The Experts below are selected from a list of 174 Experts worldwide ranked by ideXlab platform
Joan Massagué - One of the best experts on this subject based on the ideXlab platform.
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activation of signalling by the activin receptor complex
Molecular and Cellular Biology, 1996Co-Authors: Liliana Attisano, Jeffrey L Wrana, Elizabeth Montalvo, Joan MassaguéAbstract:Activin exerts its effects by simultaneously binding to two types of p rotein serine/threonine kinase receptors, each type existing in various isoforms. Using the ActR-IB and ActR-IIB receptor isoforms, we have investigated the mechanism of activin receptor activation. ActR-IIB are phosphoproteins with demonstrable affinity for each other. However, activin addition strongly promotes an interaction between these two proteins. Activin binds directly to ActR-IIB, and this complex associates with ActR-IB, which does not bind ligand on its own. In the resulting complex, ActR-IB becomes hyperphosphorylated, and this requires the kinase activity of ActR-IIB. Mutation of conserved serines and threonines in the GS Domain, a region just upstream of the kinase Domain in ActR-IB, abrogates both phosphorylation and signal propagation, suggesting that this Domain contains phosphorylation sites required for signalling. ActR-IB activation can be mimicked by mutation of Thr-206 to aspartic acid, which yields a construct, ActR-IB(T206D), that signals in the absence of ligand. Furthermore, the signalling activity of this mutant construct is undisturbed by overexpression of a dominant negative kinase-defective ActR-IIB construct, indicating that ActR-IB(T206D) can signal independently of ActR-IIB. The evidence suggests that ActR-IIB acts as a primary activin receptor and ActR-IB acts as a downstream transducer of activin signals.
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Complementation between kinase-defective and activation-defective TGF-beta receptors reveals a novel form of receptor cooperativity essential for signaling.
The EMBO Journal, 1996Co-Authors: F Weis-garcia, Joan MassaguéAbstract:Transforming growth factor-beta (TGF-beta) signals through two transmembrane serine/threonine kinases, T beta R-I and T beta R-II. TGF-beta binds to T beta R-II, allowing this receptor to associate with and phosphorylate T beta R-I which then propagates the signal. T beta R-I is phosphorylated within its GS Domain, a region immediately preceding the kinase Domain. To further understand the function of T beta R-I in this complex, we analyzed T beta R-I-inactivating mutations identified in cell lines that are defective in TGF-beta signaling yet retain ligand binding ability. The three mutations identified here all fall in the kinase Domain of T beta R-I. One mutation disrupts the kinase activity of T beta R-I, whereas the other two mutations prevent ligand-induced T beta R-I phosphorylation, and thus activation, by T beta R-II. Unexpectedly, a kinase-defective T beta R-I mutant can functionally complement an activation- defective T beta R-I mutant, by rescuing its T beta R-II- dependent phosphorylation. Together with evidence that the ligand-induced receptor complex contains two or more T beta R-I molecules, these results support a model in which the kinase Domain of one T beta R-I molecule interacts with the GS Domain of another, enabling its phosphorylation and activation by T beta R-II. This cooperative interaction between T beta R-I molecules appears essential for TGF-beta signal transduction.
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GS Domain mutations that constitutively activate t beta r i the downstream signaling component in the tgf beta receptor complex
The EMBO Journal, 1995Co-Authors: Rotraud Wieser, Jeffrey L Wrana, Joan MassaguéAbstract:The TGF-beta type II receptor (T beta R-II) is a transmembrane serine/threonine kinase that, upon ligand binding, recruits and phosphorylates a second transmembrane kinase, T beta R-I, as a requirement for signal transduction. T beta R-I is phosphorylated by T beta R-II in the GS Domain, a 30 amino acid region preceding the kinase Domain and conserved in type I receptors for other TGF-beta-related factors. The functional role of seven serines and threonines in the T beta R-I GS Domain was investigated by mutational analysis. Five of these residues are clustered (TTSGSGSG) in the middle of the GS Domain. Mutation of two or more of these residues impairs phosphorylation and signaling activity. Two additional threonines are located near the canonical start of the kinase Domain, and their individual mutation to valine strongly inhibits receptor phosphorylation and signaling activity. Replacement of one of these residues, Thr204, with aspartic acid yields a product that has elevated in vitro kinase activity and signals anti-proliferative and transcriptional responses in the absence of ligand and T beta R-II. The identification of constitutively active T beta R-I forms confirms the hypothesis that this kinase acts as a down-stream signaling component in the TGF-beta receptor complex, and its activation by T beta R-II or by mutation is necessary and sufficient for propagation of anti-proliferative and transcriptional responses.
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two distinct transmembrane serine threonine kinases from drosophila melanogaster form an activin receptor complex
Molecular and Cellular Biology, 1994Co-Authors: Jeffrey L Wrana, Hien Tran, Kavita Arora, Joan Massagué, Liliana Attisano, Steven R. Childs, Michael B OconnorAbstract:Abstract A transmembrane protein serine/threonine kinase, Atr-I, that is structurally related to receptors for members of the transforming growth factor-beta (TGF-beta) family has been cloned from Drosophila melanogaster. The spacing of extracellular cysteines and the cytoplasmic Domain of Atr-I resemble most closely those of the recently described mammalian type I receptors for TGF-beta and activin. When expressed alone in test cells, Atr-I is unable to bind TGF-beta, activin, or bone morphogenetic protein 2. However, Atr-I binds activin efficiently when coexpressed with the distantly related Drosophila activin receptor Atr-II, with which it forms a heteromeric complex. Atr-I can also bind activin in concert with mammalian activin type II receptors. Two alternative forms of Atr-I have been identified that differ in an ectoDomain region encompassing the cysteine box motif characteristic of receptors in this family. Comparison of Atr-I with other type I receptors reveals the presence of a characteristic 30-amino-acid Domain immediately upstream of the kinase region in all these receptors. This Domain, of unknown function, contains a repeated Gly-Ser sequence and is therefore referred to as the GS Domain. Maternal Atr-I transcripts are abundant in the oocyte and widespread during embryo development and in the imaginal discs of the larva. The structural properties, binding specificity, and dependence on type II receptors define Atr-I as an activin type I receptor from D. melanogaster. These results indicate that the heteromeric kinase structure is a general feature of this receptor family.
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Two distinct transmembrane serine/threonine kinases from Drosophila melanogaster form an activin receptor complex.
Molecular and Cellular Biology, 1994Co-Authors: Jeffrey L Wrana, Hien Tran, Kavita Arora, Joan Massagué, Liliana Attisano, Steven R. Childs, Michael B. O'connorAbstract:Abstract A transmembrane protein serine/threonine kinase, Atr-I, that is structurally related to receptors for members of the transforming growth factor-beta (TGF-beta) family has been cloned from Drosophila melanogaster. The spacing of extracellular cysteines and the cytoplasmic Domain of Atr-I resemble most closely those of the recently described mammalian type I receptors for TGF-beta and activin. When expressed alone in test cells, Atr-I is unable to bind TGF-beta, activin, or bone morphogenetic protein 2. However, Atr-I binds activin efficiently when coexpressed with the distantly related Drosophila activin receptor Atr-II, with which it forms a heteromeric complex. Atr-I can also bind activin in concert with mammalian activin type II receptors. Two alternative forms of Atr-I have been identified that differ in an ectoDomain region encompassing the cysteine box motif characteristic of receptors in this family. Comparison of Atr-I with other type I receptors reveals the presence of a characteristic 30-amino-acid Domain immediately upstream of the kinase region in all these receptors. This Domain, of unknown function, contains a repeated Gly-Ser sequence and is therefore referred to as the GS Domain. Maternal Atr-I transcripts are abundant in the oocyte and widespread during embryo development and in the imaginal discs of the larva. The structural properties, binding specificity, and dependence on type II receptors define Atr-I as an activin type I receptor from D. melanogaster. These results indicate that the heteromeric kinase structure is a general feature of this receptor family.
Kohei Miyazono - One of the best experts on this subject based on the ideXlab platform.
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Phosphorylation of Ser165 in TGF-beta type I receptor modulates TGF-beta1-induced cellular responses.
The EMBO Journal, 1996Co-Authors: Serhiy Souchelnytskyi, Kohei Miyazono, P. Ten Dijke, C H HeldinAbstract:Abstract Transforming growth factor-beta (TGF-beta) signals via an oligomeric complex of two serine/threonine kinase receptors denoted TGF-beta type I receptor (TbetaR-I) and type II receptor (TbetaR-II). We investigated the in vivo phosphorylation sites in TbetaR-I and TbetaR-II after complex formation. Phosphorylation of TbetaR-II was observed at residues in the C-terminus (Ser549 and Ser551) and at residues in the juxtamembrane Domain (Ser223, Ser226 and Ser227). TGF-beta1 induced in vivo phosphorylation of serine and threonine residues in the juxtamembrane Domain of TbetaR-I in a region rich in glycine, serine and threonine residues (GS Domain; Thr185, Thr186, Ser187, Ser189 and Ser191), and more N-terminal of this region (Ser165). Phosphorylation in the GS Domain has been shown previously to be involved in activation of the TbetaR-I kinase. We show here that phosphorylation of TbetaR-I at Ser165 is involved in modulation of TGF-beta1 signaling. Mutations of Ser165 in TbetaR-I led to an increase in TGF-beta1-mediated growth inhibition and extracellular matrix formation, but, in contrast, to decreased TGF-beta1-induced apoptosis. A transcriptional activation signal was not affected. Mutations of Ser165 changed the phosphorylation pattern of TbetaR-I. These observations suggest that TGF-beta receptor signaling specificity is modulated by phosphorylation of Ser165 of TbetaR-I.
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Identification of Important Regions in the Cytoplasmic Juxtamembrane Domain of Type I Receptor That Separate Signaling Pathways of Transforming Growth Factor-β
Journal of Biological Chemistry, 1996Co-Authors: Masao Saitoh, Kohei Miyazono, Hideki Nishitoh, Teruo Amagasa, Minoru Takagi, Hidenori IchijoAbstract:Abstract Proteins in the transforming growth factor-β (TGF-β) superfamily exert their effects by forming heteromeric complexes of their type I and type II serine/threonine kinase receptors. The type I and type II receptors form distinct subgroups in the serine/threonine kinase receptor family based on the sequences of the kinase Domains and the presence of a highly conserved region called the GS Domain (or type I box) located just N-terminal to the kinase Domain in the type I receptors. Recent studies have revealed that upon TGF-β binding several serine and threonine residues in the GS Domain of TGF-β type I receptor (TβR-I) are phosphorylated by TGF-β type II receptor (TβR-II) and that the phosphorylation of GS Domain is essential for TGF-β signaling. Here we investigated the role of cytoplasmic juxtamembrane region located between the transmembrane Domain and the GS Domain of TβR-I by mutational analyses using mutant mink lung epithelial cells, which lack endogenous TβR-I. Upon transfection, wild-type TβR-I restored the TGF-β signals for growth inhibition and production of plasminogen activator inhibitor-1 (PAI-1) and fibronectin. A deletion mutant, TβR-I/JD1(Δ150-181), which lacks the juxtamembrane region preceding the GS Domain, bound TGF-β in concert with TβR-II and transduced a signal leading to production of PAI-1 but not growth inhibition. Recombinant receptors with mutations that change serine 172 to alanine (S172A) or threonine 176 to valine (T176V) were similar to wild-type TβR-I in their abilities to bind TGF-β, formed complexes with TβR-II, and transduced a signal for PAI-1 and fibronectin. Similar to TβR-I/JD1(Δ150-181), however, these missense mutant receptors were impaired to mediate a growth inhibitory signal. These observations indicate that serine 172 and threonine 176 of TβR-I are dispensable for extracellular matrix protein production but essential to the growth inhibition by TGF-β.
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TGF-β receptors and signal transduction
International Journal of Hematology, 1996Co-Authors: Kohei MiyazonoAbstract:Transforming growth factor-β (TGF-β) is a family of 25-kDa dimeric proteins that regulate the cellular growth and differentiation, the formation of extracellular matrix, and the immune function. TGF-βs belong to a larger family of structurally related proteins known as the TGF-β superfamily, which includes activins and bone morphogenetic proteins. TGF-β exerts the effects through binding to type I (TβR-I; 53 kDa) and type II (TβR-II; 75 kDa) serine/threonine kinase receptors. Overall structures of TβR-I and TβR-II are similar to each other. Preceding the kinase Domain of TβR-I, there is a region termed the GS Domain, which is conserved in type I receptors, but not in type II receptors. After ligand binding, TβR-I and TβR-II form a heteromeric receptor complex, which is most likely a heterotetramer composed of two molecules each of TβR-I and TβR-II. TβR-II transphosphorylates the GS Domain of TβR-I, which then activates the TβR-I kinase and transduces signals. By yeast two-hybrid system, several proteins which interact with type I or type II receptors, and possibly transduce the signals for TGF-p, have been isolated. Mutations in the TβR-II gene have been identified in several carcinoma cells, which suggests that loss of the TβR-II protein is one of the mechanisms by which cancer cells acquire resistance to the growth inhibitory activity of TGF-β.
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the GS Domain of the transforming growth factor β type i receptor is important in signal transduction
Biochemical and Biophysical Research Communications, 1995Co-Authors: Petra Franzen, C H Heldin, Kohei MiyazonoAbstract:Abstract Signal transduction by transforming growth factor-β (TGF-β) involves the formation of a heteromeric complex of two transmembrane serine/threonine kinase receptors, type I (TβR-T) and type II (TβR-II). In the region preceeding the kinase Domain of TβR-I there is a glycine- and serine-rich sequence, termed the GS Domain, which has been shown to be phosphorylated by TβR-II. In order to determine the importance of the serine residues in this Domain, receptor mutants with one or more serine residues mutated were analyzed. All the mutants of TβR-I were able to bind ligand and their kinase activity was not abolished by the mutations. The receptor mutants with single mutated serine residues mediated transcriptional responses to TGF-β with similar efficiency as the wild type receptor, whereas those with two or three of the serine residues mutated showed only weak trancriptional responses. These results suggest that serine residues in the GS Domain are important for signal transduction by TβR-I; however,the signaling activity of TβR-I does not depend on any particular serine residue in the GS Domain, but rather on how many of the serine residues in the region are intact.
Jeffrey L Wrana - One of the best experts on this subject based on the ideXlab platform.
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activation of signalling by the activin receptor complex
Molecular and Cellular Biology, 1996Co-Authors: Liliana Attisano, Jeffrey L Wrana, Elizabeth Montalvo, Joan MassaguéAbstract:Activin exerts its effects by simultaneously binding to two types of p rotein serine/threonine kinase receptors, each type existing in various isoforms. Using the ActR-IB and ActR-IIB receptor isoforms, we have investigated the mechanism of activin receptor activation. ActR-IIB are phosphoproteins with demonstrable affinity for each other. However, activin addition strongly promotes an interaction between these two proteins. Activin binds directly to ActR-IIB, and this complex associates with ActR-IB, which does not bind ligand on its own. In the resulting complex, ActR-IB becomes hyperphosphorylated, and this requires the kinase activity of ActR-IIB. Mutation of conserved serines and threonines in the GS Domain, a region just upstream of the kinase Domain in ActR-IB, abrogates both phosphorylation and signal propagation, suggesting that this Domain contains phosphorylation sites required for signalling. ActR-IB activation can be mimicked by mutation of Thr-206 to aspartic acid, which yields a construct, ActR-IB(T206D), that signals in the absence of ligand. Furthermore, the signalling activity of this mutant construct is undisturbed by overexpression of a dominant negative kinase-defective ActR-IIB construct, indicating that ActR-IB(T206D) can signal independently of ActR-IIB. The evidence suggests that ActR-IIB acts as a primary activin receptor and ActR-IB acts as a downstream transducer of activin signals.
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GS Domain mutations that constitutively activate t beta r i the downstream signaling component in the tgf beta receptor complex
The EMBO Journal, 1995Co-Authors: Rotraud Wieser, Jeffrey L Wrana, Joan MassaguéAbstract:The TGF-beta type II receptor (T beta R-II) is a transmembrane serine/threonine kinase that, upon ligand binding, recruits and phosphorylates a second transmembrane kinase, T beta R-I, as a requirement for signal transduction. T beta R-I is phosphorylated by T beta R-II in the GS Domain, a 30 amino acid region preceding the kinase Domain and conserved in type I receptors for other TGF-beta-related factors. The functional role of seven serines and threonines in the T beta R-I GS Domain was investigated by mutational analysis. Five of these residues are clustered (TTSGSGSG) in the middle of the GS Domain. Mutation of two or more of these residues impairs phosphorylation and signaling activity. Two additional threonines are located near the canonical start of the kinase Domain, and their individual mutation to valine strongly inhibits receptor phosphorylation and signaling activity. Replacement of one of these residues, Thr204, with aspartic acid yields a product that has elevated in vitro kinase activity and signals anti-proliferative and transcriptional responses in the absence of ligand and T beta R-II. The identification of constitutively active T beta R-I forms confirms the hypothesis that this kinase acts as a down-stream signaling component in the TGF-beta receptor complex, and its activation by T beta R-II or by mutation is necessary and sufficient for propagation of anti-proliferative and transcriptional responses.
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two distinct transmembrane serine threonine kinases from drosophila melanogaster form an activin receptor complex
Molecular and Cellular Biology, 1994Co-Authors: Jeffrey L Wrana, Hien Tran, Kavita Arora, Joan Massagué, Liliana Attisano, Steven R. Childs, Michael B OconnorAbstract:Abstract A transmembrane protein serine/threonine kinase, Atr-I, that is structurally related to receptors for members of the transforming growth factor-beta (TGF-beta) family has been cloned from Drosophila melanogaster. The spacing of extracellular cysteines and the cytoplasmic Domain of Atr-I resemble most closely those of the recently described mammalian type I receptors for TGF-beta and activin. When expressed alone in test cells, Atr-I is unable to bind TGF-beta, activin, or bone morphogenetic protein 2. However, Atr-I binds activin efficiently when coexpressed with the distantly related Drosophila activin receptor Atr-II, with which it forms a heteromeric complex. Atr-I can also bind activin in concert with mammalian activin type II receptors. Two alternative forms of Atr-I have been identified that differ in an ectoDomain region encompassing the cysteine box motif characteristic of receptors in this family. Comparison of Atr-I with other type I receptors reveals the presence of a characteristic 30-amino-acid Domain immediately upstream of the kinase region in all these receptors. This Domain, of unknown function, contains a repeated Gly-Ser sequence and is therefore referred to as the GS Domain. Maternal Atr-I transcripts are abundant in the oocyte and widespread during embryo development and in the imaginal discs of the larva. The structural properties, binding specificity, and dependence on type II receptors define Atr-I as an activin type I receptor from D. melanogaster. These results indicate that the heteromeric kinase structure is a general feature of this receptor family.
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Two distinct transmembrane serine/threonine kinases from Drosophila melanogaster form an activin receptor complex.
Molecular and Cellular Biology, 1994Co-Authors: Jeffrey L Wrana, Hien Tran, Kavita Arora, Joan Massagué, Liliana Attisano, Steven R. Childs, Michael B. O'connorAbstract:Abstract A transmembrane protein serine/threonine kinase, Atr-I, that is structurally related to receptors for members of the transforming growth factor-beta (TGF-beta) family has been cloned from Drosophila melanogaster. The spacing of extracellular cysteines and the cytoplasmic Domain of Atr-I resemble most closely those of the recently described mammalian type I receptors for TGF-beta and activin. When expressed alone in test cells, Atr-I is unable to bind TGF-beta, activin, or bone morphogenetic protein 2. However, Atr-I binds activin efficiently when coexpressed with the distantly related Drosophila activin receptor Atr-II, with which it forms a heteromeric complex. Atr-I can also bind activin in concert with mammalian activin type II receptors. Two alternative forms of Atr-I have been identified that differ in an ectoDomain region encompassing the cysteine box motif characteristic of receptors in this family. Comparison of Atr-I with other type I receptors reveals the presence of a characteristic 30-amino-acid Domain immediately upstream of the kinase region in all these receptors. This Domain, of unknown function, contains a repeated Gly-Ser sequence and is therefore referred to as the GS Domain. Maternal Atr-I transcripts are abundant in the oocyte and widespread during embryo development and in the imaginal discs of the larva. The structural properties, binding specificity, and dependence on type II receptors define Atr-I as an activin type I receptor from D. melanogaster. These results indicate that the heteromeric kinase structure is a general feature of this receptor family.
Eileen M Shore - One of the best experts on this subject based on the ideXlab platform.
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Variant BMP receptor mutations causing fibrodysplasia ossificans progressiva (FOP) in humans show BMP ligand-independent receptor activation in zebrafish.
Bone, 2018Co-Authors: Bettina E. Mucha, Eileen M Shore, Megumi Hashiguchi, Joseph Zinski, Mary C. MullinsAbstract:Abstract The large majority of cases of the autosomal dominant human disease fibrodysplasia ossificans progressiva (FOP) are caused by gain-of-function Arg206His mutations in the BMP type I receptor ACVR1 (ALK2). The Arg206His mutation is located in the GS Domain of the type I receptor. This region is normally phosphorylated by the BMP type II receptor, which activates the type I receptor to phosphorylate its substrate, the signal transducer Smad1/5/8. A small subset of patients with FOP carry variant mutations in ACVR1 altering Gly328 to Trp, Glu or Arg. Since these mutations lie outside the GS Domain, the mechanism through which ACVR1 Gly328 mutations cause disease remains unclear. We used a zebrafish embryonic development assay to test the signaling of human ACVR1 Gly328 mutant receptors comparing them to the Arg206His mutant. In this assay increased or decreased BMP pathway activation alters dorsal-ventral axial patterning, providing a sensitive assay for altered BMP signaling levels. We expressed the human ACVR1 Gly328 mutant receptors in zebrafish embryos to investigate their signaling activities. We found that all ACVR1 Gly328 human mutations ventralized wild-type embryos and could partially rescue Bmp7-deficient embryos, indicating that these mutant receptors can activate BMP signaling in a BMP ligand-independent manner. The degree of ventralization or rescue was similar among all three Gly328 mutants. Smad1/5 phosphorylation, a readout of BMP receptor signaling, was mildly increased by ACVR1 Gly328 mutations. Gene expression analyses demonstrate expanded ventral and reciprocal loss of dorsal cell fate markers. This study demonstrates that Gly328 mutants increase receptor activation and BMP ligand-independent signaling through Smad phosphorylation.
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Variable signaling activity by FOP ACVR1 mutations
Bone, 2017Co-Authors: Julia Haupt, Meiqi Xu, Eileen M ShoreAbstract:Abstract Most patients with fibrodysplasia ossificans progressiva (FOP), a rare genetic disorder of heterotopic ossification, have the same causative mutation in ACVR1, R206H. However, additional mutations within the ACVR1 BMP type I receptor have been identified in a small number of FOP cases, often in patients with disease of lesser or greater severity than occurs with R206H mutations. Genotype-phenotype correlations have been suggested in patients, resulting in classification of FOP mutations based on location within different receptor Domains and structural modeling. However while each of the mutations induces increased signaling through the BMP-pSmad1/5/8 pathway, the molecular mechanisms underlying functional differences of these FOP variant receptors remained undetermined. We now demonstrate that FOP mutations within the ACVR1 receptor kinase Domain are more sensitive to low levels of BMP than mutations in the ACVR1 GS Domain. Our data additionally confirm responsiveness of cells with FOP ACVR1 mutations to both BMP and Activin A ligands. We also have determined that constructs with FOP ACVR1 mutations that are engineered without the ligand-binding Domain retain increased BMP-pSmad1/5/8 pathway activation relative to wild-type ACVR1, supporting that the mutant receptors can function through ligand-independent mechanisms either directly through mutant ACVR1 or through indirect mechanisms.
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Fibrodysplasia ossificans progressiva (FOP): A disorder of extraskeletal endochondral ossification
Seminars in Arthritis and Rheumatism, 2013Co-Authors: Eileen M ShoreAbstract:Fibrodysplasia ossificans progressiva (FOP) is a genetic disorder in which extraskeletal bone forms in soft connective tissues, initiating during childhood and continuing throughout adult life. This heterotopic bone is qualitatively normal and forms through endochondral ossification. Episodes of bone formation often occur in response to injury. In addition to heterotopic ossification, FOP is associated with altered skeletal development, the most characteristic of which is malformation of the great toes. All FOP patients that we have examined carry mutations in ACVR1 , the gene encoding the ALK2 BMP type I receptor. Most patients are heterozygous for the same mutation in codon 206 (R206H) in the GS Domain of the receptor. This ACVR1/ALK2 mutation induces mild constitutive activation of the BMP pathway and enhances signaling in response to BMP. The identification of the causative gene in FOP, together with the development of in vivo and in vitro models for heterotopic ossification and mesenchymal cell differentiation, is providing opportunities to understand the cellular and molecular mechanisms that regulate chondrogenesis and osteogenesis and control the pathological induction of heterotopic bone formation. This knowledge will lead to novel approaches to modulate BMP signaling and bone formation and to the development of treatments for FOP and other disorders of bone and cartilage.
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a recurrent mutation in the bmp type i receptor acvr1 causes inherited and sporadic fibrodysplasia ossificans progressiva
Nature Genetics, 2006Co-Authors: Eileen M Shore, Meiqi Xu, George J Feldman, David A Fenstermacher, In Ho Choi, Michael J Connor, Patricia Delai, David L Glaser, Martine Lemerrer, Rolf MorhartAbstract:Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder of skeletal malformations and progressive extraskeletal ossification. We mapped FOP to chromosome 2q23-24 by linkage analysis and identified an identical heterozygous mutation (617G→A; R206H) in the glycine-serine (GS) activation Domain of ACVR1, a BMP type I receptor, in all affected individuals examined. Protein modeling predicts destabilization of the GS Domain, consistent with constitutive activation of ACVR1 as the underlying cause of the ectopic chondrogenesis, osteogenesis and joint fusions seen in FOP.
Petra Franzen - One of the best experts on this subject based on the ideXlab platform.
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the GS Domain of the transforming growth factor β type i receptor is important in signal transduction
Biochemical and Biophysical Research Communications, 1995Co-Authors: Petra Franzen, C H Heldin, Kohei MiyazonoAbstract:Abstract Signal transduction by transforming growth factor-β (TGF-β) involves the formation of a heteromeric complex of two transmembrane serine/threonine kinase receptors, type I (TβR-T) and type II (TβR-II). In the region preceeding the kinase Domain of TβR-I there is a glycine- and serine-rich sequence, termed the GS Domain, which has been shown to be phosphorylated by TβR-II. In order to determine the importance of the serine residues in this Domain, receptor mutants with one or more serine residues mutated were analyzed. All the mutants of TβR-I were able to bind ligand and their kinase activity was not abolished by the mutations. The receptor mutants with single mutated serine residues mediated transcriptional responses to TGF-β with similar efficiency as the wild type receptor, whereas those with two or three of the serine residues mutated showed only weak trancriptional responses. These results suggest that serine residues in the GS Domain are important for signal transduction by TβR-I; however,the signaling activity of TβR-I does not depend on any particular serine residue in the GS Domain, but rather on how many of the serine residues in the region are intact.
