The Experts below are selected from a list of 132 Experts worldwide ranked by ideXlab platform
Jie Zheng - One of the best experts on this subject based on the ideXlab platform.
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autoinhibition of Dishevelled Protein regulated by its extreme c terminus plays a distinct role in wnt β catenin and wnt planar cell polarity pcp signaling pathways
Journal of Biological Chemistry, 2017Co-Authors: Jing Qi, Jie Zheng, Audrey Saquet, Xiaoning Cheng, Ming ShaoAbstract:Dishevelled (Dvl) is a key intracellular signaling molecule that mediates the activation of divergent Wnt pathways. It contains three highly conserved domains known as DIX, PDZ, and DEP, the functions of which have been well characterized in β-catenin-dependent canonical and β-catenin-independent noncanonical Wnt signaling. The C-terminal region is also highly conserved from invertebrates to vertebrates. However, its function in regulating the activation of different Wnt signals remains unclear. We reported previously that Dvl conformational change triggered by the highly conserved PDZ-binding C terminus is important for the pathway specificity. Here we provide further evidence demonstrating that binding of the C terminus to the PDZ domain results in Dvl autoinhibition in the Wnt signaling pathways. Therefore, the forced binding of the C terminus to the PDZ domain reduces the activity of Dvl in noncanonical Wnt signaling, whereas obstruction of this interaction releases Dvl autoinhibition, impairs its functional interaction with LRP6 in canonical Wnt signaling, and increases its specificity in noncanonical Wnt signaling, which is closely correlated with an enhanced Dvl membrane localization. Our findings highlight the importance of the C terminus in keeping Dvl in an appropriate autoinhibited state, accessible for regulation by other partners to switch pathway specificity. Particularly, the C-terminally tagged Dvl fusion Proteins that have been widely used to study the function and cellular localization of Dvl may not truly represent the wild-type Dvl because those Proteins cannot be autoinhibited.
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Autoinhibition of Dishevelled Protein regulated by its extreme C terminus plays a distinct role in Wnt/β-catenin and Wnt/planar cell polarity (PCP) signaling pathways.
Journal of Biological Chemistry, 2017Co-Authors: Jing Qi, Audrey Saquet, Xiaoning Cheng, Ming Shao, Jie ZhengAbstract:Dishevelled (Dvl) is a key intracellular signaling molecule that mediates the activation of divergent Wnt pathways. It contains three highly conserved domains known as DIX, PDZ, and DEP, the functions of which have been well characterized in β-catenin-dependent canonical and β-catenin-independent noncanonical Wnt signaling. The C-terminal region is also highly conserved from invertebrates to vertebrates. However, its function in regulating the activation of different Wnt signals remains unclear. We reported previously that Dvl conformational change triggered by the highly conserved PDZ-binding C terminus is important for the pathway specificity. Here we provide further evidence demonstrating that binding of the C terminus to the PDZ domain results in Dvl autoinhibition in the Wnt signaling pathways. Therefore, the forced binding of the C terminus to the PDZ domain reduces the activity of Dvl in noncanonical Wnt signaling, whereas obstruction of this interaction releases Dvl autoinhibition, impairs its functional interaction with LRP6 in canonical Wnt signaling, and increases its specificity in noncanonical Wnt signaling, which is closely correlated with an enhanced Dvl membrane localization. Our findings highlight the importance of the C terminus in keeping Dvl in an appropriate autoinhibited state, accessible for regulation by other partners to switch pathway specificity. Particularly, the C-terminally tagged Dvl fusion Proteins that have been widely used to study the function and cellular localization of Dvl may not truly represent the wild-type Dvl because those Proteins cannot be autoinhibited.
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an antagonist of Dishevelled Protein Protein interaction suppresses beta catenin dependent tumor cell growth
Cancer Research, 2007Co-Authors: Naoaki Fujii, Lillian R. Edmondson, Zhidong Xu, Iwao Mikami, Jufang Shan, Geoffrey Neale, Kazutsugu Uematsu, Biao He, Jie Zheng, David M JablonsAbstract:Recent progress in the development of inhibitors of Protein-Protein interactions has opened the door for developing drugs that act by novel and selective mechanisms. Building on that work, we designed a small-molecule inhibitor of the Wnt signaling pathway, which is aberrantly activated across a wide range of human tumors. The compound, named FJ9, disrupts the interaction between the Frizzed-7 Wnt receptor and the PDZ domain of Dishevelled, down-regulating canonical Wnt signaling and suppressing tumor cell growth. The antitumorigenic effects of FJ9 were pronounced, including induction of apoptosis in human cancer cell lines and tumor growth inhibition in a mouse xenograft model. FJ9 is thus among the first non-peptide inhibitors to show therapeutic efficacy through disruption of PDZ Protein-Protein interactions.
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An antagonist of Dishevelled Protein-Protein interaction suppresses β-catenin-dependent tumor cell growth
Cancer Research, 2007Co-Authors: Naoaki Fujii, Liang You, Lillian R. Edmondson, Zhidong Xu, Iwao Mikami, Jufang Shan, Geoffrey Neale, Kazutsugu Uematsu, Biao He, Jie ZhengAbstract:Recent progress in the development of inhibitors of Protein-Protein interactions has opened the door for developing drugs that act by novel and selective mechanisms. Building on that work, we designed a small-molecule inhibitor of the Wnt signaling pathway, which is aberrantly activated across a wide range of human tumors. The compound, named FJ9, disrupts the interaction between the Frizzed-7 Wnt receptor and the PDZ domain of Dishevelled, down-regulating canonical Wnt signaling and suppressing tumor cell growth. The antitumorigenic effects of FJ9 were pronounced, including induction of apoptosis in human cancer cell lines and tumor growth inhibition in a mouse xenograft model. FJ9 is thus among the first non-peptide inhibitors to show therapeutic efficacy through disruption of PDZ Protein-Protein interactions. © 2007 American Association for Cancer Research.
Hiroaki Miki - One of the best experts on this subject based on the ideXlab platform.
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nucleoredoxin sustains wnt β catenin signaling by retaining a pool of inactive Dishevelled Protein
Current Biology, 2010Co-Authors: Yosuke Funato, Takeshi Terabayashi, Reiko Sakamoto, Daisuke Okuzaki, Hirotake Ichise, Hiroshi Nojima, Nobuaki Yoshida, Hiroaki MikiAbstract:Summary Overexpression of Dishevelled (Dvl), an essential component of the Wnt signaling pathway, is frequently associated with tumors [1, 2], and thus the Dvl Protein level must be tightly controlled to sustain Wnt signaling without causing tumors. Kelch-like 12 (KLHL12) targets Dvl for ubiquitination and degradation [3], suggesting its potential importance in avoiding aberrant Dvl overexpression. However, the regulatory mechanism of the KLHL12 activity remained elusive. We show here that nucleoredoxin (NRX) determines the Dvl Protein level, which is revealed by analyses on NRX −/− mice showing skeletal and cardiovascular defects. Consistent with the previously reported Dvl-inhibiting function of NRX [4], Wnt/β-catenin signaling is hyperactivated in NRX −/− osteoblasts. However, the signal activity is suppressed in cardiac cells, where KLHL12 is highly expressed. Biochemical analyses reveal that Dvl is rapidly degraded by accelerated ubiquitination in NRX −/− mouse embryonic fibroblasts, and they fail to activate Wnt/β-catenin signaling in response to Wnt ligands. Moreover, experiments utilizing purified Proteins show that NRX expels KLHL12 from Dvl and inhibits ubiquitination. These findings reveal an unexpected function of NRX, retaining a pool of inactive Dvl for robust activation of Wnt/β-catenin signaling upon Wnt stimulation.
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Nucleoredoxin Sustains Wnt/β-Catenin Signaling by Retaining a Pool of Inactive Dishevelled Protein
Current Biology, 2010Co-Authors: Yosuke Funato, Takeshi Terabayashi, Reiko Sakamoto, Daisuke Okuzaki, Hirotake Ichise, Hiroshi Nojima, Nobuaki Yoshida, Hiroaki MikiAbstract:Summary Overexpression of Dishevelled (Dvl), an essential component of the Wnt signaling pathway, is frequently associated with tumors [1, 2], and thus the Dvl Protein level must be tightly controlled to sustain Wnt signaling without causing tumors. Kelch-like 12 (KLHL12) targets Dvl for ubiquitination and degradation [3], suggesting its potential importance in avoiding aberrant Dvl overexpression. However, the regulatory mechanism of the KLHL12 activity remained elusive. We show here that nucleoredoxin (NRX) determines the Dvl Protein level, which is revealed by analyses on NRX −/− mice showing skeletal and cardiovascular defects. Consistent with the previously reported Dvl-inhibiting function of NRX [4], Wnt/β-catenin signaling is hyperactivated in NRX −/− osteoblasts. However, the signal activity is suppressed in cardiac cells, where KLHL12 is highly expressed. Biochemical analyses reveal that Dvl is rapidly degraded by accelerated ubiquitination in NRX −/− mouse embryonic fibroblasts, and they fail to activate Wnt/β-catenin signaling in response to Wnt ligands. Moreover, experiments utilizing purified Proteins show that NRX expels KLHL12 from Dvl and inhibits ubiquitination. These findings reveal an unexpected function of NRX, retaining a pool of inactive Dvl for robust activation of Wnt/β-catenin signaling upon Wnt stimulation.
Roel Nusse - One of the best experts on this subject based on the ideXlab platform.
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a mutational analysis of Dishevelled in drosophila defines novel domains in the Dishevelled Protein as well as novel suppressing alleles of axin
Genetics, 2002Co-Authors: Andrea Penton, Andreas Wodarz, Roel NusseAbstract:Drosophila Dishevelled (dsh) functions in two pathways: it is necessary to transduce Wingless (Wg) signaling and it is required in planar cell polarity. To learn more about how Dsh can discriminate between these functions, we performed genetic screens to isolate additional dsh alleles and we examined the potential role of Protein phosphorylation by site-directed mutagenesis. We identified two alleles with point mutations in the Dsh DEP domain that specifically disrupt planar polarity signaling. When positioned in the structure of the DEP domain, these mutations are located close to each other and to a previously identified planar polarity mutation. In addition to the requirement for the DEP domain, we found that a cluster of potential phosphorylation sites in a binding domain for the Protein kinase PAR-1 is also essential for planar polarity signaling. To identify regions of dsh that are necessary for Wg signaling, we screened for mutations that modified a GMR-GAL4;UAS-dsh overexpression phenotype in the eye. We recovered many alleles of the transgene containing missense mutations, including mutations in the DIX domain and in the DEP domain, the latter group mapping separately from the planar polarity mutations. In addition, several transgenes had mutations within a domain containing a consensus sequence for an SH3-binding Protein. We also recovered second-site-suppressing mutations in axin, mapping at a region that may specifically interact with overexpressed Dsh.
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the Dishevelled Protein is modified by wingless signaling in drosophila
Genes & Development, 1995Co-Authors: Shinichi Yanagawa, F E Van Leeuwen, Andreas Wodarz, John Klingensmith, Roel NusseAbstract:: Wingless (Wg) is an important signaling molecule in the development of Drosophila, but little is known about its signal transduction pathway. Genetic evidence indicates that another segment polarity gene, Dishevelled (dsh) is required for Wg signaling. We have recently developed a cell culture system for Wg Protein activity, and using this in vitro system as well as intact Drosophila embryos, we have analyzed biochemical changes in the Dsh Protein as a consequence of Wg signaling. We find that Dsh is a phosphoProtein, normally present in the cytoplasm. Wg signaling generates a hyperphosphorylated form of Dsh, which is associated with a membrane fraction. Overexpressed Dsh becomes hyperphosphorylated in the absence of extracellular Wg and increases levels of the Armadillo Protein, thereby mimicking the Wg signal. A deletional analysis of Dsh identifies several conserved domains essential for activity, among which is a so-called GLGF/DHR motif. We conclude that dsh, a highly conserved gene, is not merely a permissive factor in Wg signaling but encodes a novel signal transduction molecule, which may function between the Wg receptor and more downstream signaling molecules.
Jing Qi - One of the best experts on this subject based on the ideXlab platform.
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autoinhibition of Dishevelled Protein regulated by its extreme c terminus plays a distinct role in wnt β catenin and wnt planar cell polarity pcp signaling pathways
Journal of Biological Chemistry, 2017Co-Authors: Jing Qi, Jie Zheng, Audrey Saquet, Xiaoning Cheng, Ming ShaoAbstract:Dishevelled (Dvl) is a key intracellular signaling molecule that mediates the activation of divergent Wnt pathways. It contains three highly conserved domains known as DIX, PDZ, and DEP, the functions of which have been well characterized in β-catenin-dependent canonical and β-catenin-independent noncanonical Wnt signaling. The C-terminal region is also highly conserved from invertebrates to vertebrates. However, its function in regulating the activation of different Wnt signals remains unclear. We reported previously that Dvl conformational change triggered by the highly conserved PDZ-binding C terminus is important for the pathway specificity. Here we provide further evidence demonstrating that binding of the C terminus to the PDZ domain results in Dvl autoinhibition in the Wnt signaling pathways. Therefore, the forced binding of the C terminus to the PDZ domain reduces the activity of Dvl in noncanonical Wnt signaling, whereas obstruction of this interaction releases Dvl autoinhibition, impairs its functional interaction with LRP6 in canonical Wnt signaling, and increases its specificity in noncanonical Wnt signaling, which is closely correlated with an enhanced Dvl membrane localization. Our findings highlight the importance of the C terminus in keeping Dvl in an appropriate autoinhibited state, accessible for regulation by other partners to switch pathway specificity. Particularly, the C-terminally tagged Dvl fusion Proteins that have been widely used to study the function and cellular localization of Dvl may not truly represent the wild-type Dvl because those Proteins cannot be autoinhibited.
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Autoinhibition of Dishevelled Protein regulated by its extreme C terminus plays a distinct role in Wnt/β-catenin and Wnt/planar cell polarity (PCP) signaling pathways.
Journal of Biological Chemistry, 2017Co-Authors: Jing Qi, Audrey Saquet, Xiaoning Cheng, Ming Shao, Jie ZhengAbstract:Dishevelled (Dvl) is a key intracellular signaling molecule that mediates the activation of divergent Wnt pathways. It contains three highly conserved domains known as DIX, PDZ, and DEP, the functions of which have been well characterized in β-catenin-dependent canonical and β-catenin-independent noncanonical Wnt signaling. The C-terminal region is also highly conserved from invertebrates to vertebrates. However, its function in regulating the activation of different Wnt signals remains unclear. We reported previously that Dvl conformational change triggered by the highly conserved PDZ-binding C terminus is important for the pathway specificity. Here we provide further evidence demonstrating that binding of the C terminus to the PDZ domain results in Dvl autoinhibition in the Wnt signaling pathways. Therefore, the forced binding of the C terminus to the PDZ domain reduces the activity of Dvl in noncanonical Wnt signaling, whereas obstruction of this interaction releases Dvl autoinhibition, impairs its functional interaction with LRP6 in canonical Wnt signaling, and increases its specificity in noncanonical Wnt signaling, which is closely correlated with an enhanced Dvl membrane localization. Our findings highlight the importance of the C terminus in keeping Dvl in an appropriate autoinhibited state, accessible for regulation by other partners to switch pathway specificity. Particularly, the C-terminally tagged Dvl fusion Proteins that have been widely used to study the function and cellular localization of Dvl may not truly represent the wild-type Dvl because those Proteins cannot be autoinhibited.
Andreas Wodarz - One of the best experts on this subject based on the ideXlab platform.
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a mutational analysis of Dishevelled in drosophila defines novel domains in the Dishevelled Protein as well as novel suppressing alleles of axin
Genetics, 2002Co-Authors: Andrea Penton, Andreas Wodarz, Roel NusseAbstract:Drosophila Dishevelled (dsh) functions in two pathways: it is necessary to transduce Wingless (Wg) signaling and it is required in planar cell polarity. To learn more about how Dsh can discriminate between these functions, we performed genetic screens to isolate additional dsh alleles and we examined the potential role of Protein phosphorylation by site-directed mutagenesis. We identified two alleles with point mutations in the Dsh DEP domain that specifically disrupt planar polarity signaling. When positioned in the structure of the DEP domain, these mutations are located close to each other and to a previously identified planar polarity mutation. In addition to the requirement for the DEP domain, we found that a cluster of potential phosphorylation sites in a binding domain for the Protein kinase PAR-1 is also essential for planar polarity signaling. To identify regions of dsh that are necessary for Wg signaling, we screened for mutations that modified a GMR-GAL4;UAS-dsh overexpression phenotype in the eye. We recovered many alleles of the transgene containing missense mutations, including mutations in the DIX domain and in the DEP domain, the latter group mapping separately from the planar polarity mutations. In addition, several transgenes had mutations within a domain containing a consensus sequence for an SH3-binding Protein. We also recovered second-site-suppressing mutations in axin, mapping at a region that may specifically interact with overexpressed Dsh.
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the Dishevelled Protein is modified by wingless signaling in drosophila
Genes & Development, 1995Co-Authors: Shinichi Yanagawa, F E Van Leeuwen, Andreas Wodarz, John Klingensmith, Roel NusseAbstract:: Wingless (Wg) is an important signaling molecule in the development of Drosophila, but little is known about its signal transduction pathway. Genetic evidence indicates that another segment polarity gene, Dishevelled (dsh) is required for Wg signaling. We have recently developed a cell culture system for Wg Protein activity, and using this in vitro system as well as intact Drosophila embryos, we have analyzed biochemical changes in the Dsh Protein as a consequence of Wg signaling. We find that Dsh is a phosphoProtein, normally present in the cytoplasm. Wg signaling generates a hyperphosphorylated form of Dsh, which is associated with a membrane fraction. Overexpressed Dsh becomes hyperphosphorylated in the absence of extracellular Wg and increases levels of the Armadillo Protein, thereby mimicking the Wg signal. A deletional analysis of Dsh identifies several conserved domains essential for activity, among which is a so-called GLGF/DHR motif. We conclude that dsh, a highly conserved gene, is not merely a permissive factor in Wg signaling but encodes a novel signal transduction molecule, which may function between the Wg receptor and more downstream signaling molecules.