The Experts below are selected from a list of 5256 Experts worldwide ranked by ideXlab platform
Xiaojiang Li - One of the best experts on this subject based on the ideXlab platform.
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a huntingtin hap1 pcm1 pathway in Ciliogenesis
Expert Review of Proteomics, 2012Co-Authors: Shihua Li, Xiaojiang LiAbstract:Evaluation of: Keryer G, Pineda JR, Liot G et al. Ciliogenesis is regulated by a huntingtin–HAP1–PCM1 pathway and is altered in Huntington disease. J. Clin. Invest. 121(11), 4372–4382 (2011).Huntington’s disease (HD) is caused by expansion of a polyglutamine repeat in the N-terminal region of huntingtin (htt), a large protein that has been found to interact with a variety of proteins. It remains to be determined how the interactions of htt with other proteins are involved in the pathogenesis of HD. A recent publication by Keryer et al. demonstrates that htt regulates Ciliogenesis by interacting with PCM1 through HAP1. This recent study shows that htt and HAP1 are essential for protein trafficking to the centrosome, as well as normal Ciliogenesis, and that mutant htt causes abnormal Ciliogenesis, providing a novel insight into the pathogenesis of HD.
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a huntingtin hap1 pcm1 pathway in Ciliogenesis
Expert Review of Proteomics, 2012Co-Authors: Shihua Li, Xiaojiang LiAbstract:Evaluation of: Keryer G, Pineda JR, Liot G et al. Ciliogenesis is regulated by a huntingtin–HAP1–PCM1 pathway and is altered in Huntington disease. J. Clin. Invest. 121(11), 4372–4382 (2011).Huntington’s disease (HD) is caused by expansion of a polyglutamine repeat in the N-terminal region of huntingtin (htt), a large protein that has been found to interact with a variety of proteins. It remains to be determined how the interactions of htt with other proteins are involved in the pathogenesis of HD. A recent publication by Keryer et al. demonstrates that htt regulates Ciliogenesis by interacting with PCM1 through HAP1. This recent study shows that htt and HAP1 are essential for protein trafficking to the centrosome, as well as normal Ciliogenesis, and that mutant htt causes abnormal Ciliogenesis, providing a novel insight into the pathogenesis of HD.
Suzanne R Pfeffer - One of the best experts on this subject based on the ideXlab platform.
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LRRK2-phosphorylated Rab10 sequesters Myosin Va with RILPL2 during Ciliogenesis blockade.
Life science alliance, 2021Co-Authors: Herschel S Dhekne, Francesca Tonelli, Federico Diez, Izumi Yanatori, Edmundo G Vides, Yuriko Sobu, Suzanne R PfefferAbstract:Activating mutations in LRRK2 kinase causes Parkinson's disease. Pathogenic LRRK2 phosphorylates a subset of Rab GTPases and blocks Ciliogenesis. Thus, defining novel phospho-Rab interacting partners is critical to our understanding of the molecular basis of LRRK2 pathogenesis. RILPL2 binds with strong preference to LRRK2-phosphorylated Rab8A and Rab10. RILPL2 is a binding partner of the motor protein and Rab effector, Myosin Va. We show here that the globular tail domain of Myosin Va also contains a high affinity binding site for LRRK2-phosphorylated Rab10. In the presence of pathogenic LRRK2, RILPL2 and MyoVa relocalize to the peri-centriolar region in a phosphoRab10-dependent manner. PhosphoRab10 retains Myosin Va over pericentriolar membranes as determined by fluorescence loss in photobleaching microscopy. Without pathogenic LRRK2, RILPL2 is not essential for Ciliogenesis but RILPL2 over-expression blocks Ciliogenesis in RPE cells independent of tau tubulin kinase recruitment to the mother centriole. These experiments show that LRRK2 generated-phosphoRab10 dramatically redistributes a significant fraction of Myosin Va and RILPL2 to the mother centriole in a manner that likely interferes with Myosin Va's role in Ciliogenesis.
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lrrk2 phosphorylated rab10 sequesters myosin va with rilpl2 during Ciliogenesis blockade
bioRxiv, 2020Co-Authors: Izumi Yanatori, Federico Diez, Herschel S Dhekne, Edmundo G Vides, Yuriko Sobu, Suzanne R PfefferAbstract:Activating mutations in LRRK2 kinase cause Parkinson9s disease. Pathogenic LRRK2 phosphorylates a subset of Rab GTPases and blocks Ciliogenesis. Thus, defining novel phospho-Rab interacting partners is critical to our understanding of the molecular basis of LRRK2 pathogenesis. RILPL2 binds with strong preference to LRRK2-phosphorylated Rab8A and Rab10. RILPL2 is a binding partner of the motor protein and Rab effector, Myosin Va. We show here that the globular tail domain of Myosin Va also contains a high affinity binding site for LRRK2-phosphorylated Rab10, and certain tissue-specific Myosin Va isoforms strongly prefer to bind phosphorylated Rab10. In the presence of pathogenic LRRK2, RILPL2 relocalizes to the peri-centriolar region in a phosphoRab10- and Myosin Va-dependent manner. In the absence of phosphoRab10, expression of RILPL2 or depletion of Myosin Va increase centriolar RILPL2 levels, and either condition is sufficient to block Ciliogenesis in RPE cells. These experiments show that LRRK2 generated phosphoRab10 dramatically redistributes Myosin Va-RILPL2 complexes to the mother centriole, which may sequester Myosin Va and RILPL2 in a manner that blocks their normal roles in Ciliogenesis.
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systematic proteomic analysis of lrrk2 mediated rab gtpase phosphorylation establishes a connection to Ciliogenesis
eLife, 2017Co-Authors: Martin Steger, Francesca Tonelli, Federico Diez, Suzanne R Pfeffer, Terina N Martinez, Herschel S Dhekne, Raja S Nirujogi, Ozge Karayel, Esben Lorentzen, Dario R AlessiAbstract:We previously reported that Parkinson’s disease (PD) kinase LRRK2 phosphorylates a subset of Rab GTPases on a conserved residue in their switch-II domains (Steger et al., 2016) (PMID: 26824392). Here, we systematically analyzed the Rab protein family and found 14 of them (Rab3A/B/C/D, Rab5A/B/C, Rab8A/B, Rab10, Rab12, Rab29, Rab35 and Rab43) to be specifically phosphorylated by LRRK2, with evidence for endogenous phosphorylation for ten of them (Rab3A/B/C/D, Rab8A/B, Rab10, Rab12, Rab35 and Rab43). Affinity enrichment mass spectrometry revealed that the primary Ciliogenesis regulator, RILPL1 specifically interacts with the LRRK2-phosphorylated forms of Rab8A and Rab10, whereas RILPL2 binds to phosphorylated Rab8A, Rab10, and Rab12. Induction of primary cilia formation by serum starvation led to a two-fold reduction in Ciliogenesis in fibroblasts derived from pathogenic LRRK2-R1441G knock-in mice. These results implicate LRRK2 in primary Ciliogenesis and suggest that Rab-mediated protein transport and/or signaling defects at cilia may contribute to LRRK2-dependent pathologies.
Herschel S Dhekne - One of the best experts on this subject based on the ideXlab platform.
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LRRK2-phosphorylated Rab10 sequesters Myosin Va with RILPL2 during Ciliogenesis blockade.
Life science alliance, 2021Co-Authors: Herschel S Dhekne, Francesca Tonelli, Federico Diez, Izumi Yanatori, Edmundo G Vides, Yuriko Sobu, Suzanne R PfefferAbstract:Activating mutations in LRRK2 kinase causes Parkinson's disease. Pathogenic LRRK2 phosphorylates a subset of Rab GTPases and blocks Ciliogenesis. Thus, defining novel phospho-Rab interacting partners is critical to our understanding of the molecular basis of LRRK2 pathogenesis. RILPL2 binds with strong preference to LRRK2-phosphorylated Rab8A and Rab10. RILPL2 is a binding partner of the motor protein and Rab effector, Myosin Va. We show here that the globular tail domain of Myosin Va also contains a high affinity binding site for LRRK2-phosphorylated Rab10. In the presence of pathogenic LRRK2, RILPL2 and MyoVa relocalize to the peri-centriolar region in a phosphoRab10-dependent manner. PhosphoRab10 retains Myosin Va over pericentriolar membranes as determined by fluorescence loss in photobleaching microscopy. Without pathogenic LRRK2, RILPL2 is not essential for Ciliogenesis but RILPL2 over-expression blocks Ciliogenesis in RPE cells independent of tau tubulin kinase recruitment to the mother centriole. These experiments show that LRRK2 generated-phosphoRab10 dramatically redistributes a significant fraction of Myosin Va and RILPL2 to the mother centriole in a manner that likely interferes with Myosin Va's role in Ciliogenesis.
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lrrk2 phosphorylated rab10 sequesters myosin va with rilpl2 during Ciliogenesis blockade
bioRxiv, 2020Co-Authors: Izumi Yanatori, Federico Diez, Herschel S Dhekne, Edmundo G Vides, Yuriko Sobu, Suzanne R PfefferAbstract:Activating mutations in LRRK2 kinase cause Parkinson9s disease. Pathogenic LRRK2 phosphorylates a subset of Rab GTPases and blocks Ciliogenesis. Thus, defining novel phospho-Rab interacting partners is critical to our understanding of the molecular basis of LRRK2 pathogenesis. RILPL2 binds with strong preference to LRRK2-phosphorylated Rab8A and Rab10. RILPL2 is a binding partner of the motor protein and Rab effector, Myosin Va. We show here that the globular tail domain of Myosin Va also contains a high affinity binding site for LRRK2-phosphorylated Rab10, and certain tissue-specific Myosin Va isoforms strongly prefer to bind phosphorylated Rab10. In the presence of pathogenic LRRK2, RILPL2 relocalizes to the peri-centriolar region in a phosphoRab10- and Myosin Va-dependent manner. In the absence of phosphoRab10, expression of RILPL2 or depletion of Myosin Va increase centriolar RILPL2 levels, and either condition is sufficient to block Ciliogenesis in RPE cells. These experiments show that LRRK2 generated phosphoRab10 dramatically redistributes Myosin Va-RILPL2 complexes to the mother centriole, which may sequester Myosin Va and RILPL2 in a manner that blocks their normal roles in Ciliogenesis.
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systematic proteomic analysis of lrrk2 mediated rab gtpase phosphorylation establishes a connection to Ciliogenesis
eLife, 2017Co-Authors: Martin Steger, Francesca Tonelli, Federico Diez, Suzanne R Pfeffer, Terina N Martinez, Herschel S Dhekne, Raja S Nirujogi, Ozge Karayel, Esben Lorentzen, Dario R AlessiAbstract:We previously reported that Parkinson’s disease (PD) kinase LRRK2 phosphorylates a subset of Rab GTPases on a conserved residue in their switch-II domains (Steger et al., 2016) (PMID: 26824392). Here, we systematically analyzed the Rab protein family and found 14 of them (Rab3A/B/C/D, Rab5A/B/C, Rab8A/B, Rab10, Rab12, Rab29, Rab35 and Rab43) to be specifically phosphorylated by LRRK2, with evidence for endogenous phosphorylation for ten of them (Rab3A/B/C/D, Rab8A/B, Rab10, Rab12, Rab35 and Rab43). Affinity enrichment mass spectrometry revealed that the primary Ciliogenesis regulator, RILPL1 specifically interacts with the LRRK2-phosphorylated forms of Rab8A and Rab10, whereas RILPL2 binds to phosphorylated Rab8A, Rab10, and Rab12. Induction of primary cilia formation by serum starvation led to a two-fold reduction in Ciliogenesis in fibroblasts derived from pathogenic LRRK2-R1441G knock-in mice. These results implicate LRRK2 in primary Ciliogenesis and suggest that Rab-mediated protein transport and/or signaling defects at cilia may contribute to LRRK2-dependent pathologies.
Brian David Dynlacht - One of the best experts on this subject based on the ideXlab platform.
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tethering of an e3 ligase by pcm1 regulates the abundance of centrosomal kiaa0586 talpid3 and promotes Ciliogenesis
eLife, 2016Co-Authors: Lei Wang, Ryan Malonis, Irma Sanchez, Brian David DynlachtAbstract:To elucidate the role of centriolar satellites in Ciliogenesis, we deleted the gene encoding the PCM1 protein, an integral component of satellites. PCM1 null human cells show marked defects in Ciliogenesis, precipitated by the loss of specific proteins from satellites and their relocation to centrioles. We find that an amino-terminal domain of PCM1 can restore Ciliogenesis and satellite localization of certain proteins, but not others, pinpointing unique roles for PCM1 and a group of satellite proteins in cilium assembly. Remarkably, we find that PCM1 is essential for tethering the E3 ligase, Mindbomb1 (Mib1), to satellites. In the absence of PCM1, Mib1 destabilizes Talpid3 through poly-ubiquitylation and suppresses cilium assembly. Loss of PCM1 blocks Ciliogenesis by abrogating recruitment of ciliary vesicles associated with the Talpid3-binding protein, Rab8, which can be reversed by inactivating Mib1. Thus, PCM1 promotes Ciliogenesis by tethering a key E3 ligase to satellites and restricting it from centrioles.
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cp110 suppresses primary cilia formation through its interaction with cep290 a protein deficient in human ciliary disease
Developmental Cell, 2008Co-Authors: William Y Tsang, Carine Bossard, Hemant Khanna, Johan Peranen, Anand Swaroop, Vivek Malhotra, Brian David DynlachtAbstract:Summary Primary cilia are nonmotile organelles implicated in signaling and sensory functions. Understanding how primary cilia assemble could shed light on the many human diseases caused by mutations in ciliary proteins. The centrosomal protein CP110 is known to suppress Ciliogenesis through an unknown mechanism. Here, we report that CP110 interacts with CEP290— a protein whose deficiency is implicated in human ciliary disease—in a discrete complex separable from other CP110 complexes involved in regulating the centrosome cycle. Ablation of CEP290 prevents Ciliogenesis without affecting centrosome function or cell-cycle progression. Interaction with CEP290 is absolutely required for the ability of CP110 to suppress primary cilia formation. Furthermore, CEP290 and CP110 interact with Rab8a, a small GTPase required for cilia assembly. Depletion of CEP290 interferes with localization of Rab8a to centrosomes and cilia. Our results suggest that CEP290 cooperates with Rab8a to promote Ciliogenesis and that this function is antagonized by CP110.
Federico Diez - One of the best experts on this subject based on the ideXlab platform.
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LRRK2-phosphorylated Rab10 sequesters Myosin Va with RILPL2 during Ciliogenesis blockade.
Life science alliance, 2021Co-Authors: Herschel S Dhekne, Francesca Tonelli, Federico Diez, Izumi Yanatori, Edmundo G Vides, Yuriko Sobu, Suzanne R PfefferAbstract:Activating mutations in LRRK2 kinase causes Parkinson's disease. Pathogenic LRRK2 phosphorylates a subset of Rab GTPases and blocks Ciliogenesis. Thus, defining novel phospho-Rab interacting partners is critical to our understanding of the molecular basis of LRRK2 pathogenesis. RILPL2 binds with strong preference to LRRK2-phosphorylated Rab8A and Rab10. RILPL2 is a binding partner of the motor protein and Rab effector, Myosin Va. We show here that the globular tail domain of Myosin Va also contains a high affinity binding site for LRRK2-phosphorylated Rab10. In the presence of pathogenic LRRK2, RILPL2 and MyoVa relocalize to the peri-centriolar region in a phosphoRab10-dependent manner. PhosphoRab10 retains Myosin Va over pericentriolar membranes as determined by fluorescence loss in photobleaching microscopy. Without pathogenic LRRK2, RILPL2 is not essential for Ciliogenesis but RILPL2 over-expression blocks Ciliogenesis in RPE cells independent of tau tubulin kinase recruitment to the mother centriole. These experiments show that LRRK2 generated-phosphoRab10 dramatically redistributes a significant fraction of Myosin Va and RILPL2 to the mother centriole in a manner that likely interferes with Myosin Va's role in Ciliogenesis.
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lrrk2 phosphorylated rab10 sequesters myosin va with rilpl2 during Ciliogenesis blockade
bioRxiv, 2020Co-Authors: Izumi Yanatori, Federico Diez, Herschel S Dhekne, Edmundo G Vides, Yuriko Sobu, Suzanne R PfefferAbstract:Activating mutations in LRRK2 kinase cause Parkinson9s disease. Pathogenic LRRK2 phosphorylates a subset of Rab GTPases and blocks Ciliogenesis. Thus, defining novel phospho-Rab interacting partners is critical to our understanding of the molecular basis of LRRK2 pathogenesis. RILPL2 binds with strong preference to LRRK2-phosphorylated Rab8A and Rab10. RILPL2 is a binding partner of the motor protein and Rab effector, Myosin Va. We show here that the globular tail domain of Myosin Va also contains a high affinity binding site for LRRK2-phosphorylated Rab10, and certain tissue-specific Myosin Va isoforms strongly prefer to bind phosphorylated Rab10. In the presence of pathogenic LRRK2, RILPL2 relocalizes to the peri-centriolar region in a phosphoRab10- and Myosin Va-dependent manner. In the absence of phosphoRab10, expression of RILPL2 or depletion of Myosin Va increase centriolar RILPL2 levels, and either condition is sufficient to block Ciliogenesis in RPE cells. These experiments show that LRRK2 generated phosphoRab10 dramatically redistributes Myosin Va-RILPL2 complexes to the mother centriole, which may sequester Myosin Va and RILPL2 in a manner that blocks their normal roles in Ciliogenesis.
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systematic proteomic analysis of lrrk2 mediated rab gtpase phosphorylation establishes a connection to Ciliogenesis
eLife, 2017Co-Authors: Martin Steger, Francesca Tonelli, Federico Diez, Suzanne R Pfeffer, Terina N Martinez, Herschel S Dhekne, Raja S Nirujogi, Ozge Karayel, Esben Lorentzen, Dario R AlessiAbstract:We previously reported that Parkinson’s disease (PD) kinase LRRK2 phosphorylates a subset of Rab GTPases on a conserved residue in their switch-II domains (Steger et al., 2016) (PMID: 26824392). Here, we systematically analyzed the Rab protein family and found 14 of them (Rab3A/B/C/D, Rab5A/B/C, Rab8A/B, Rab10, Rab12, Rab29, Rab35 and Rab43) to be specifically phosphorylated by LRRK2, with evidence for endogenous phosphorylation for ten of them (Rab3A/B/C/D, Rab8A/B, Rab10, Rab12, Rab35 and Rab43). Affinity enrichment mass spectrometry revealed that the primary Ciliogenesis regulator, RILPL1 specifically interacts with the LRRK2-phosphorylated forms of Rab8A and Rab10, whereas RILPL2 binds to phosphorylated Rab8A, Rab10, and Rab12. Induction of primary cilia formation by serum starvation led to a two-fold reduction in Ciliogenesis in fibroblasts derived from pathogenic LRRK2-R1441G knock-in mice. These results implicate LRRK2 in primary Ciliogenesis and suggest that Rab-mediated protein transport and/or signaling defects at cilia may contribute to LRRK2-dependent pathologies.