Disease relevance of TGFBR3

• Oncogenic Ki-ras confers a more aggressive colon cancer phenotype through modification of transforming growth factor-beta receptor III [1].
• Here we demonstrate that the type III TGF-beta receptor (TbetaRIII, or betaglycan), a ubiquitously expressed TGF-beta coreceptor, regulated breast cancer progression and metastasis [2].
• Treatment of ovarian cancer HEY cells with 500 nM 5alpha-dihydrotestosterone (DHT), but not estradiol-17beta or progesterone, for 60 h down-regulated the expression of mRNA for TGF-beta receptors I and II (TbetaR-I and TbetaR-II), betaglycan, and endoglin but had no effect on TGF-beta1 mRNA levels [3].
• Expression of betaglycan, an inhibin coreceptor, in normal human ovaries and ovarian sex cord-stromal tumors and its regulation in cultured human granulosa-luteal cells [4].
• Furthermore, betaglycan expression was detected in the vast majority of granulosa cell tumors, thecomas, and fibromas, with weaker staining in granulosa cell tumors compared with fibrothecomas [4].

High impact information on TGFBR3

• Betaglycan presents TGF beta directly to the kinase subunit of the signaling receptor, forming a high affinity ternary complex [5].
• The transmembrane region and the short cytoplasmic tail of betaglycan are very similar to these regions in human endoglin, an endothelial cell membrane glycoprotein involved in intercellular recognition [6].
• The unique features of betaglycan suggest important roles in cell interaction with TGF-beta [6].
• Finally, betaglycan confers inhibin sensitivity to cell lines that otherwise respond poorly to this hormone [7].
• Most human breast cancers lost TbetaRIII expression, with loss of heterozygosity of the TGFBR3 gene locus correlating with decreased TbetaRIII expression [2].

Chemical compound and disease context of TGFBR3

• TGF-beta antagonists, such as decorin, betaglycan, and possibly also heparin, might be potential candidates for future therapy to prevent diabetic vascular disease [8].

Biological context of TGFBR3

• We found 11 single nucleotide polymorphisms and one triple nucleotide insertion in the cDNA of the human transforming growth factor beta (TGF-beta) III receptor gene (TGFBR3) located on 1p33-p32, encoding beta-glycan, a component of the TGF-beta receptor system [9].
• The results suggest that release of betaglycan into the medium converts this enhancer of TGF-beta action into a TGF-beta antagonist [10].
• Endoglin, a dimeric membrane glycoprotein expressed at high levels on human vascular endothelial cells, shares regions of sequence identity with betaglycan, a major binding protein for transforming growth factor-beta (TGF-beta) that co-exists with TGF-beta receptors I and II in a variety of cell lines but is low or absent in endothelial cells [11].
• We now show that the betaglycan form of TbetaRIII is highly modified following translation when transiently expressed in Ki-ras(G12V) cells, whereas no such post-translational modification of TbetaRIII occurs in control cells [1].
• CONCLUSIONS: TGFBR3 downregulation is an important step in prostate tumorigenesis [12].

Anatomical context of TGFBR3

• A natural soluble form of betaglycan is found in serum and extracellular matrices [13].
• Furthermore, we knocked down TGFBR3 in prostate epithelial cells and analyzed the consequences of TGFBR3 knockdown [12].
• TGFBR3 knockdown led to focus formation and enhanced expression of CD133, a marker found on prostate cancer stem cells [12].
• Affinity labelling showed that the binding of TGF-beta to betaglycan and the type-I receptors in Mv 1 Lu cells and to endoglin in endothelial cells was reduced, but the binding to the type-II receptors was unaffected [14].
• Furthermore, it is a dynamic component of the TGF-beta receptor system in human chondrocytes, forming heteromeric complexes with the types I and II TGF-beta receptors, betaglycan and endoglin [15].

Associations of TGFBR3 with chemical compounds

• Their mutation to alanine prevents GAG attachment but does not interfere with betaglycan stability or ability to bind and present TGF-beta to receptor II [10].
• Using a panel of deletion mutants, we found that TGF-beta binds to the NH2-terminal endoglin-related region of betaglycan [10].
• Here we present evidence showing that in certain cell types, pervanadate, a general tyrosine phosphatase inhibitor, induces the release of the previously described fragment that encompasses almost the entire extracellular domain of betaglycan (sBG-120) [16].
• However, modulation of integrin and PECAM-1 levels and stimulation of mRNA levels for TGF-beta 1 and its receptors R-I, R-II, and betaglycan occurred normally in the endoglin transfectants [17].
• In cultured granulosa-luteal cells, FSH and LH treatment increased dose-dependently the accumulation of betaglycan mRNA, as did the protein kinase A activator dibutyryl cAMP and the protein kinase C inhibitor staurosporine [4].

Physical interactions of TGFBR3

• Betaglycan is a membrane-anchored proteoglycan that binds transforming growth factor-beta (TGF-beta) via its core protein [16].
• On the other hand, we found that the recently described ability of the wild type betaglycan to bind inhibin A is a property of the core protein that resides in the uromodulin-related region [18].
• Collectively, these data show that the inhibin isoforms have different affinities for the activin type II receptors but bind betaglycan with high affinity [19].
• Betaglycan also enables inhibin to bind to and compete with BMPs for binding to the BMP-specific type II receptor BMPRII, which does not bind inhibin in the absence of betaglycan [20].

Regulatory relationships of TGFBR3

• Specific cleavage of betaglycan represents a novel mechanism whereby plasmin may regulate the assortment of receptors available for TGF-beta [21].
• Transforming growth factor-beta-1 latency-associated peptide and soluble betaglycan prevent a glucose-induced increase in fibronectin production in cultured human mesangial cells [22].

Other interactions of TGFBR3

• Because the membrane and soluble forms of betaglycan have opposite effects regulating the availability of TGF-beta, it is important to characterize the shedding of betaglycan further [16].
• Assignment of human transforming growth factor-beta type I and type III receptor genes (TGFBR1 and TGFBR3) to 9q33-q34 and 1p32-p33, respectively [23].
• Unexpectedly, during the course of these experiments, we observed that MT2-MMP decreases the levels of MT1-MMP and betaglycan [16].
• The 38-kDa TGF-beta binding component, an N-linked glycoprotein, exhibits a higher affinity for TGF-beta 2 than for -beta 1 that is strikingly similar to that of the type III/betaglycan receptor [24].
• Together with betaglycan, CD105 is considered as a TGF-betaR accessory molecule (also called TGF-betaRIII), but its functions in the receptor-ligand interactions are still poorly understood [25].

Analytical, diagnostic and therapeutic context of TGFBR3

• End-terminal sequence analysis of the soluble betaglycan showed that Gly(24) is the first residue of the mature protein [13].
• DNA microarray analysis of TGFBR3 knockdown cells identified 101 genes regulated by TGFBR3 [12].
• METHODS: We have conducted a systematic analysis of TGF-beta pathway components with a meta-analysis of seven microarray studies using Oncomine and evaluated the results of TGFBR3 expression in prostate cell lines [12].
• Antitumor activity of a recombinant soluble betaglycan in human breast cancer xenograft [26].
• To monitor the expression of betaglycan in HSC, we used the commercially available antibody sc-6199 in Western blot analysis [27].

References