Alternative titles; symbols
HGNC Approved Gene Symbol: TGFBR3
Cytogenetic location: 1p22.1 Genomic coordinates (GRCh38): 1:91,680,343-91,906,002 (from NCBI)
Transforming growth factor (TGF)-beta is a multifunctional cytokine that modulates several tissue development and repair processes, including cell differentiation, cell cycle progression, cellular migration, adhesion, and extracellular matrix production. Three TGF-beta forms are encoded by separate genes: TGFB1 (190180), TGFB2 (190220), and TGFB3 (190230). The diverse effects of TGF-beta are mediated by the TGF-beta receptors and cell surface-binding proteins. Three TGF-beta receptors exist: type I (TGFBR1; 190181), type II (TFGBR2; 190182), and type III (TGFBR3). TGFBR3 is a glycoprotein that binds TGFB and exists in both a membrane-bound and a soluble form (Johnson et al., 1995).
Johnson et al. (1995) used PCR with a human/rodent somatic cell hybrid mapping panel and fluorescence in situ hybridization to localize the TGFBR3 gene to chromosome 1p33-p32.
Brown et al. (1999) noted that TGFBR3 lacks a recognizable signaling domain and has no clearly defined role in TGF-beta signaling. To investigate TGFBR3 function, Brown et al. (1999) studied cardiac endothelial cells in chick atrioventricular cushion explants. Endothelial cells undergoing epithelial-mesenchymal transformation expressed TGFBR3, and TGFBR3-specific antisera were found to inhibit mesenchyme formation and migration. Misexpression of TGFBR3 in nontransforming ventricular endothelial cells conferred transformation in response to TGFB2. These results supported a model where TGFBR3 localizes transformation in the heart and plays an essential, nonredundant role in TGF-beta signaling.
Lewis et al. (2000) demonstrated that the type III TGF-beta receptor, or beta-glycan, can function as an inhibin (see 147380) coreceptor with ActRII (102581). Beta-glycan binds inhibin with high affinity and enhances binding in cells coexpressing ActRII and beta-glycan. Inhibin also forms crosslinked complexes with both recombinant and endogenously expressed beta-glycan and ActRII. Lewis et al. (2000) demonstrated that beta-glycan confers inhibin sensitivity to cell lines that otherwise respond poorly to this hormone. The ability of beta-glycan to inhibit to facilitate inhibin antagonism of activin (see 147290) provided a variation on the emerging roles of proteoglycans as coreceptors modulating ligand-receptor sensitivity, selectivity, and function.
Chen et al. (2003) found that beta-arrestin-2 (107941) binds to TGFBR3. Binding of beta-arrestin-2 to TGFBR3 was also triggered by phosphorylation of the receptor on its cytoplasmic domain, likely at threonine-841. Chen et al. (2003) found that phosphorylation was mediated by TGFBR2, which is itself a kinase, rather than by a G protein-coupled receptor kinase. Association with beta-arrestin-2 led to internalization of both receptors and downregulation of TGF-beta signaling. Chen et al. (2003) concluded that the regulatory actions of beta-arrestins are broader than previously appreciated, extending to the TGF-beta receptor family as well.
By cDNA array and immunohistochemistry analyses, Dong et al. (2007) found that TGFBR3 expression was lost in most breast cancers examined in association with loss of heterozygosity of the TGFBR3 locus. TGFBR3 expression decreased during breast cancer progression, and low levels predicted decreased recurrence-free survival in patients. Restoration of TGFBR3 expression in breast cancer cells dramatically inhibited tumor invasiveness in vitro and in vivo. TGFBR3 appeared to inhibit tumor invasion by undergoing ectodomain shedding and producing soluble TGFBR3, which bound to and sequestered TGFB, thus decreasing TGFB signaling. Dong et al. (2007) concluded that loss of TGFBR3 through allelic imbalance is a frequent genetic event during breast cancer development that increases metastatic potential.
For discussion of a possible association between variation in the TGFBR3 gene and bone mineral density, see BMND14 (612728).
Brown, C. B., Boyer, A. S., Runyan, R. B., Barnett, J. V. Requirement of type III TGF-beta receptor for endocardial cell transformation in the heart. Science 283: 2080-2082, 1999. [PubMed: 10092230] [Full Text: https://doi.org/10.1126/science.283.5410.2080]
Chen, W., Kirkbride, K. C., How, T., Nelson, C. D., Mo, J., Frederick, J. P., Wang, X.-F., Lefkowitz, R. J., Blobe, G. C. Beta-arrestin 2 mediates endocytosis of type III TGF-beta receptor and down-regulation of its signaling. Science 301: 1394-1397, 2003. [PubMed: 12958365] [Full Text: https://doi.org/10.1126/science.1083195]
Dong, M., How, T., Kirkbride, K. C., Gordon, K. J., Lee, J. D., Hempel, N., Kelly, P., Moeller, B. J., Marks, J. R., Blobe, G. C. The type III TGF-beta receptor suppresses breast cancer progression. J. Clin. Invest. 117: 206-217, 2007. [PubMed: 17160136] [Full Text: https://doi.org/10.1172/JCI29293]
Johnson, D. W., Qumsiyeh, M., Benkhalifa, M., Marchuk, D. A. 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: 356-357, 1995. [PubMed: 8530052] [Full Text: https://doi.org/10.1006/geno.1995.1157]
Lewis, K. A., Gray, P. C., Blount, A. L., MacConell, L. A., Wiater, E., Bilezikjian, L. M., Vale, W. Betaglycan binds inhibin and can mediate functional antagonism of activin signalling. Nature 404: 411-414, 2000. [PubMed: 10746731] [Full Text: https://doi.org/10.1038/35006129]