10.1016/j.immuni.2019.03.024. ISSN 1074-7613. PMC 7507121. PMID 30995507.
9. 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. doi:10.1074/jbc.m306499200. ISSN 0021-9258. PMID 14672946.
10. 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. 48 (49): 11755–11765. doi:10.1021/bi901528w. ISSN 0006-2960. PMC 2796082. PMID 19842711.
11. 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. 235 (3): 1903–1914. doi:10.1002/jcp.29108. ISSN 0021-9541. PMID 31332789. S2CID 198172452.
12. 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. 7 (3): e33163. Bibcode:2012PLoSO...733163B. doi:10.1371/journal.pone.0033163. ISSN 1932-6203. PMC 3316562. PMID 22479366.

Further reading

• Massagué J (1992). "Receptors for the TGF-beta family". Cell. 69 (7): 1067–70. doi:10.1016/0092-8674(92)90627-O. PMID 1319842. S2CID 54268875.
• Border WA, Noble NA (1994). "Transforming growth factor beta in tissue fibrosis". N. Engl. J. Med. 331 (19): 1286–92. doi:10.1056/NEJM199411103311907. PMID 7935686.
• Morén A, Ichijo H, Miyazono K (1992). "Molecular cloning and characterization of the human and porcine transforming growth factor-beta type III receptors". Biochem. Biophys. Res. Commun. 189 (1): 356–62. doi:10.1016/0006-291X(92)91566-9. PMID 1333192.
• López-Casillas F, Cheifetz S, Doody J, et al. (1991). "Structure and expression of the membrane proteoglycan betaglycan, a component of the TGF-beta receptor system". Cell. 67 (4): 785–95. doi:10.1016/0092-8674(91)90073-8. PMID 1657406. S2CID 54304782.
• Wang XF, Lin HY, Ng-Eaton E, et al. (1991). "Expression cloning and characterization of the TGF-beta type III receptor". Cell. 67 (4): 797–805. doi:10.1016/0092-8674(91)90074-9. PMID 1657407. S2CID 54258148.
• Lin HY, Moustakas A, Knaus P, et al. (1995). "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. doi:10.1074/jbc.270.6.2747. PMID 7852346.
• López-Casillas F, Payne HM, Andres JL, Massagué J (1994). "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. doi:10.1083/jcb.124.4.557. PMC 2119924. PMID 8106553.
• Maruyama K, Sugano S (1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
• Johnson DW, Qumsiyeh M, Benkhalifa M, Marchuk DA (1996). "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. doi:10.1006/geno.1995.1157. PMID 8530052.
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, et al. (1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
• Brown CB, Boyer AS, Runyan RB, Barnett JV (1999). "Requirement of type III TGF-beta receptor for endocardial cell transformation in the heart". Science. 283 (5410): 2080–2. doi:10.1126/science.283.5410.2080. PMID 10092230.
• Gao J, Symons AL, Bartold PM (1999). "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. doi:10.1111/j.1600-0765.1999.tb02230.x. PMID 10207840.
• Lewis KA, Gray PC, Blount AL, et al. (2000). "Betaglycan binds inhibin and can mediate functional antagonism of activin signalling". Nature. 404 (6776): 411–4. Bibcode:2000Natur.404..411L. doi:10.1038/35006129. PMID 10746731. S2CID 4393629.
• Zippert R, Bässler A, Holmer SR, et al. (2000). "Eleven single nucleotide polymorphisms and one triple nucleotide insertion of the human TGF-beta III receptor gene". J. Hum. Genet. 45 (4): 250–3. doi:10.1007/s100380070035. PMID 10944857.
• Rotzer D, Roth M, Lutz M, et al. (2001). "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. doi:10.1093/emboj/20.3.480. PMC 133482. PMID 11157754.
• Blobe GC, Schiemann WP, Pepin MC, et al. (2001). "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. doi:10.1074/jbc.M100188200. PMID 11323414.
• De Crescenzo G, Grothe S, Zwaagstra J, et al. (2001). "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. doi:10.1074/jbc.M009765200. PMID 11382746.
• Blobe GC, Liu X, Fang SJ, et al. (2001). "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. doi:10.1074/jbc.M106831200. PMID 11546783.

External links

• betaglycan at the U.S. National Library of Medicine Medical Subject Headings (MeSH)