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PubMed1976

Microbial transformation of antibiotics II. Additional transformation products of maridomycin III.

Streptomyces sp. strain No. K-245 was found to transform maridomycin III into four derivatives (A1, A2, A3 and A4) in addition to the transformation products reported previously. Isolation of the main product A1 was carried out by column chromatography on silica gel developed with CHCl3-MeOH (19:1). From the partial investigation of the structure of A1, it proved to have a C-18-aldehyde group and C 4''-propionyl group but no antimicrobial activity. The relationships between A group's derivatives and known derivatives of maridomycin III are also discussed.

Anti-Bacterial Agents↗

PubMed2005

Conversations with young people in rural and remote places: transforming the emerging self (ANZAP 16th Annual Conference "Trauma and the Transformational Conversation").

This paper describes the laying of a foundation for transformation of the inner world and the emergence of "self" in young people using the Conversational Model. The author works with young people in a technical college in a remote part of Victoria Australia. Some of the clients have experienced extreme trauma as children and live in an ongoing state of traumatic stress. The young clients are deep thinkers and intelligent, yet trapped by dysfunctional family settings. Their situations are compounded by the remote and rural location of their community. The conversational process promotes the gradual transformation of their inner world and the emergence of a healthier "self."

Adolescent↗

PubMed1989

[Mechanical properties and phase transformation of super-elastic Ni-Ti alloy wires. Part 1: Relation between super-elasticity and phase transformation].

The relationship between mechanical properties and thermal behavior of super-elastic Ni-Ti alloy orthodontic wires was investigated in order to use them effectively in clinics. Three types of super-elastic Ni-Ti alloy orthodontic wires, SENTALLOY-BLUE(SB), YELLOW(SY) and RED(SR), were used. Two parameters were introduced from the load-deflection curves in three point bending test to evaluate their mechanical properties. One was the super-elastic index (SEI) for super-elasticity, and the other was the E-load for the load in the super-elastic region. Their thermal behavior in the course of the transformation analyzed with DSC, and compared with the mechanical properties. The specimens heat-treated at 500 degrees C for 30 min were also examined. The differences in mechanical properties of the super-elastic Ni-Ti alloy orthodontic wires used in this study were thought to be more affected by the height of the thermic peak and the form of the DSC curves than the transformation temperature. The higher the thermic peak, the higher tended to be the SEI and the lower E-load. To the contrary, the lower thermic peak, the higher was the E-load and the lower was the SEI, and the continuous force could not be achieved. The remaining work-hardened structure was thought to influence these differences.

Dental Alloys↗

PubMed2001

Blockade of endogenous transforming growth factor beta signaling prevents up-regulated collagen synthesis in scleroderma fibroblasts: association with increased expression of transforming growth factor beta receptors.

OBJECTIVE: To elucidate the role of transforming growth factor beta (TGFbeta) in the increased expression of the collagen gene in scleroderma fibroblasts. METHODS: Dermal fibroblasts from 10 patients with diffuse systemic sclerosis (SSc) of recent onset and from 10 healthy individuals were studied. The production of active and total (active + latent) TGFbeta1 levels from cultured dermal fibroblasts was measured using a TGFbeta1 enzyme-linked immunosorbent assay system. Expression of the TGFbeta type I and type II receptor proteins in dermal fibroblasts was determined by immunoblotting, and the level of expression of human alpha2(I) collagen messenger RNA (mRNA) was evaluated by Northern blot analysis. The transcriptional activity of the human alpha2(I) collagen gene was examined with chloramphenicol acetyltransferase (CAT) assays using the -772 COL1A2/CAT construct. RESULTS: SSc fibroblasts expressed increased levels of TGFbeta type I and type II receptors but secreted amounts of TGFbeta similar to those secreted by normal fibroblasts. The blockade of TGFbeta signaling with anti-TGFbeta antibodies or a TGFbeta1 antisense oligonucleotide abolished the increased mRNA expression, as well as the up-regulated transcriptional activity of the human alpha2(I) collagen gene in SSc fibroblasts. CONCLUSION: These results suggest that TGFbeta plays a crucial role in the pathogenesis of SSc and raise the possibility of a therapeutic approach with anti-TGFbeta antibodies or a TGF11 antisense oligonucleotide.

Antibodies↗

PubMed1996

Post-transcriptional stimulation of transforming growth factor beta 1 mRNA by TGF-beta 1 treatment of transformed human osteoblasts.

Following exogenous administration of transforming growth factor-beta 1 (TGF-beta 1) polypeptide to the human osteosarcoma cell line TE-85, we observed a 2- to 6-fold stimulation of steady-state TGF-beta 1 mRNA. The stimulation was dose- and time-dependent, as judged from Northern blot hybridization analyses. A 2- to 6-fold increase of the TGF-beta 1 polypeptide was also found in the media of these cells after TGF-beta 1 treatments. The autostimulation of TGF-beta 1 mRNA was nullified by cycloheximide treatment of the cells. The in vitro transcription rates of the TGF-beta 1 gene by isolated nuclei were not altered by TGF-beta 1 treatment. Under conditions of transcriptional inhibition, the stability of TGF-beta 1 mRNA was enhanced nearly two-fold by TGF-beta 1 treatment. Our findings indicate that TGF-beta 1 can stimulate autologous gene expression and subsequent polypeptide translation by a post-transcriptional mechanism requiring protein synthesis in human osteoblast-like cells. The recognized versatility of TGF-beta 1 autostimulation mechanisms (transcriptional and post-transcriptional) in other mesenchymal cells may apply also to skeletal cells, further underscoring the broad and potent activities of this cytokine.

Cell Line, Transformed↗

PubMed1985

Cell growth and differentiation in vitro in mouse macrophages transformed by a tsA mutant of simian virus 40. III. Large T antigen level and cell proliferation and survival in an SV40 tsA640-transformed macrophage line.

The levels of simian virus 40 (SV40) large T antigen in a tsA-transformed mouse macrophage line at the permissive (33 degrees C) and the nonpermissive (39 degrees C) temperature were examined by immunofluorescence, sodium dodecylsulfate-polyacrylamide gel electrophoresis, complement fixation, and enzyme-linked immunosorbent assay. When the cells were confluent and rested at 33 degrees C, and then were shifted to 39 degrees C, the amount of large T antigen per cell decreased, and most cells survived and remained phagocytic. When the cells were proliferating at 33 degrees C, and then were shifted to 39 degrees C, the cells died with only a small reduction in the amount of large T antigen. Therefore, the physiological state of the cells may determine the survival of cells by affecting the level of large T antigen after exposure to 39 degrees. The confluent cells may be rested with a concomitant decrease of large T antigen. The proliferating cells may not survive in the presence of a relatively high level of functionally defective large T antigen at 39 degrees C.

Animals↗

PubMed2000

Retinoic acid resistance at late stages of human papillomavirus type 16-mediated transformation of human keratinocytes arises despite intact retinoid signaling and is due to a loss of sensitivity to transforming growth factor-beta.

In our in vitro model of human cell carcinogenesis, normal human foreskin keratinocytes (HKc) transfected with human papillomavirus type 16 DNA (HKc/HPV16) progress toward malignancy through several phenotypically defined and reproducible "steps" that include immortalization, growth factor independence (HKc/GFI), differentiation resistance (HKc/DR), and ultimately malignant conversion. While HKc/HPV16 are very sensitive to growth inhibition by all-trans-retinoic acid (RA) at early passages, they lose their sensitivity to RA during progression in culture. However, gel mobility shift assays using the retinoid response elements DR1 and DR5 showed no changes in binding activity of nuclear extracts obtained from HKc/HPV16 at different stages of in vitro progression. Similarly, Western blot analyses for retinoic acid receptor gamma-1 and the retinoid X receptors failed to reveal any decreases in the levels of these retinoid receptors throughout progression. In addition, luciferase activity driven by the SV40 promoter with a DR5 enhancer element was activated following RA treatment of HKc/DR that were resistant to growth inhibition by RA. Since RA induces transforming growth factor-beta2 (TGF-beta2) in normal HKc and HKc/HPV16, we investigated whether this response changed during progression. Again, RA induced TGF-beta2 mRNA in early and late passage HKc/HPV16, HKc/GFI, and HKc/DR approximately to the same extent, confirming that the RA signaling pathways remained intact during in vitro progression despite the fact that the cells become resistant to growth inhibition by RA. We then investigated the sensitivity of HKc/HPV16 to growth inhibition by TGF-beta. While early passage HKc/HPV16 were as sensitive as normal HKc to growth inhibition by TGF-beta1 and TGF-beta2, the cells became increasingly resistant to both TGF-beta isotypes during in vitro progression. In addition, while both RA and TGF-beta produced a decrease in the levels of mRNA for the HPV16 oncogenes E6 and E7 in early passage HKc/HPV16, this effect was also lost at later stages of progression. Finally, blocking anti-TGF-beta antibodies partially prevented RA inhibition of growth and E6/E7 expression in early passage HKc/HPV16. Taken together, these data strongly suggest that inhibition of growth and HPV16 early gene expression in HKc/HPV16 by RA is mediated by TGF-beta and that a loss of RA sensitivity is linked to TGF-beta resistance rather than alterations in RA signaling.

Antineoplastic Agents↗

PubMed1999

Differential regulation of transforming growth factor receptors by angiotensin II and transforming growth factor-beta1 in vascular smooth muscle.

Angiotensin II (Ang II) and transforming growth factor (TGF) beta1 play a role in vascular remodeling in hypertension. In this process they may interact on various levels, including that of receptor regulation. This consideration prompted the present study on transcriptional regulation of TGF-beta receptors by Ang II and TGF-beta in vascular smooth muscle cells. Transcriptional expression of the components of the TGF-beta system was demonstrated for TGF-beta and for TGF-beta receptors I, II, and III. As measured by quantitative reverse transcriptase polymerase chain reaction, TGF-beta mRNA increased about 2.4-fold in the presence of 40 pM exogenous TGF-beta. Ang II at 10(-6) M increased TGF-beta mRNA 2.5-fold compared to control cells (P<0.05). Ang II also significantly increased TGF-beta protein concentration in the supernatant of confluent vascular smooth muscle cells. Ang II caused the induction of TGF-beta, but short-term experiments showed TGF-beta receptor II mRNA to be differentially regulated by Ang II and TGF-beta; while TGF-beta caused a 40% decrease in TGF-beta receptor II mRNA after 4 h (P<0.05), Ang II caused an increase by about 70%. In contrast, both TGF-beta and Ang II increased TGF-beta receptor I mRNA to about 260% or 180% of controls (P<0.05). TGF-beta effects were abrogated by coincubation with a TGF-beta neutralizing antibody, and Ang II effects were abrogated by losartan, an AT-1 receptor antagonist. Coincubation of Ang II with the TGF-beta neutralizing antibody did not inhibit the effect of Ang II, indicating that the short-term effects of Ang II on the expression of the TGF-beta receptors are not mediated via TGF-beta. Furthermore, Ang II stimulated DNA synthesis even in the presence of the TGF-beta neutralizing antibody. In conclusion, this study indicates (a) that in vascular smooth muscle TGF-beta receptors are regulated on the RNA level by TGF-beta and Ang II, and (b) that Ang II dependent regulation of TGF-beta receptors is at least partially independent of endogenous TGF-beta. Stimulation of the transcriptional expression of TGF-beta receptors by Ang II may increase sensitivity of vascular smooth muscle cells to TGF-beta.

Angiotensin II↗

PubMed2004

Decreased expression of transforming growth factor-beta II receptor is associated with that of p27KIP1 in giant cell tumor of bone: a possible link between transforming growth factor-beta and cell cycle-related protein.

Transforming growth factor (TGF)-beta is a potential regulator of cell growth that sends its signals through a heteromeric complex composed of type I and II receptors (IR and IIR). This study examined a correlation between TGF-beta1, TGF-beta-IR and -IIR, and cell cycle-related proteins in giant cell tumor (GCT) of bone, using immunohistochemical and Western blot analysis. First, an immunohistochemical study for TGF-beta1, TGF-beta-IR and -IIR, p27KIP1 (p27), p21WAF1 (p21), cyclin D1, and cyclin E was carried out on 92 cases of GCT of bone; the expression of these proteins was evaluated in multinucleated giant cells (MGCs) and mononucleated stromal cells (MSCs) separately; and proliferative activity was assessed using MIB-1. Next, to confirm our immunohistochemical results, Western blot analysis was performed in 19 cases for which frozen samples were available. Immunoreactivity for TGF-beta-IR and -IIR showed a tendency to be greater in MGCs than in MSCs; however, no differences were observed in TGF-beta1. Cyclin D1 expression was correlated with the occurrence of vascular invasion in both MGCs and MSCs (P = 0.0255 and 0.0183, respectively). The expression of TGF-beta-IIR and p27 was concordantly decreased in both MGSs and MSCs (P = 0.0014 and 0.0317, respectively). The expression for TGF-beta-IIR and p27 in Western blot analysis was related to the results from immunohistochemical analysis, and the expression of TGF-beta-IIR and p27 was concordant in almost all GCT cases. Furthermore, there was a statistically significant inverse relationship between p27 expression and MIB-1 labeling index in MSCs (P = 0.0397). In GCT of bone, TGF-beta-IIR and p27 expression were concordantly decreased; this result supports the possibility that these 2 factors may play an important role in cell proliferation of this tumor. Furthermore, our results provide a possible link between the effects of extracellular growth factors and cell cycle control. In addition, p27 expression may be a useful indicator of cell proliferation in MSCs of this tumor.

Adolescent↗

PubMed1991

Transforming growth factor-beta up-regulates type VII collagen gene expression in normal and transformed epidermal keratinocytes in culture.

Transforming growth factor-betas (TGF-betas) have been shown to enhance the expression of extracellular matrix genes, including several collagens. In this study, the effects of TGF-beta 1 and TGF-beta 2 on the expression of the gene for type VII collagen, the major component of anchoring fibrils, in human epidermal cell cultures were examined. Incubation of human epidermal keratinocytes or oral epidermoid carcinoma KB cells with TGF-beta 1 or TGF-beta 2 markedly (up to 6.3-fold) elevated the alpha 1(VII) collagen mRNA levels. This elevation was accompanied by enhanced synthesis of type VII collagen, as demonstrated by indirect immunofluorescence with a monoclonal antibody. The results indicate that TGF-beta 1 and TGF-beta 2 have similar biological activities with respect to enhanced type VII collagen gene expression.

Adult↗

PubMed1999

Transforming growth factor-beta-induced upregulation of transforming growth factor-beta receptor expression in pancreatic regeneration.

The transforming growth factor-beta (TGFbeta) signaling pathway is one important player in the regulation of extracellular matrix turnover and cell proliferation in epithelial regeneration. We used cerulein-induced pancreatitis in rats as a model to investigate the regulation of TGFbeta receptor type I and type II expression on protein and messenger RNA level during regeneration. In the regenerating pancreas, mRNA levels of TGFbeta receptor I and II were significantly increased with a maximum after 2 days. On protein level, expression of TGFbeta receptor II was significantly increased after three to 3-5 days. This elevated expression could be inhibited by neutralizing the endogenous biological activity of TGFbeta1 with a specific antibody. In cultured pancreatic epithelial cells, TGFbeta1 reduced cell proliferation as measured by [3H]thymidine incorporation. Furthermore the transcript levels of TGFbeta1 as well as mRNA and protein concentrations of type I and type II receptor increased during TGFbeta stimulation in vitro. These results indicate that epithelial pancreatic cells contribute to the enhanced TGFbeta1 synthesis during pancreatic regeneration by an autocrine mechanism. TGFbeta1, furthermore, upregulates the expression of its own receptors during the regenerative process, thereby contributing to the increase of the TGFbeta-induced cellular responses.

Animals↗

PubMed2001

Beta(2)-adrenoceptor stimulation enhances latent transforming growth factor-beta-binding protein-1 and transforming growth factor-beta1 expression in rat hippocampus after transient forebrain ischemia.

A protective capacity of transforming growth factor-beta1 (TGF-beta1) against various insults inducing neurone cell death in vitro and in vivo has been well established. We have recently shown the rapid up-regulation and persistent expression of TGF-beta1 in surviving CA1 pyramidal cells after cerebral ischemia suggesting an endogenous mechanism of neuroprotection by this multifunctional cytokine. In the present study, we demonstrated that intraperitoneal administration of clenbuterol, a lipophilic beta(2)-adrenoceptor agonist, caused an increase in TGF-beta1 expression in non-ischemic rats and further enhanced TGF-beta1 protein levels in rat CA1 pyramidal neurones after transient forebrain ischemia. In the hippocampus neuroprotection by clenbuterol (0.5 mg/kg) was accompanied by increased TGF-beta1 immunoreactivity as early as 3 h, and remained elevated up to 2 days after ischemia. The corresponding increased TGF-beta1 mRNA levels after ischemia were not further enhanced by clenbuterol, suggesting post-transcriptional regulation of TGF-beta1 protein after beta(2)-adrenoceptor stimulation. In saline-treated rats latent TGF-beta-binding protein-1 (LTBP-1) immunoreactivity was moderately elevated 3 and 6 h after ischemia, and returned to control levels after 1 day of reperfusion. In parallel with the up-regulation of TGF-beta1 immunoreactivity, LTBP-1 levels in the hippocampus were considerably increased by clenbuterol from 3 h to 2 days after ischemia. Our data demonstrate a concomitant increase in LTBP-1 and TGF-beta1 expression in the ischemic hippocampus after stimulation of beta(2)-adrenoceptors.

Adrenergic beta-Agonists↗

PubMedDate not supplied

Differential expression of transforming growth factor-beta 1 and transforming growth factor-beta receptors in myometrium of women with failed induction of labor, no labor, and preterm labor.

OBJECTIVE: Comparative analysis of transforming growth factor-beta 1 (TGF-beta 1) and TGF-beta receptor type I and type II messenger RNA (mRNA) and protein expression in myometrium of women who had unsuccessful labor induction, with those without labor or in preterm labor complicated by chorioamnionitis. METHODS: Small segments of myometrium were collected from women who were undergoing cesarean delivery for unsuccessful labor induction (n = 5), elective cesarean without labor (n = 5), or cesarean delivery for complications related to preterm labor and chorioamnionitis (n = 5). Total RNA was isolated from these tissues and subjected to competitive quantitative reverse-transcription-polymerase chain reaction (Q-RT-PCR) to determine the level of TGF-beta 1, and TGF-beta type I and type II receptor mRNA expression. Tissue sections were prepared from paraffin-embedded specimens and immunostained for TGF-beta 1 and receptor proteins using specific polycolonal antibodies. The data were analyzed by impaired Student t test and Kruskal-Wallis analysis of variance. RESULTS: Myometrium from women who had unsuccessful labor induction expressed higher levels of TGF-beta 1 mRNA (2.21 +/- 0.28 x 10(6) copies/microgram of total cellular RNA) than those with preterm labor (4.53 +/- 0.2 x 10(5) copies), or without labor [3.13 +/- 2.6 x 10(4) copies (P < .05)]. The level of TGF-beta type I receptor mRNA expression did not vary; however, type II receptor expression was significantly lower in myometrium from preterm labor (1.36 +/- 0.36 x 10(5) copies) compared with those from unsuccessful labor induction (3.42 +/- 0.42 x 10(6) copies) or without labor (9.65 +/- 3.2 x 10(5) copies). Immunoreactive TGF-beta 1 and TGF-beta receptor proteins were present in all myometrial tissues, and their intensity reflected that of the mRNA expression in these tissues. CONCLUSION: TGF-beta 1 and TGF-beta type II receptors are expressed differently in myometrium of women who had unsuccessful labor induction compared with those without labor or with preterm labor complicated by chorioamnionitis. Because TGF-beta is a key regulator of tissue remodeling which is central to initiation of normal labor, alterations in TGF-beta and/or TGF-beta receptor expression may lead to changes in the outcome of labor, at least at the myometrial level.

Cesarean Section↗

PubMed2006

Dihydropyrrolopyrazole transforming growth factor-beta type I receptor kinase domain inhibitors: a novel benzimidazole series with selectivity versus transforming growth factor-beta type II receptor kinase and mixed lineage kinase-7.

Novel dihydropyrrolopyrazole-substituted benzimidazoles were synthesized and evaluated in vitro as inhibitors of transforming growth factor-beta type I receptor (TGF-beta RI), TGF-beta RII, and mixed lineage kinase-7 (MLK-7). These compounds were found to be potent TGF-beta RI inhibitors and selective versus TGF-beta RII and MLK-7 kinases. Benzimidazole derivative 8b was active in an in vivo target (TGF-beta RI) inhibition assay.

Animals↗

PubMed1992

Differential pathways (phospholipase C and phospholipase D) of bradykinin-induced biphasic 1,2-diacylglycerol formation in non-transformed and K-ras-transformed NIH-3T3 fibroblasts. Involvement of intracellular Ca2+ oscillations in phosphatidylcholine breakdown.

Bradykinin (BK) induced a biphasic increase in 1,2-diacylglycerol (DAG) in both K-ras-transformed fibroblasts (DT) and the parent NIH-3T3 cells. The first phase was coincident with the increase in Ins(1,4,5)P3 resulting from PtdIns(4,5)P2 hydrolysis, and the second, sustained, phase was derived from phosphatidylcholine (PtdCho) hydrolysis. In NIH-3T3 cells, stimulation by BK induced greater production of choline than phosphocholine in [3H]choline-labelled cells and appreciable phosphatidylethanol (PtdEtOH) formation in [3H]myristic acid-labelled cells, suggesting that PtdCho was hydrolysed mainly by a phospholipase D (PLD) activity. Pretreatment with propranolol, an inhibitor of phosphatidate phosphohydrolase, markedly diminished the second DAG accumulation, supporting the above notion. In DT cells, BK induced predominantly phosphocholine generation and little PtdEtOH formation, indicating that the PtdCho hydrolysis was due to a phospholipase C (PLC) activity. The BK-induced oscillations in intracellular Ca2+ concentration ([Ca2+]i) observed in single DT cells [Fu, Sugimoto, Oki, Murakami, Okano & Nozawa (1991) FEBS Lett. 281, 263-266] were detected as a sustained [Ca2+]i elevation when assayed in a cell suspension. A receptor-operated Ca2+ channel blocker, SK&F 96365, suppressed both the BK-induced phosphocholine generation and the sustained [Ca2+]i elevation in a similar dose-dependent manner. These results thus suggested that oscillations in [Ca2+]i are involved in the activation of PtdCho-specific PLC in DT cells.

3T3 Cells↗

PubMed1996

The recombinant proregion of transforming growth factor beta1 (latency-associated peptide) inhibits active transforming growth factor beta1 in transgenic mice.

All three isoforms of transforming growth factors beta (TGF-betal, TGF-beta2, and TGF-beta3) are secreted as latent complexes and activated extracellularly, leading to the release of the mature cytokines from their noncovalently associated proregions, also known as latency-associated peptides (LAPs). The LAP region of TGF-beta1 was expressed in a baculovirus expression system and purified to homogeneity. In vitro assays of growth inhibition and gene induction mediated by TGF-beta3 demonstrate that recombinant TGF-beta1 LAP is a potent inhibitor of the activities of TGF-betal, -beta2, and -beta3. Effective dosages of LAP for 50% neutralization of TGF-beta activities range from 4.7- to 80-fold molar excess depending on the TGF-beta isoform and activity examined. Using 125I-labeled LAP, we show that the intraperitoneal application route is effective for systemic administration of LAP. Comparison of concentrations of LAP in tissues shows a homogenous pattern in most organs with the exception of heart and muscle, in which levels of LAP are 4- to 8-fold lower. In transgenic mice with elevated hepatic levels of bioactive TGF-betal, treatment with recombinant LAP completely reverses suppression of the early proliferative response induced by TGF-beta1 in remnant livers after partial hepatectomy. The results suggest that recombinant LAP is a potent inhibitor of bioactive TGF-beta both in vitro and in vivo, after intraperitoneal administration. Recombinant LAP should be a useful tool for novel approaches to study and therapeutically modulate pathophysiological processes mediated by TGF-beta3.

Animals↗

PubMed1995

Expression of transforming growth factor type III receptor in vascular endothelial cells increases their responsiveness to transforming growth factor beta 2.

Bovine aortic endothelial cells (BAECs) express both type I and type II receptors for transforming growth factor beta (TGF beta). These cells respond to TGF beta 1 but are relatively refractory to another isoform of TGF beta, termed TGF beta 2. TGF beta s are thought to signal through receptor complexes composed of type I and/or type II receptors, both of which appear to be functional serine-threonine kinases. The TGF beta type III receptor, on the other hand, does not seem to have any direct signaling capacity. We have now stably transfected BAECs with the type III receptor cDNA. These cells displayed surface expression of the type III receptor protein, as determined by cross-linking with iodinated TGF beta 1 and immunoprecipitation with antibodies to the type III receptor protein. Transfected BAECs exhibit increased responsiveness to TGF beta 2 by several different criteria including an increase in plasminogen activator inhibitor-1 protein and inhibition of migration and proliferation. Thus, the type III receptor protein may play a role in presenting TGF beta 2 to the type II receptor and increase responsiveness to TGF beta 2 to a level comparable to that of TGF beta 1.

Animals↗

PubMed2001

Ligand binding and functional properties of betaglycan, a co-receptor of the transforming growth factor-beta superfamily. Specialized binding regions for transforming growth factor-beta and inhibin A.

Betaglycan, also known as the transforming growth factor-beta (TGF-beta) type III receptor, is a membrane-anchored proteoglycan that binds TGF-beta via its core protein. Deletion mutagenesis analysis has revealed two regions of betaglycan ectodomain capable of binding TGF-beta: one at the amino-terminal half, the endoglin-related region (López-Casillas, F., Payne, H., Andres, J. L., and Massagué, J. (1994) J. Cell Biol. 124, 557-568), and the other at the carboxyl-terminal half, the uromodulin-related region (Pepin, M.-C., Beauchemin, M., Plamondon, J., and O'Connor-McCourt, M. D. (1994) Proc. Natl. Acad. Sci. U. S. A 91, 6997-7001). In the present work we have functionally characterized these ligand binding regions. Similar to the wild type receptor, both regions bind TGF-beta2 with higher affinity than TGF-beta1. However, only the endoglin-related region increases the TGF-beta2 labeling of the TGF-beta type II receptor, the so-called "TGF-beta -presentation" function of the wild type receptor. Despite this preference, both regions as well as the wild type receptor mediate the TGF-beta2-dependent Smad2 phosphorylation, indicating that they can function indistinguishably as TGF-beta-enhancing co-receptors. 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. Binding competition experiments indicate that this region binds inhibin and TGF-beta with the following relative affinities: TGF-beta2 > inhibin A > TGF-beta1. All together, the present results suggest that betaglycan ectodomain is endowed with two bona fide independent ligand binding domains that can perform specialized functions as co-receptors of distinct members of the TGF-beta superfamily.

Animals↗