CK1 activates minus-end–directed transport of membrane organelles along microtubules

Ikeda, Kazuho; Brodsky, Ilya; Семенова, И. В.; Tirnauer, Jennifer S.; Zaliapin, Ilya; Rodionov, Vladimir

doi:10.1091/mbc.e10-09-0741

Cited by 37 publications

(35 citation statements)

References 56 publications

(92 reference statements)

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“…Still, the phenotype of fragmentation of perinuclear membrane-bound compartments by IC261 can be prevented by pre-treatment with taxol. However, interphase microtubules could be partially stabilized through pre- and co-treatment with taxol (figure 3), nevertheless our study also shows that in cells treated with taxol and IC261 MT dynamics are severely disturbed, and one cannot assume unaffected MT dynamics as suggested in a recent report [30]. In highly dynamic processes like the formation of mitotic spindles, neither pre- nor post-treatment with taxol could rescue the effect of IC261 on MTs (figure 5).…”

Section: Discussioncontrasting

confidence: 46%

Microtubules Depolymerization Caused by the CK1 Inhibitor IC261 May Be Not Mediated by CK1 Blockage

et al. 2014

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The ubiquitously expressed serine/threonine specific casein kinase 1 (CK1) family plays important roles in the regulation of various physiological processes. Small-molecule inhibitors, such as the CK1δ/ε selectively inhibitor IC261, have been used to antagonize CK1 phosphorylation events in cells in many studies. Here we present data to show that, similarly to the microtubule destabilizing agent nocodazole, IC261 depolymerizes microtubules in interphase cells. IC261 treatment of interphase cells affects the morphology of the TGN and Golgi apparatus as well as the localization of CK1δ, which co-localizes with COPI positive membranes. IC261-induced depolymerization of microtubules is rapid, reversible and can be antagonized by pre-treatment of cells with taxol. At lower concentrations of IC261, mitotic spindle microtubule dynamics are affected; this leads to cell cycle arrest and, depending on the cellular background, to apoptosis in a dose-dependent manner. In addition, FACS analysis revealed that IC261 could induce apoptosis independent of cell cycle arrest. In summary this study provides additional and valuable information about various IC261-induced effects that could be caused by microtubule depolymerization rather than by inhibition of CK1. Data from studies that have used IC261 as an inhibitor of CK1 should be interpreted in light of these observations.

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Section: Discussioncontrasting

confidence: 46%

Microtubules Depolymerization Caused by the CK1 Inhibitor IC261 May Be Not Mediated by CK1 Blockage

et al. 2014

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“…The enzyme responsible for phosphorylation in this system has not been identified; however, polo-like kinase (25) and casein kinase (26,27) have been reported to phosphorylate dynein IC in vitro and in Xenopus melanophores (27), and also activations of MAPK, CDK5, GSK3, and ROCK in NF1-KD PC12 cells were found in our previous study (7). Thus, these enzymes may be involved in the regulation of neurite outgrowth in NF1-KD cells.…”

Section: Discussionmentioning

confidence: 81%

Integrated Proteomics Identified Novel Activation of Dynein IC2-GR-COX-1 Signaling in Neurofibromatosis Type I (NF1) Disease Model Cells

Hirayama

Kobayashi

Mizuguchi

et al. 2013

Molecular & Cellular Proteomics

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Neurofibromatosis type 1 (NF1) tumor suppressor gene product, neurofibromin, functions in part as a Ras-GAP, and though its loss is implicated in the neuronal abnormality of NF1 patients, its precise cellular function remains unclear. To study the molecular mechanism of NF1 pathogenesis, we prepared NF1 gene knockdown (KD) PC12 cells, as a NF1 disease model, and analyzed their molecular (gene and protein) expression profiles with a unique integrated proteomics approach, comprising iTRAQ, 2D-DIGE, and DNA microarrays, using an integrated protein and gene expression analysis chart (iPEACH). In NF1-KD PC12 cells showing abnormal neuronal differentiation after NGF treatment, of 3198 molecules quantitatively identified and listed in iPEACH, 97 molecules continuously up-or down-regulated over time were extracted. Pathway and network analysis further revealed overrepresentation of calcium signaling and transcriptional regulation by glucocorticoid receptor (GR) in the up-regulated protein set, whereas nerve system development was overrepresented in the down-regulated protein set. The novel up-regulated network we discovered, "dynein IC2-GR-COX-1 signaling," was then examined in NF1-KD cells. Validation studies confirmed that NF1 knockdown induces altered splicing and phosphorylation patterns of dynein IC2 isomers, up-regulation and accumulation of nuclear GR, and increased COX-1 expression in NGF-treated cells. Moreover, the neurite retraction phenotype observed in NF1-KD cells was significantly recovered by knockdown of the dynein IC2-C isoform and COX-1. In addition, dynein IC2 siRNA significantly inhibited nuclear translocation and accumulation of GR and up-regulation of COX-1 expression. These results suggest that dynein IC2 up-regulates GR nuclear translocation and accumulation, and subsequently causes increased COX-1 expression, in this NF1 disease model. Our integrated proteomics strategy, which combines multiple approaches, demonstrates that NF1-related neural abnormalities are, in part, caused by upregulation of dynein IC2-GR-COX-1 signaling, which may be a novel therapeutic target for NF1. Neurofibromatosis type 1 (NF1)1 is an autosomal dominantly inherited disorder with an estimated prevalence of 1 in 3000 people (1). The hallmarks of NF1 include development of benign tumors of the peripheral nervous system and increased risk of malignancies. The phenotype of NF1 is highly variable, with several organ systems affected including the skin, bones, irises, and central and peripheral nervous systems. The effects on the nervous system are manifested in multiple neurofibroma, gliomas, and learning disabilities.The NF1 gene is located on chromosome 17q11.2 and encodes a large protein of 2818 amino acids, neurofibromin (2). Because the great majority of NF1 gene mutations frequently found in NF1 patients disturb the expression of intact neurofibromin, functional disruption of neurofibromin is potentially relevant to the expression of some or all of the abnormalities that occur in NF1 patients (3). A region centered 1...

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“…69 Recently, it was shown that this control of directionality is mediated by phosphorylation of the dynein intermediate chain, where phosphorylating dynein apparently stimulates its activity. 70 This type of regulation has also been seen in Huntington’s disease, as one of the downstream effects of pathogenic huntingtin protein is kinesin phosphorylation, which appears to inhibit kinesin. 71 In addition, phosphorylation of the scaffolding protein JIP-1 modulates the directionality of Amyloid Precursor Protein (APP) motility in mouse axons.…”

Section: The Transport Complex In Vivo: Examining Organelles In LIVmentioning

confidence: 92%

Single-Molecule Fluorescence and in Vivo Optical Traps: How Multiple Dyneins and Kinesins Interact

Blehm

Selvin

2014

Chem. Rev.

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CK1 activates minus-end–directed transport of membrane organelles along microtubules

Cited by 37 publications

References 56 publications

Microtubules Depolymerization Caused by the CK1 Inhibitor IC261 May Be Not Mediated by CK1 Blockage

Microtubules Depolymerization Caused by the CK1 Inhibitor IC261 May Be Not Mediated by CK1 Blockage

Integrated Proteomics Identified Novel Activation of Dynein IC2-GR-COX-1 Signaling in Neurofibromatosis Type I (NF1) Disease Model Cells

Single-Molecule Fluorescence and in Vivo Optical Traps: How Multiple Dyneins and Kinesins Interact

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