Activins and inhibins, structurally related members of the TGF-beta superfamily of growth and differentiation factors, are mutually antagonistic regulators of reproductive and other functions. Activins bind specific type II receptor serine kinases (ActRII or IIB) to promote the recruitment and phosphorylation of the type I receptor serine kinase, ALK4 (refs 7-9), which then regulates gene expression by activating Smad proteins. Inhibins also bind type II activin receptors but do not recruit ALK4, providing a competitive model for the antagonism of activin by inhibin. Inhibins fail to antagonize activin in some tissues and cells, however, suggesting that additional components are required for inhibin action. Here we show that the type III TGF-beta receptor, betaglycan, can function as an inhibin co-receptor with ActRII. Betaglycan binds inhibin with high affinity and enhances binding in cells co-expressing ActRII and betaglycan. Inhibin also forms crosslinked complexes with both recombinant and endogenously expressed betaglycan and ActRII. Finally, betaglycan confers inhibin sensitivity to cell lines that otherwise respond poorly to this hormone. The ability of betaglycan to facilitate inhibin antagonism of activin provides a variation on the emerging roles of proteoglycans as co-receptors modulating ligand-receptor sensitivity, selectivity and function.
Full-length cDNAs for the transforming growth factor-beta (TGF-beta) type III receptors were isolated from porcine uterus and human placenta cDNA libraries. The human TGF-beta type III receptor coding region encodes a protein of 849 amino acids with a single transmembrane domain and a short stretch of the intracellular domain. Potential glycosaminoglycan attachment sites were found in the extracellular domain. The overall amino acid sequence identities with those of the porcine and rat TGF-beta type III receptors were 83% and 81%, respectively. A high degree of sequence conservation was observed in the transmembrane and intracellular domains, which also have sequence similarity with human endoglin. In addition, two portions with 29 and 52 amino acids in the extracellular domain were found to be substantially similar with human endoglin.
Interacting selectively and non-covalently with heparin, any member of a group of glycosaminoglycans found mainly as an intracellular component of mast cells and which consist predominantly of alternating alpha-(1->4)-linked D-galactose and N-acetyl-D-glucosamine-6-sulfate residues.
Evidence
1:
Inferred from Sequence or Structural SimilarityBHF-UCL
Full-length cDNAs for the transforming growth factor-beta (TGF-beta) type III receptors were isolated from porcine uterus and human placenta cDNA libraries. The human TGF-beta type III receptor coding region encodes a protein of 849 amino acids with a single transmembrane domain and a short stretch of the intracellular domain. Potential glycosaminoglycan attachment sites were found in the extracellular domain. The overall amino acid sequence identities with those of the porcine and rat TGF-beta type III receptors were 83% and 81%, respectively. A high degree of sequence conservation was observed in the transmembrane and intracellular domains, which also have sequence similarity with human endoglin. In addition, two portions with 29 and 52 amino acids in the extracellular domain were found to be substantially similar with human endoglin.
Interacting selectively and non-covalently with any protein or protein complex (a complex of two or more proteins that may include other nonprotein molecules).
Evidence
1:
Inferred from Physical InteractionBHF-UCL
beta-Arrestins bind to activated seven transmembrane-spanning (7TMS) receptors (G protein-coupled receptors) after the receptors are phosphorylated by G protein-coupled receptor kinases (GRKs), thereby regulating their signaling and internalization. Here, we demonstrate an unexpected and analogous role of beta-arrestin 2 (betaarr2) for the single transmembrane-spanning type III transforming growth factor-beta (TGF-beta) receptor (TbetaRIII, also referred to as betaglycan). Binding of betaarr2 to TbetaRIII was also triggered by phosphorylation of the receptor on its cytoplasmic domain (likely at threonine 841). However, such phosphorylation was mediated by the type II TGF-beta receptor (TbetaRII), which is itself a kinase, rather than by a GRK. Association with betaarr2 led to internalization of both receptors and down-regulation of TGF-beta signaling. Thus, the regulatory actions of beta-arrestins are broader than previously appreciated, extending to the TGF-beta receptor family as well.
Evidence
2:
Inferred from Physical InteractionBHF-UCL
The bone morphogenetic protein (BMP) family, the largest subfamily of the structurally conserved transforming growth factor-beta (TGF-beta) superfamily of growth factors, are multifunctional regulators of development, proliferation, and differentiation. The TGF-beta type III receptor (TbetaRIII or betaglycan) is an abundant cell surface proteoglycan that has been well characterized as a TGF-beta and inhibin receptor. Here we demonstrate that TbetaRIII functions as a BMP cell surface receptor. TbetaRIII directly and specifically binds to multiple members of the BMP subfamily, including BMP-2, BMP-4, BMP-7, and GDF-5, with similar kinetics and ligand binding domains as previously identified for TGF-beta. TbetaRIII also enhances ligand binding to the BMP type I receptors, whereas short hairpin RNA-mediated silencing of endogenous TbetaRIII attenuates BMP-mediated Smad1 phosphorylation. Using a biologically relevant model for TbetaRIII function, we demonstrate that BMP-2 specifically stimulates TbetaRIII-mediated epithelial to mesenchymal cell transformation. The ability of TbetaRIII to serve as a cell surface receptor and mediate BMP, inhibin, and TGF-beta signaling suggests a broader role for TbetaRIII in orchestrating TGF-beta superfamily signaling.
Evidence
3:
Inferred from Physical InteractionBHF-UCL
Activins and inhibins, structurally related members of the TGF-beta superfamily of growth and differentiation factors, are mutually antagonistic regulators of reproductive and other functions. Activins bind specific type II receptor serine kinases (ActRII or IIB) to promote the recruitment and phosphorylation of the type I receptor serine kinase, ALK4 (refs 7-9), which then regulates gene expression by activating Smad proteins. Inhibins also bind type II activin receptors but do not recruit ALK4, providing a competitive model for the antagonism of activin by inhibin. Inhibins fail to antagonize activin in some tissues and cells, however, suggesting that additional components are required for inhibin action. Here we show that the type III TGF-beta receptor, betaglycan, can function as an inhibin co-receptor with ActRII. Betaglycan binds inhibin with high affinity and enhances binding in cells co-expressing ActRII and betaglycan. Inhibin also forms crosslinked complexes with both recombinant and endogenously expressed betaglycan and ActRII. Finally, betaglycan confers inhibin sensitivity to cell lines that otherwise respond poorly to this hormone. The ability of betaglycan to facilitate inhibin antagonism of activin provides a variation on the emerging roles of proteoglycans as co-receptors modulating ligand-receptor sensitivity, selectivity and function.
Evidence
4:
Inferred from Physical InteractionIntAct
Tumor cell plasticity enables certain types of highly malignant tumor cells to dedifferentiate and engage a plastic multipotent embryonic-like phenotype, which enables them to 'adapt' during tumor progression and escape conventional therapeutic strategies. This plastic phenotype of aggressive cancer cells enables them to express endothelial cell-specific markers and form tube-like structures, a phenotype that has been linked to aggressive behavior and poor prognosis. We demonstrate here that the transforming growth factor (TGF)-β co-receptor endoglin, an endothelial cell marker, is expressed by tumor cells and its expression correlates with tumor cell plasticity in two types of human cancer, Ewing sarcoma and melanoma. Moreover, endoglin expression was significantly associated with worse survival of Ewing sarcoma patients. Endoglin knockdown in tumor cells interferes with tumor cell plasticity and reduces invasiveness and anchorage-independent growth in vitro. Ewing sarcoma and melanoma cells with reduced endoglin levels showed reduced tumor growth in vivo. Mechanistically, we provide evidence that endoglin, while interfering with TGF-β signaling, is required for efficient bone morphogenetic protein, integrin, focal adhesion kinase and phosphoinositide-3-kinase signaling in order to maintain tumor cell plasticity. The present study delineates an important role of endoglin in tumor cell plasticity and progression of aggressive tumors.
Evidence
5:
Inferred from Physical InteractionBHF-UCL
Transforming growth factor-beta (TGF-beta) signals through membrane-bound serine/threonine kinase receptors, which upon stimulation phosphorylate Smad proteins and thereby trigger their nuclear translocation and transcriptional activity. Although the three mammalian isoforms of TGF-beta are highly homologous at the level of sequence, analysis of their in vivo function by gene knockouts revealed striking differences, suggesting no significant functional redundancy between TGF-beta1, -2 and -3. While signal transduction by TGF-beta1 has been well characterized, receptor binding and activation by the TGF-beta2 isoform is less well understood. Here, we show that TbetaRII-B, an alternatively spliced variant of the TGF-beta type II receptor, is a TGF-beta2 binding receptor, which mediates signalling via the Smad pathway in the absence of any TGF-beta type III receptor (TbetaRIII). L6 cells lacking endogenous TbetaRIII as well as TbetaRII-B do not respond to TGF-beta2. Transfection of these cells with TbetaRII-B restores TGF-beta2 sensitivity. The expression of TbetaRII-B is restricted to cells originating from tissues such as bone where the isoform TGF-beta2 has a predominant role. This reflects the importance of this receptor in TGF-beta isoform-specific signalling.
Transforming growth factor-beta (TGF-beta) signals through membrane-bound serine/threonine kinase receptors, which upon stimulation phosphorylate Smad proteins and thereby trigger their nuclear translocation and transcriptional activity. Although the three mammalian isoforms of TGF-beta are highly homologous at the level of sequence, analysis of their in vivo function by gene knockouts revealed striking differences, suggesting no significant functional redundancy between TGF-beta1, -2 and -3. While signal transduction by TGF-beta1 has been well characterized, receptor binding and activation by the TGF-beta2 isoform is less well understood. Here, we show that TbetaRII-B, an alternatively spliced variant of the TGF-beta type II receptor, is a TGF-beta2 binding receptor, which mediates signalling via the Smad pathway in the absence of any TGF-beta type III receptor (TbetaRIII). L6 cells lacking endogenous TbetaRIII as well as TbetaRII-B do not respond to TGF-beta2. Transfection of these cells with TbetaRII-B restores TGF-beta2 sensitivity. The expression of TbetaRII-B is restricted to cells originating from tissues such as bone where the isoform TGF-beta2 has a predominant role. This reflects the importance of this receptor in TGF-beta isoform-specific signalling.
Interacting selectively and non-covalently with TGF-beta, transforming growth factor beta, a multifunctional peptide that controls proliferation, differentiation and other functions in many cell types.
Transforming growth factor-beta (TGF-beta) signals through membrane-bound serine/threonine kinase receptors, which upon stimulation phosphorylate Smad proteins and thereby trigger their nuclear translocation and transcriptional activity. Although the three mammalian isoforms of TGF-beta are highly homologous at the level of sequence, analysis of their in vivo function by gene knockouts revealed striking differences, suggesting no significant functional redundancy between TGF-beta1, -2 and -3. While signal transduction by TGF-beta1 has been well characterized, receptor binding and activation by the TGF-beta2 isoform is less well understood. Here, we show that TbetaRII-B, an alternatively spliced variant of the TGF-beta type II receptor, is a TGF-beta2 binding receptor, which mediates signalling via the Smad pathway in the absence of any TGF-beta type III receptor (TbetaRIII). L6 cells lacking endogenous TbetaRIII as well as TbetaRII-B do not respond to TGF-beta2. Transfection of these cells with TbetaRII-B restores TGF-beta2 sensitivity. The expression of TbetaRII-B is restricted to cells originating from tissues such as bone where the isoform TGF-beta2 has a predominant role. This reflects the importance of this receptor in TGF-beta isoform-specific signalling.
beta-Arrestins bind to activated seven transmembrane-spanning (7TMS) receptors (G protein-coupled receptors) after the receptors are phosphorylated by G protein-coupled receptor kinases (GRKs), thereby regulating their signaling and internalization. Here, we demonstrate an unexpected and analogous role of beta-arrestin 2 (betaarr2) for the single transmembrane-spanning type III transforming growth factor-beta (TGF-beta) receptor (TbetaRIII, also referred to as betaglycan). Binding of betaarr2 to TbetaRIII was also triggered by phosphorylation of the receptor on its cytoplasmic domain (likely at threonine 841). However, such phosphorylation was mediated by the type II TGF-beta receptor (TbetaRII), which is itself a kinase, rather than by a GRK. Association with betaarr2 led to internalization of both receptors and down-regulation of TGF-beta signaling. Thus, the regulatory actions of beta-arrestins are broader than previously appreciated, extending to the TGF-beta receptor family as well.
Combining with transforming growth factor beta to initiate a change in cell activity; facilitates ligand binding to type I and type II TGF-beta receptors.
Activins and inhibins, structurally related members of the TGF-beta superfamily of growth and differentiation factors, are mutually antagonistic regulators of reproductive and other functions. Activins bind specific type II receptor serine kinases (ActRII or IIB) to promote the recruitment and phosphorylation of the type I receptor serine kinase, ALK4 (refs 7-9), which then regulates gene expression by activating Smad proteins. Inhibins also bind type II activin receptors but do not recruit ALK4, providing a competitive model for the antagonism of activin by inhibin. Inhibins fail to antagonize activin in some tissues and cells, however, suggesting that additional components are required for inhibin action. Here we show that the type III TGF-beta receptor, betaglycan, can function as an inhibin co-receptor with ActRII. Betaglycan binds inhibin with high affinity and enhances binding in cells co-expressing ActRII and betaglycan. Inhibin also forms crosslinked complexes with both recombinant and endogenously expressed betaglycan and ActRII. Finally, betaglycan confers inhibin sensitivity to cell lines that otherwise respond poorly to this hormone. The ability of betaglycan to facilitate inhibin antagonism of activin provides a variation on the emerging roles of proteoglycans as co-receptors modulating ligand-receptor sensitivity, selectivity and function.
Transforming growth factor-beta (TGF-beta) signals through membrane-bound serine/threonine kinase receptors, which upon stimulation phosphorylate Smad proteins and thereby trigger their nuclear translocation and transcriptional activity. Although the three mammalian isoforms of TGF-beta are highly homologous at the level of sequence, analysis of their in vivo function by gene knockouts revealed striking differences, suggesting no significant functional redundancy between TGF-beta1, -2 and -3. While signal transduction by TGF-beta1 has been well characterized, receptor binding and activation by the TGF-beta2 isoform is less well understood. Here, we show that TbetaRII-B, an alternatively spliced variant of the TGF-beta type II receptor, is a TGF-beta2 binding receptor, which mediates signalling via the Smad pathway in the absence of any TGF-beta type III receptor (TbetaRIII). L6 cells lacking endogenous TbetaRIII as well as TbetaRII-B do not respond to TGF-beta2. Transfection of these cells with TbetaRII-B restores TGF-beta2 sensitivity. The expression of TbetaRII-B is restricted to cells originating from tissues such as bone where the isoform TGF-beta2 has a predominant role. This reflects the importance of this receptor in TGF-beta isoform-specific signalling.
Full-length cDNAs for the transforming growth factor-beta (TGF-beta) type III receptors were isolated from porcine uterus and human placenta cDNA libraries. The human TGF-beta type III receptor coding region encodes a protein of 849 amino acids with a single transmembrane domain and a short stretch of the intracellular domain. Potential glycosaminoglycan attachment sites were found in the extracellular domain. The overall amino acid sequence identities with those of the porcine and rat TGF-beta type III receptors were 83% and 81%, respectively. A high degree of sequence conservation was observed in the transmembrane and intracellular domains, which also have sequence similarity with human endoglin. In addition, two portions with 29 and 52 amino acids in the extracellular domain were found to be substantially similar with human endoglin.
Combining with a transforming growth factor beta (TGFbeta) and transmitting the signal from one side of the membrane to the other to initiate a change in cell activity by catalysis of the reaction: ATP protein serine = ADP + protein serine phosphate, and ATP + protein threonine = ADP + protein threonine phosphate.
beta-Arrestins bind to activated seven transmembrane-spanning (7TMS) receptors (G protein-coupled receptors) after the receptors are phosphorylated by G protein-coupled receptor kinases (GRKs), thereby regulating their signaling and internalization. Here, we demonstrate an unexpected and analogous role of beta-arrestin 2 (betaarr2) for the single transmembrane-spanning type III transforming growth factor-beta (TGF-beta) receptor (TbetaRIII, also referred to as betaglycan). Binding of betaarr2 to TbetaRIII was also triggered by phosphorylation of the receptor on its cytoplasmic domain (likely at threonine 841). However, such phosphorylation was mediated by the type II TGF-beta receptor (TbetaRII), which is itself a kinase, rather than by a GRK. Association with betaarr2 led to internalization of both receptors and down-regulation of TGF-beta signaling. Thus, the regulatory actions of beta-arrestins are broader than previously appreciated, extending to the TGF-beta receptor family as well.
Transforming growth factor-beta (TGF-beta) signals through membrane-bound serine/threonine kinase receptors, which upon stimulation phosphorylate Smad proteins and thereby trigger their nuclear translocation and transcriptional activity. Although the three mammalian isoforms of TGF-beta are highly homologous at the level of sequence, analysis of their in vivo function by gene knockouts revealed striking differences, suggesting no significant functional redundancy between TGF-beta1, -2 and -3. While signal transduction by TGF-beta1 has been well characterized, receptor binding and activation by the TGF-beta2 isoform is less well understood. Here, we show that TbetaRII-B, an alternatively spliced variant of the TGF-beta type II receptor, is a TGF-beta2 binding receptor, which mediates signalling via the Smad pathway in the absence of any TGF-beta type III receptor (TbetaRIII). L6 cells lacking endogenous TbetaRIII as well as TbetaRII-B do not respond to TGF-beta2. Transfection of these cells with TbetaRII-B restores TGF-beta2 sensitivity. The expression of TbetaRII-B is restricted to cells originating from tissues such as bone where the isoform TGF-beta2 has a predominant role. This reflects the importance of this receptor in TGF-beta isoform-specific signalling.
The process whose specific outcome is the progression of the blastocyst over time, from its formation to the mature structure. The mammalian blastocyst is a hollow ball of cells containing two cell types, the inner cell mass and the trophectoderm.
The process whose specific outcome is the progression of a blood vessel over time, from its formation to the mature structure. The blood vessel is the vasculature carrying blood.
A series of molecular signals initiated by the binding of a member of the BMP (bone morphogenetic protein) family to a receptor on the surface of a target cell, and ending with regulation of a downstream cellular process, e.g. transcription.
The bone morphogenetic protein (BMP) family, the largest subfamily of the structurally conserved transforming growth factor-beta (TGF-beta) superfamily of growth factors, are multifunctional regulators of development, proliferation, and differentiation. The TGF-beta type III receptor (TbetaRIII or betaglycan) is an abundant cell surface proteoglycan that has been well characterized as a TGF-beta and inhibin receptor. Here we demonstrate that TbetaRIII functions as a BMP cell surface receptor. TbetaRIII directly and specifically binds to multiple members of the BMP subfamily, including BMP-2, BMP-4, BMP-7, and GDF-5, with similar kinetics and ligand binding domains as previously identified for TGF-beta. TbetaRIII also enhances ligand binding to the BMP type I receptors, whereas short hairpin RNA-mediated silencing of endogenous TbetaRIII attenuates BMP-mediated Smad1 phosphorylation. Using a biologically relevant model for TbetaRIII function, we demonstrate that BMP-2 specifically stimulates TbetaRIII-mediated epithelial to mesenchymal cell transformation. The ability of TbetaRIII to serve as a cell surface receptor and mediate BMP, inhibin, and TGF-beta signaling suggests a broader role for TbetaRIII in orchestrating TGF-beta superfamily signaling.
A transition where a cardiac epithelial cell loses apical/basolateral polarity, severs intercellular adhesive junctions, degrades basement membrane components and becomes a migratory mesenchymal cell.
The bone morphogenetic protein (BMP) family, the largest subfamily of the structurally conserved transforming growth factor-beta (TGF-beta) superfamily of growth factors, are multifunctional regulators of development, proliferation, and differentiation. The TGF-beta type III receptor (TbetaRIII or betaglycan) is an abundant cell surface proteoglycan that has been well characterized as a TGF-beta and inhibin receptor. Here we demonstrate that TbetaRIII functions as a BMP cell surface receptor. TbetaRIII directly and specifically binds to multiple members of the BMP subfamily, including BMP-2, BMP-4, BMP-7, and GDF-5, with similar kinetics and ligand binding domains as previously identified for TGF-beta. TbetaRIII also enhances ligand binding to the BMP type I receptors, whereas short hairpin RNA-mediated silencing of endogenous TbetaRIII attenuates BMP-mediated Smad1 phosphorylation. Using a biologically relevant model for TbetaRIII function, we demonstrate that BMP-2 specifically stimulates TbetaRIII-mediated epithelial to mesenchymal cell transformation. The ability of TbetaRIII to serve as a cell surface receptor and mediate BMP, inhibin, and TGF-beta signaling suggests a broader role for TbetaRIII in orchestrating TGF-beta superfamily signaling.
The process in which a cell irreversibly increases in size over time by accretion and biosynthetic production of matter similar to that already present.
Evidence
1:
Inferred from Sequence or Structural SimilarityBHF-UCL
Full-length cDNAs for the transforming growth factor-beta (TGF-beta) type III receptors were isolated from porcine uterus and human placenta cDNA libraries. The human TGF-beta type III receptor coding region encodes a protein of 849 amino acids with a single transmembrane domain and a short stretch of the intracellular domain. Potential glycosaminoglycan attachment sites were found in the extracellular domain. The overall amino acid sequence identities with those of the porcine and rat TGF-beta type III receptors were 83% and 81%, respectively. A high degree of sequence conservation was observed in the transmembrane and intracellular domains, which also have sequence similarity with human endoglin. In addition, two portions with 29 and 52 amino acids in the extracellular domain were found to be substantially similar with human endoglin.
A second wave of blood cell production that, in vertebrates, generates long-term hemopoietic stem cells that continously provide erythroid, myeloid and lymphoid lineages throughout adulthood.
A transition where an epithelial cell loses apical/basolateral polarity, severs intercellular adhesive junctions, degrades basement membrane components and becomes a migratory mesenchymal cell.
The bone morphogenetic protein (BMP) family, the largest subfamily of the structurally conserved transforming growth factor-beta (TGF-beta) superfamily of growth factors, are multifunctional regulators of development, proliferation, and differentiation. The TGF-beta type III receptor (TbetaRIII or betaglycan) is an abundant cell surface proteoglycan that has been well characterized as a TGF-beta and inhibin receptor. Here we demonstrate that TbetaRIII functions as a BMP cell surface receptor. TbetaRIII directly and specifically binds to multiple members of the BMP subfamily, including BMP-2, BMP-4, BMP-7, and GDF-5, with similar kinetics and ligand binding domains as previously identified for TGF-beta. TbetaRIII also enhances ligand binding to the BMP type I receptors, whereas short hairpin RNA-mediated silencing of endogenous TbetaRIII attenuates BMP-mediated Smad1 phosphorylation. Using a biologically relevant model for TbetaRIII function, we demonstrate that BMP-2 specifically stimulates TbetaRIII-mediated epithelial to mesenchymal cell transformation. The ability of TbetaRIII to serve as a cell surface receptor and mediate BMP, inhibin, and TGF-beta signaling suggests a broader role for TbetaRIII in orchestrating TGF-beta superfamily signaling.
The developmental process in which the heart is generated and organized. The heart is a hollow, muscular organ, which, by contracting rhythmically, keeps up the circulation of the blood.
Infection and bacteremia are common in sickle cell disease. We hypothesized that, consistent with evidence for the genetic modulation of other disease complications, the risk of developing bacteremia might also be genetically modulated. Accordingly, we studied the association of single nucleotide polymorphisms (SNPs) in candidate genes with the risk of bacteremia in sickle cell anemia. We found significant associations with SNPs in IGF1R and genes of the TGF-beta /BMP pathway (BMP6, TGFBR3, BMPR1A, SMAD6 and SMAD3). We suggest that both IGF1R and the TGF-beta /BMP pathway could play important roles in immune function in sickle cell anemia and their polymorphisms may help identify a "bacteremia-prone" phenotype.
A series of reactions in which a signal is passed on to downstream proteins within the cell by sequential protein phosphorylation and activation of the cascade components.
J. Clin. Endocrinol. Metab. 88, 5002-5008 (2003)[PubMed:14557487]
Activins and inhibins are often antagonistic in the regulation of ovarian function. TGFbeta type III receptor, betaglycan, has been identified as a coreceptor to enhance the binding of inhibins to activin type II receptor and thus to prevent the binding of activins to their receptor. In this study we characterized the expression and regulation pattern of betaglycan gene in normal ovaries and sex cord-stromal tumors and in cultured human granulosa-luteal cells from women undergoing in vitro fertilization. Expression of betaglycan mRNA was detected by RT-PCR or Northern blotting in normal ovarian granulosa, thecal, and stroma cells as well as in granulosa-luteal cells. Immunohistochemical analysis revealed positive staining for betaglycan in antral and preovulatory follicular granulosa and thecal cells and in corpora lutea of normal ovaries. 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. 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. In contrast, the protein kinase C activator 12-O-tetradecanoyl phorbol 13-acetate had no significant effect on betaglycan mRNA levels. Treatment with prostaglandin E(2) and with its receptor EP2 subtype agonist butaprost increased betaglycan mRNA accumulation and progesterone secretion dose- and time-dependently. In summary, betaglycan gene is expressed in normal human ovarian steroidogenic cells and sex cord-stromal ovarian tumors. The accumulation of its mRNA in cultured granulosa-luteal cells is up-regulated by gonadotropins and prostaglandin E(2), probably via the protein kinase A pathway. The specific expression and regulation pattern of betaglycan gene may be related to the functional antagonism of inhibins to activin signal transduction in human ovaries.
The process whose specific outcome is the progression of the liver over time, from its formation to the mature structure. The liver is an exocrine gland which secretes bile and functions in metabolism of protein and carbohydrate and fat, synthesizes substances involved in the clotting of the blood, synthesizes vitamin A, detoxifies poisonous substances, stores glycogen, and breaks down worn-out erythrocytes.
Epithelial to mesenchymal transitions (EMTs) contribute to increases in cellular motility and invasiveness during embryonic development and tumorigenesis. The transforming growth factor beta (TGF-beta) signaling pathway is a key regulator of EMT. The TGF-beta superfamily coreceptor, the type III TGF-beta receptor (TbetaRIII or betaglycan), is required for EMT during embryonic heart development and palate fusion. Here, we establish that in a pancreatic cancer model of EMT, TbetaRIII expression is specifically lost during EMT at the mRNA and protein levels, whereas levels of the TGF-beta type I and type II receptors are maintained at the mRNA level. Loss of TbetaRIII expression at the protein level precedes the loss of E-cadherin and cytoskeletal reorganization during early stages of EMT. However, maintaining TbetaRIII expression does not block these aspects of EMT, but instead suppresses the increased motility and invasiveness associated with EMT. Reciprocally, shRNA-mediated knockdown of endogenous TbetaRIII increases cellular motility without affecting Snail or E-cadherin levels. The ability of TbetaRIII to suppress motility and invasiveness does not depend on its cytoplasmic domain or its coreceptor function. Instead, this suppression of invasion is partially mediated by ectodomain shedding of TbetaRIII, generating soluble TbetaRIII (sTbetaRIII). In human pancreatic cancer specimens, TbetaRIII expression decreases at both the mRNA and protein levels, with the degree of loss correlating with worsening tumor grade. Taken together, these studies support a role for loss of TbetaRIII expression during the EMT of pancreatic cancer progression, with a specific role for sTbetaRIII in suppressing EMT-associated increases in motility and invasion.
Any process that stops, prevents or reduces the rate or extent of epithelial cell proliferation.
ISSOrtholog Curator
Negative regulation of epithelial to mesenchymal transitiondefinition[GO:0010719]‹silver
Any process that decreases the rate, frequency, or extent of epithelial to mesenchymal transition. Epithelial to mesenchymal transition where an epithelial cell loses apical/basolateral polarity, severs intercellular adhesive junctions, degrades basement membrane components and becomes a migratory mesenchymal cell.
IEAOrtholog Compara
Negative regulation of transforming growth factor beta receptor signaling pathwaydefinition[GO:0030512]‹silver
Any process that stops, prevents, or reduces the frequency, rate or extent of any TGF-beta receptor signaling pathway.
The biological process whose specific outcome is the progression of the palate from an initial condition to its mature state. This process begins with the formation of the structure and ends with the mature structure. The palate is the partition that separates the nasal and oral cavities.
The process of introducing a phosphate group on to a pathway restricted SMAD protein. A pathway restricted SMAD protein is an effector protein that acts directly downstream of the transforming growth factor family receptor.
Transforming growth factor-beta (TGF-beta) signals through membrane-bound serine/threonine kinase receptors, which upon stimulation phosphorylate Smad proteins and thereby trigger their nuclear translocation and transcriptional activity. Although the three mammalian isoforms of TGF-beta are highly homologous at the level of sequence, analysis of their in vivo function by gene knockouts revealed striking differences, suggesting no significant functional redundancy between TGF-beta1, -2 and -3. While signal transduction by TGF-beta1 has been well characterized, receptor binding and activation by the TGF-beta2 isoform is less well understood. Here, we show that TbetaRII-B, an alternatively spliced variant of the TGF-beta type II receptor, is a TGF-beta2 binding receptor, which mediates signalling via the Smad pathway in the absence of any TGF-beta type III receptor (TbetaRIII). L6 cells lacking endogenous TbetaRIII as well as TbetaRII-B do not respond to TGF-beta2. Transfection of these cells with TbetaRII-B restores TGF-beta2 sensitivity. The expression of TbetaRII-B is restricted to cells originating from tissues such as bone where the isoform TGF-beta2 has a predominant role. This reflects the importance of this receptor in TGF-beta isoform-specific signalling.
Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a follicle-stimulating hormone stimulus.
J. Clin. Endocrinol. Metab. 88, 5002-5008 (2003)[PubMed:14557487]
Activins and inhibins are often antagonistic in the regulation of ovarian function. TGFbeta type III receptor, betaglycan, has been identified as a coreceptor to enhance the binding of inhibins to activin type II receptor and thus to prevent the binding of activins to their receptor. In this study we characterized the expression and regulation pattern of betaglycan gene in normal ovaries and sex cord-stromal tumors and in cultured human granulosa-luteal cells from women undergoing in vitro fertilization. Expression of betaglycan mRNA was detected by RT-PCR or Northern blotting in normal ovarian granulosa, thecal, and stroma cells as well as in granulosa-luteal cells. Immunohistochemical analysis revealed positive staining for betaglycan in antral and preovulatory follicular granulosa and thecal cells and in corpora lutea of normal ovaries. 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. 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. In contrast, the protein kinase C activator 12-O-tetradecanoyl phorbol 13-acetate had no significant effect on betaglycan mRNA levels. Treatment with prostaglandin E(2) and with its receptor EP2 subtype agonist butaprost increased betaglycan mRNA accumulation and progesterone secretion dose- and time-dependently. In summary, betaglycan gene is expressed in normal human ovarian steroidogenic cells and sex cord-stromal ovarian tumors. The accumulation of its mRNA in cultured granulosa-luteal cells is up-regulated by gonadotropins and prostaglandin E(2), probably via the protein kinase A pathway. The specific expression and regulation pattern of betaglycan gene may be related to the functional antagonism of inhibins to activin signal transduction in human ovaries.
Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a stimulus indicating lowered oxygen tension. Hypoxia, defined as a decline in O2 levels below normoxic levels of 20.8 - 20.95%, results in metabolic adaptation at both the cellular and organismal level.
Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a luteinizing hormone stimulus.
J. Clin. Endocrinol. Metab. 88, 5002-5008 (2003)[PubMed:14557487]
Activins and inhibins are often antagonistic in the regulation of ovarian function. TGFbeta type III receptor, betaglycan, has been identified as a coreceptor to enhance the binding of inhibins to activin type II receptor and thus to prevent the binding of activins to their receptor. In this study we characterized the expression and regulation pattern of betaglycan gene in normal ovaries and sex cord-stromal tumors and in cultured human granulosa-luteal cells from women undergoing in vitro fertilization. Expression of betaglycan mRNA was detected by RT-PCR or Northern blotting in normal ovarian granulosa, thecal, and stroma cells as well as in granulosa-luteal cells. Immunohistochemical analysis revealed positive staining for betaglycan in antral and preovulatory follicular granulosa and thecal cells and in corpora lutea of normal ovaries. 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. 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. In contrast, the protein kinase C activator 12-O-tetradecanoyl phorbol 13-acetate had no significant effect on betaglycan mRNA levels. Treatment with prostaglandin E(2) and with its receptor EP2 subtype agonist butaprost increased betaglycan mRNA accumulation and progesterone secretion dose- and time-dependently. In summary, betaglycan gene is expressed in normal human ovarian steroidogenic cells and sex cord-stromal ovarian tumors. The accumulation of its mRNA in cultured granulosa-luteal cells is up-regulated by gonadotropins and prostaglandin E(2), probably via the protein kinase A pathway. The specific expression and regulation pattern of betaglycan gene may be related to the functional antagonism of inhibins to activin signal transduction in human ovaries.
Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a prostagladin E stimulus.
J. Clin. Endocrinol. Metab. 88, 5002-5008 (2003)[PubMed:14557487]
Activins and inhibins are often antagonistic in the regulation of ovarian function. TGFbeta type III receptor, betaglycan, has been identified as a coreceptor to enhance the binding of inhibins to activin type II receptor and thus to prevent the binding of activins to their receptor. In this study we characterized the expression and regulation pattern of betaglycan gene in normal ovaries and sex cord-stromal tumors and in cultured human granulosa-luteal cells from women undergoing in vitro fertilization. Expression of betaglycan mRNA was detected by RT-PCR or Northern blotting in normal ovarian granulosa, thecal, and stroma cells as well as in granulosa-luteal cells. Immunohistochemical analysis revealed positive staining for betaglycan in antral and preovulatory follicular granulosa and thecal cells and in corpora lutea of normal ovaries. 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. 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. In contrast, the protein kinase C activator 12-O-tetradecanoyl phorbol 13-acetate had no significant effect on betaglycan mRNA levels. Treatment with prostaglandin E(2) and with its receptor EP2 subtype agonist butaprost increased betaglycan mRNA accumulation and progesterone secretion dose- and time-dependently. In summary, betaglycan gene is expressed in normal human ovarian steroidogenic cells and sex cord-stromal ovarian tumors. The accumulation of its mRNA in cultured granulosa-luteal cells is up-regulated by gonadotropins and prostaglandin E(2), probably via the protein kinase A pathway. The specific expression and regulation pattern of betaglycan gene may be related to the functional antagonism of inhibins to activin signal transduction in human ovaries.
The aggregation, arrangement and bonding together of a ligand-bound type II transforming growth factor beta (TGF-beta) receptor dimer with a type I TGF-beta receptor dimer, following ligand binding, to form a heterotetrameric TGF-beta receptor complex.
A series of molecular signals initiated by the binding of an extracellular ligand to a transforming growth factor beta receptor on the surface of a target cell, and ending with regulation of a downstream cellular process, e.g. transcription.
beta-Arrestins bind to activated seven transmembrane-spanning (7TMS) receptors (G protein-coupled receptors) after the receptors are phosphorylated by G protein-coupled receptor kinases (GRKs), thereby regulating their signaling and internalization. Here, we demonstrate an unexpected and analogous role of beta-arrestin 2 (betaarr2) for the single transmembrane-spanning type III transforming growth factor-beta (TGF-beta) receptor (TbetaRIII, also referred to as betaglycan). Binding of betaarr2 to TbetaRIII was also triggered by phosphorylation of the receptor on its cytoplasmic domain (likely at threonine 841). However, such phosphorylation was mediated by the type II TGF-beta receptor (TbetaRII), which is itself a kinase, rather than by a GRK. Association with betaarr2 led to internalization of both receptors and down-regulation of TGF-beta signaling. Thus, the regulatory actions of beta-arrestins are broader than previously appreciated, extending to the TGF-beta receptor family as well.
Transforming growth factor-beta (TGF-beta) signals through membrane-bound serine/threonine kinase receptors, which upon stimulation phosphorylate Smad proteins and thereby trigger their nuclear translocation and transcriptional activity. Although the three mammalian isoforms of TGF-beta are highly homologous at the level of sequence, analysis of their in vivo function by gene knockouts revealed striking differences, suggesting no significant functional redundancy between TGF-beta1, -2 and -3. While signal transduction by TGF-beta1 has been well characterized, receptor binding and activation by the TGF-beta2 isoform is less well understood. Here, we show that TbetaRII-B, an alternatively spliced variant of the TGF-beta type II receptor, is a TGF-beta2 binding receptor, which mediates signalling via the Smad pathway in the absence of any TGF-beta type III receptor (TbetaRIII). L6 cells lacking endogenous TbetaRIII as well as TbetaRII-B do not respond to TGF-beta2. Transfection of these cells with TbetaRII-B restores TGF-beta2 sensitivity. The expression of TbetaRII-B is restricted to cells originating from tissues such as bone where the isoform TGF-beta2 has a predominant role. This reflects the importance of this receptor in TGF-beta isoform-specific signalling.
A reference proteome is a set of protein sequences derived from a complete proteome which constitutes a defined standard for a particular user community. Reference proteomes are manually defined according to a number of criteria. They cover the proteomes of well- studied model organisms and other proteomes of interest for biomedical and biotechnological research. Reference proteomes have been selected to provide broad coverage of the tree of life, and constitute a representative cross-section of the taxonomic diversity to be found within UniProtKB.
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