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
AliasesTGFBR3, BGCAN, betaglycan, transforming growth factor beta receptor 3
External IDsOMIM: 600742 MGI: 104637 HomoloGene: 2436 GeneCards: TGFBR3
Orthologs
SpeciesHumanMouse
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 MbChr 5: 107.25 – 107.44 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/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

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

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