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]
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
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000069702 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000029287 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ Andres JL, Stanley K, Cheifetz S, Massagué J (December 1989). "Membrane-anchored and soluble forms of betaglycan, a polymorphic proteoglycan that binds transforming growth factor-beta". The Journal of Cell Biology. 109 (6 Pt 1): 3137–3145. doi:10.1083/jcb.109.6.3137. PMC 2115961. PMID 2592419.
- ^ a b Andres JL, DeFalcis D, Noda M, Massagué J (March 1992). "Binding of two growth factor families to separate domains of the proteoglycan betaglycan". The Journal of Biological Chemistry. 267 (9): 5927–5930. doi:10.1016/S0021-9258(18)42643-9. PMID 1556106.
- ^ a b c d Vander Ark A, Cao J, Li X (December 2018). "TGF-β receptors: In and beyond TGF-β signaling". Cellular Signalling. 52: 112–120. doi:10.1016/j.cellsig.2018.09.002. PMID 30184463. S2CID 52164499.
- ^ Batlle E, Massagué J (April 2019). "Transforming Growth Factor-β Signaling in Immunity and Cancer". Immunity. 50 (4): 924–940. doi:10.1016/j.immuni.2019.03.024. PMC 7507121. PMID 30995507.
- ^ a b Velasco-Loyden G, Arribas J, López-Casillas F (February 2004). "The shedding of betaglycan is regulated by pervanadate and mediated by membrane type matrix metalloprotease-1". The Journal of Biological Chemistry. 279 (9): 7721–7733. doi:10.1074/jbc.m306499200. PMID 14672946.
- ^ a b Mendoza V, Vilchis-Landeros MM, Mendoza-Hernández G, Huang T, Villarreal MM, Hinck AP, et al. (December 2009). "Betaglycan has two independent domains required for high affinity TGF-beta binding: proteolytic cleavage separates the domains and inactivates the neutralizing activity of the soluble receptor". Biochemistry. 48 (49): 11755–11765. doi:10.1021/bi901528w. PMC 2796082. PMID 19842711.
- ^ Chen Y, Di C, Zhang X, Wang J, Wang F, Yan JF, et al. (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. PMID 31332789. S2CID 198172452.
- ^ Boivin WA, Shackleford M, Vanden Hoek A, Zhao H, Hackett TL, Knight DA, et al. (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. PMC 3316562. PMID 22479366.
Further reading
- Massagué J (June 1992). "Receptors for the TGF-beta family". Cell. 69 (7): 1067–1070. doi:10.1016/0092-8674(92)90627-O. PMID 1319842. S2CID 54268875.
- Border WA, Noble NA (November 1994). "Transforming growth factor beta in tissue fibrosis". The New England Journal of Medicine. 331 (19): 1286–1292. doi:10.1056/NEJM199411103311907. PMID 7935686.
- Morén A, Ichijo H, Miyazono K (November 1992). "Molecular cloning and characterization of the human and porcine transforming growth factor-beta type III receptors". Biochemical and Biophysical Research Communications. 189 (1): 356–362. doi:10.1016/0006-291X(92)91566-9. PMID 1333192.
- López-Casillas F, Cheifetz S, Doody J, Andres JL, Lane WS, Massagué J (November 1991). "Structure and expression of the membrane proteoglycan betaglycan, a component of the TGF-beta receptor system". Cell. 67 (4): 785–795. doi:10.1016/0092-8674(91)90073-8. PMID 1657406. S2CID 54304782.
- Wang XF, Lin HY, Ng-Eaton E, Downward J, Lodish HF, Weinberg RA (November 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, Wells RG, Henis YI, Lodish HF (February 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". The Journal of Biological Chemistry. 270 (6): 2747–2754. doi:10.1074/jbc.270.6.2747. PMID 7852346.
- López-Casillas F, Payne HM, Andres JL, Massagué J (February 1994). "Betaglycan can act as a dual modulator of TGF-beta access to signaling receptors: mapping of ligand binding and GAG attachment sites". The Journal of Cell Biology. 124 (4): 557–568. doi:10.1083/jcb.124.4.557. PMC 2119924. PMID 8106553.
- Maruyama K, Sugano S (January 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–174. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
- Johnson DW, Qumsiyeh M, Benkhalifa M, Marchuk DA (July 1995). "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): 356–357. doi:10.1006/geno.1995.1157. PMID 8530052.
- Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (October 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–156. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
- Brown CB, Boyer AS, Runyan RB, Barnett JV (March 1999). "Requirement of type III TGF-beta receptor for endocardial cell transformation in the heart". Science. 283 (5410): 2080–2082. doi:10.1126/science.283.5410.2080. PMID 10092230.
- Gao J, Symons AL, Bartold PM (February 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): 113–122. doi:10.1111/j.1600-0765.1999.tb02230.x. PMID 10207840.
- Lewis KA, Gray PC, Blount AL, MacConell LA, Wiater E, Bilezikjian LM, et al. (March 2000). "Betaglycan binds inhibin and can mediate functional antagonism of activin signalling". Nature. 404 (6776): 411–414. Bibcode:2000Natur.404..411L. doi:10.1038/35006129. PMID 10746731. S2CID 4393629.
- Zippert R, Bässler A, Holmer SR, Hengstenberg C, Schunkert H (2000). "Eleven single nucleotide polymorphisms and one triple nucleotide insertion of the human TGF-beta III receptor gene". Journal of Human Genetics. 45 (4): 250–253. doi:10.1007/s100380070035. PMID 10944857.
- Rotzer D, Roth M, Lutz M, Lindemann D, Sebald W, Knaus P (February 2001). "Type III TGF-beta receptor-independent signalling of TGF-beta2 via TbetaRII-B, an alternatively spliced TGF-beta type II receptor". The EMBO Journal. 20 (3): 480–490. doi:10.1093/emboj/20.3.480. PMC 133482. PMID 11157754.
- Blobe GC, Schiemann WP, Pepin MC, Beauchemin M, Moustakas A, Lodish HF, et al. (July 2001). "Functional roles for the cytoplasmic domain of the type III transforming growth factor beta receptor in regulating transforming growth factor beta signaling". The Journal of Biological Chemistry. 276 (27): 24627–24637. doi:10.1074/jbc.M100188200. PMID 11323414.
- De Crescenzo G, Grothe S, Zwaagstra J, Tsang M, O'Connor-McCourt MD (August 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". The Journal of Biological Chemistry. 276 (32): 29632–29643. doi:10.1074/jbc.M009765200. PMID 11382746.
- Blobe GC, Liu X, Fang SJ, How T, Lodish HF (October 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". The Journal of Biological Chemistry. 276 (43): 39608–39617. doi:10.1074/jbc.M106831200. PMID 11546783.
External links
- betaglycan at the U.S. National Library of Medicine Medical Subject Headings (MeSH)