The Experts below are selected from a list of 12282 Experts worldwide ranked by ideXlab platform
David M Virshup - One of the best experts on this subject based on the ideXlab platform.
-
Casein Kinase 1 dynamics underlie the per2 circadian phosphoswitch
bioRxiv, 2019Co-Authors: Jonathan M Philpott, Rajesh Narasimamurthy, Clarisse G Ricci, Alfred M Freeberg, Sabrina R Hunt, Rebecca S Pelofsky, David M Virshup, Sarvind Tripathi, Carrie L PartchAbstract:Summary Post-translational control of PERIOD stability by Casein Kinase 1δ and e (CK1) plays a key regulatory role in metazoan circadian rhythms. Despite the deep evolutionary conservation of CK1 in eukaryotes, little is known about its regulation and the factors that influence substrate selectivity on functionally antagonistic sites in PERIOD that directly control circadian period. Here we describe a molecular switch involving a highly conserved anion binding site in CK1. This switch controls conformation of the activation loop to define substrate selectivity on mammalian PER2, thereby directly regulating its stability. Integrated experimental and computational studies shed light on the allosteric linkage between two anion binding sites that dynamically regulate Kinase activity. We show that period-altering Kinase mutations from humans to Drosophila differentially modulate this activation loop switch to elicit predictable changes in PER2 stability, providing a foundation to understand and further manipulate CK1 regulation of circadian rhythms.
-
Casein Kinase i in the mammalian circadian clock
Methods in Enzymology, 2005Co-Authors: Erik J Eide, Stephanie Crapo, Monica Gallego, Heeseog Kang, David M VirshupAbstract:The circadian clock is characterized by daily fluctuations in gene expression, protein abundance, and posttranslational modification of regulatory proteins. The Drosophila PERIOD (dPER) protein is phosphorylated by the serine⧸threonine protein Kinase, DOUBLETIME (DBT). Similarly, the murine PERIOD proteins, mPER1 and mPER2, are phosphorylated by Casein Kinase I e (CKIe), the mammalian homolog of DBT. CKIe also phosphorylates and partially activates the transcription factor BMAL1. Given the variety of potential targets for CKIe and other cellular Kinases, the precise role of phosphorylation is likely to be a complex one. Biochemical analysis of these and other circadian regulatory proteins has proven to be a fruitful approach in determining how they function within the context of the molecular clockworks.
-
human Casein Kinase iδ phosphorylation of human circadian clock proteins period 1 and 2
FEBS Letters, 2001Co-Authors: David M Virshup, F Camacho, M Cilio, K Patel, O KhorkovaAbstract:Casein Kinase Iϵ (CKIϵ), a central component of the circadian clock, interacts with and phosphorylates human period protein 1 (hPER1) [Keesler, G.A. et al. (2000) NeuroReport 5, 951–955]. A mutation in CKIϵ causes a shortened circadian period in Syrian Golden hamster. We have now extended our previous studies to show that human Casein Kinase Iδ (hCKIδ), the closest homologue to hCKIϵ, associates with and phosphorylates hPER1 and causes protein instability. Furthermore, we observed that both hCKIδ and hCKIϵ phosphorylated and caused protein instability of human period 2 protein (hPER2). Immunohistochemical staining of rat brains demonstrates that CKIδ protein is localized in the suprachiasmatic nuclei, the central location of the master clock. These results indicate that CKIδ may play a role similar to CKIϵ, suggesting that it may also be involved in regulating circadian rhythmicity by post-translation modification of mammalian clock proteins hPER1 and 2.
-
Casein Kinase i from obscurity to center stage
Iubmb Life, 2001Co-Authors: Erica Vielhaber, David M VirshupAbstract:The Casein Kinase I (CKI) family of protein Kinases is a group of highly related, ubiquitously expressed serine/threonine Kinases found in all eukaryotic organisms from protozoa to man. Recent advances in diverse fields, including developmental biology and chronobiology, have elucidated roles for CKI in regulating critical processes such as Wnt signaling, circadian rhythm, nuclear import, and Alzheimer's disease progression.
-
Casein Kinase i another cog in the circadian clockworks
Chronobiology International, 2001Co-Authors: Erik J Eide, David M VirshupAbstract:Multiple components of the circadian central clock are phosphoproteins,and it has become increasingly clear that posttranslational modification isan important regulator of circadian rhythm in diverse organisms, from dinoflagellatesto humans. Genetic studies in Drosophilahave identified double-time (dbt), a serine/threonine protein Kinase that is highlyhomologous to human Casein Kinase I epsilon (CKIe), as the first Kinaselinked to behavioral rhythms. Identification of a missense mutation in CKIeas the tau mutation in the Syrian hamsterplaces CKIe within the core clock machinery in mammals. Most recently,identification of a phosphorylation site mutant of hPER2 in a family withan inherited circadian rhythm abnormality strongly suggests that PER2 is aphysiologically relevant substrate of CKI. Phosphorylation may regulate multipleproperties of clock proteins, including stability and intracellular localization.(Chronobiology International, 18(3), 389–398,2001)
Jeanantoine Girault - One of the best experts on this subject based on the ideXlab platform.
-
phosphorylation of darpp 32 a dopamine and camp regulated phosphoprotein by Casein Kinase i in vitro and in vivo
Journal of Biological Chemistry, 1995Co-Authors: Frederic Desdouits, Angus C. Nairn, David Cohen, Paul Greengard, Jeanantoine GiraultAbstract:Abstract DARPP-32 (dopamine- and c AMP- regulated phospho protein, Mr= 32,000) is a potent inhibitor of protein phosphatase-1 when it is phosphorylated on Thr-34 by cAMP-dependent protein Kinase. DARPP-32 is highly enriched in some specific cell populations such as striatonigral neurons and choroid plexus epithelial cells. Here we show that recombinant rat DARPP-32 is phosphorylated by Casein Kinase I on seryl residues to a stoichiometry of ≈2 mol of phosphate/mol of protein. DARPP-32 is one of the best known substrates for Casein Kinase I (K= 3.4 ± 0.3 μ M), whereas the homologous phosphatase-1 inhibitor, inhibitor-1, is not. Phosphorylation of DARPP-32 by Casein Kinase I does not alter its ability to inhibit protein phosphatase-1. Residues phosphorylated by Casein Kinase I were identified as Ser-137 and Ser-189 by site-directed mutagenesis and by protein sequencing. Ser-137 and the preceding stretch of 16-18 acidic residues are conserved in DARPP-32 among all species examined, whereas Ser-189 is not. Phosphorylation of Ser-137 induces an unusual increase in DARPP-32 electrophoretic mobility in polyacrylamide gels in the presence of SDS. In striatonigral neurons, DARPP-32 is phosphorylated on Ser-137 and the stoichiometry of phosphorylation on this residue in vivo appears to be higher in the substantia nigra (axon terminals) than in the striatum (soma and dendrites). These results indicate that Casein Kinase I is highly active in striatonigral neurons in which it may play important roles, including in protein phosphatase-1 modulation via phosphorylation of DARPP-32.
-
dopamine and camp regulated phosphoprotein darpp 32 phosphorylation of ser 137 by Casein Kinase i inhibits dephosphorylation of thr 34 by calcineurin
Proceedings of the National Academy of Sciences of the United States of America, 1995Co-Authors: Frederic Desdouits, Julio Siciliano, Paul Greengard, Jeanantoine GiraultAbstract:Abstract Although protein phosphatases appear to be highly controlled in intact cells, relatively little is known about the physiological regulation of their activity. DARPP-32, a dopamine- and cAMP-regulated phosphoprotein of apparent M(r) 32,000, is phosphorylated in vitro by Casein Kinase I, Casein Kinase II, and cAMP-dependent protein Kinase on sites phosphorylated in vivo. DARPP-32 phosphorylated on Thr-34 by cAMP-dependent protein Kinase is a potent inhibitor of protein phosphatase 1 and an excellent substrate for calcineurin, a Ca2+/calmodulin-dependent protein phosphatase. Here we provide evidence, using both purified proteins and brain slices, that phosphorylation of DARPP-32 on Ser-137 by Casein Kinase I inhibits the dephosphorylation of Thr-34 by calcineurin. This inhibition occurs only when phospho-Ser-137 and phospho-Thr-34 are located on the same DARPP-32 molecule and is not dependent on the mode of activation of calcineurin. The results demonstrate that the inhibition is due to a modification in the properties of the substrate which alters its dephosphorylation rate. Thus, Casein Kinase I may play a physiological role in striatonigral neurons as a modulator of the regulation of protein phosphatase 1 via DARPP-32.
Uwe Knippschild - One of the best experts on this subject based on the ideXlab platform.
-
the role of the Casein Kinase 1 ck1 family in different signaling pathways linked to cancer development
Onkologie, 2005Co-Authors: Uwe Knippschild, Sonja Wolff, Mathias Wittau, Peter Uwe Wurl, Thorsten Eismann, Georgios Giamas, Claas Brockschmidt, Martin StoterAbstract:The members of the Casein Kinase 1 (CK1) family are highly conserved and are expressed in many eukaryotes ranging from yeast to humans. Mammalian CK1 isoforms (a, s, ?, d, e) and their splice varia
-
ic261 a specific inhibitor of the protein Kinases Casein Kinase 1 delta and epsilon triggers the mitotic checkpoint and induces p53 dependent postmitotic effects
Oncogene, 2000Co-Authors: Lars Behrend, Wolfgang Deppert, Martin Stoter, D. M. Milne, Linda E Campbell, David W. Meek, Uwe KnippschildAbstract:IC261, a specific inhibitor of the protein Kinases Casein Kinase 1-delta and -epsilon, triggers the mitotic checkpoint and induces p53-dependent postmitotic effects
-
interaction of Casein Kinase 1 delta ck1delta with post golgi structures microtubules and the spindle apparatus
European Journal of Cell Biology, 2000Co-Authors: Lars Behrend, Jochen Heukeshoven, Gabriel Rutter, Wolfgang Deppert, Marion Kurth, Martin Stoter, Uwe KnippschildAbstract:Summary Members of the Casein Kinase 1 family of serine/threonine Kinases are highly conserved from yeast to mammals and seem to play an important role in vesicular trafficking, DNA repair, cell cycle progression and cytokinesis. We here report that in interphase cells of various mammalian species Casein Kinase 1 delta (CK1δ) specifically interacts with the trans Golgi network and cytoplasmic, granular particles that associate with microtubules. Furthermore, at mitosis CK1δ is recruited to the spindle apparatus and the centrosomes in cells, which have been exposed to DNA-damaging agents like etoposide or γ-irradiation. In addition, determination of the affinity of CK1δ to different tubulin isoforms in immunoprecipitation-Western analysis revealed a dramatically enhanced complex formation between CK1δ and tubulins from mitotic extracts after introducing DNA damage. The high affinity of CK1δ to the spindle apparatus in DNA-damaged cells and its ability to phosphorylate several microtubule-associated proteins points to a regulatory role of CK1δ at mitosis.
Frederic Desdouits - One of the best experts on this subject based on the ideXlab platform.
-
phosphorylation of darpp 32 a dopamine and camp regulated phosphoprotein by Casein Kinase i in vitro and in vivo
Journal of Biological Chemistry, 1995Co-Authors: Frederic Desdouits, Angus C. Nairn, David Cohen, Paul Greengard, Jeanantoine GiraultAbstract:Abstract DARPP-32 (dopamine- and c AMP- regulated phospho protein, Mr= 32,000) is a potent inhibitor of protein phosphatase-1 when it is phosphorylated on Thr-34 by cAMP-dependent protein Kinase. DARPP-32 is highly enriched in some specific cell populations such as striatonigral neurons and choroid plexus epithelial cells. Here we show that recombinant rat DARPP-32 is phosphorylated by Casein Kinase I on seryl residues to a stoichiometry of ≈2 mol of phosphate/mol of protein. DARPP-32 is one of the best known substrates for Casein Kinase I (K= 3.4 ± 0.3 μ M), whereas the homologous phosphatase-1 inhibitor, inhibitor-1, is not. Phosphorylation of DARPP-32 by Casein Kinase I does not alter its ability to inhibit protein phosphatase-1. Residues phosphorylated by Casein Kinase I were identified as Ser-137 and Ser-189 by site-directed mutagenesis and by protein sequencing. Ser-137 and the preceding stretch of 16-18 acidic residues are conserved in DARPP-32 among all species examined, whereas Ser-189 is not. Phosphorylation of Ser-137 induces an unusual increase in DARPP-32 electrophoretic mobility in polyacrylamide gels in the presence of SDS. In striatonigral neurons, DARPP-32 is phosphorylated on Ser-137 and the stoichiometry of phosphorylation on this residue in vivo appears to be higher in the substantia nigra (axon terminals) than in the striatum (soma and dendrites). These results indicate that Casein Kinase I is highly active in striatonigral neurons in which it may play important roles, including in protein phosphatase-1 modulation via phosphorylation of DARPP-32.
-
dopamine and camp regulated phosphoprotein darpp 32 phosphorylation of ser 137 by Casein Kinase i inhibits dephosphorylation of thr 34 by calcineurin
Proceedings of the National Academy of Sciences of the United States of America, 1995Co-Authors: Frederic Desdouits, Julio Siciliano, Paul Greengard, Jeanantoine GiraultAbstract:Abstract Although protein phosphatases appear to be highly controlled in intact cells, relatively little is known about the physiological regulation of their activity. DARPP-32, a dopamine- and cAMP-regulated phosphoprotein of apparent M(r) 32,000, is phosphorylated in vitro by Casein Kinase I, Casein Kinase II, and cAMP-dependent protein Kinase on sites phosphorylated in vivo. DARPP-32 phosphorylated on Thr-34 by cAMP-dependent protein Kinase is a potent inhibitor of protein phosphatase 1 and an excellent substrate for calcineurin, a Ca2+/calmodulin-dependent protein phosphatase. Here we provide evidence, using both purified proteins and brain slices, that phosphorylation of DARPP-32 on Ser-137 by Casein Kinase I inhibits the dephosphorylation of Thr-34 by calcineurin. This inhibition occurs only when phospho-Ser-137 and phospho-Thr-34 are located on the same DARPP-32 molecule and is not dependent on the mode of activation of calcineurin. The results demonstrate that the inhibition is due to a modification in the properties of the substrate which alters its dephosphorylation rate. Thus, Casein Kinase I may play a physiological role in striatonigral neurons as a modulator of the regulation of protein phosphatase 1 via DARPP-32.
Xiaodong Wang - One of the best experts on this subject based on the ideXlab platform.
-
Casein Kinase 1g2 suppresses necroptosis promoted testis aging by inhibiting receptor interacting Kinase 3
eLife, 2020Co-Authors: Jia Guo, Baijun Dong, Gaihong Cai, She Chen, Fengchao Wang, Xiaodong WangAbstract:Casein Kinases are a large family of intracellular serine/threonine Kinases that control a variety of cellular signaling functions. Here we report that a member of Casein Kinase 1 family, Casein Kinase 1G2, CSNK1G2, binds and inhibits the activation of receptor-interacting Kinase 3, RIPK3, thereby attenuating RIPK3-mediated necroptosis. The binding of CSNK1G2 to RIPK3 is triggered by auto-phosphorylation at serine 211/threonine 215 sites in its C-terminal domain. CSNK1G2-knockout mice showed significantly enhanced necroptosis response and premature aging of their testis, a phenotype that was rescued by either double knockout of the Ripk3 gene or feeding the animal with a RIPK1 Kinase inhibitor-containing diet. Moreover, CSNK1G2 is also co-expressed with RIPK3 in human testis, and the necroptosis activation marker phospho-MLKL was observed in the testis of old (>80) but not young men, indicating that the testis-aging program carried out by the RIPK3-mediated and CSNK1G2-attenuated necroptosis is evolutionarily conserved between mice and men.
-
Casein Kinase 1g2 suppresses necroptosis promoted testis aging by inhibiting receptor interacting Kinase 3
bioRxiv, 2020Co-Authors: Jia Guo, Baijun Dong, Gaihong Cai, She Chen, Fengchao Wang, Xiaodong WangAbstract:Abstract Casein Kinases are a large family of intracellular serine/threonine Kinases that control a variety of cellular signaling functions. Here we report that a member of Casein Kinase 1 family, Casein Kinase 1G2, CSNK1G2, binds and inhibits the activation of receptor-interacting Kinase 3, RIP3, thereby attenuating RIP3-mediated necroptosis. The binding of CSNK1G2 to RIP3 is triggered by auto-phosphorylation at serine 211/threonine 215 sites in its C-terminal domain. CSNK1G2-knockout mice showed significantly enhanced necroptosis response and pre-maturing aging of their testis, a phenotype that was rescued by either double knockout of the RIP3 gene or feeding the animal with a RIP1 Kinase inhibitor-containing diet. Moreover, CSNK1G2 is also co-expressed with RIP3 in human testis, and the necroptosis activation marker phospho-MLKL was observed in the testis of old (>80) but not young men, indicating that the testis-aging program carried out by the RIP3-mediated and CSNK1G2-attenuated necroptosis is evolutionarily conserved between mice and men.