Structure, regulation, and (patho-)physiological functions of the stress-induced protein kinase CK1 delta (CSNK1D)

Xu, Pengfei; Ianes, Chiara; Gärtner, Fabian; Liu, Congxing; Burster, Timo; Бакулев, В. А.; Rachidi, Najma; Knippschild, Uwe; Bischof, Joachim

doi:10.1016/j.gene.2019.144005

Cited by 61 publications

(95 citation statements)

References 340 publications

(502 reference statements)

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“…It seems that IGS-2.7 selectively prevents the aberrant hyperphosphorylation found in the transgenic TDP-43 mice. Whether the overactivation of CK-1δ in pathological conditions, is due to changes in mRNA, protein expression levels, posttranslational modifications, or in the sequestration of the enzyme in subcellular compartments 24 remains to be elucidated. Among the pathological events ameliorated by CK-1δ inhibitor treatment, IGS-2.7 attenuated the typical animal weight losses, prevented the death of spinal motor neurons and reversed the glial reactivity affecting both microglial cells and especially astrocytes, which are particularly abundant in this experimental model.…”

Section: Discussionmentioning

confidence: 99%

Motor neuron preservation and decrease of in vivo TDP-43 phosphorylation by protein CK-1δ kinase inhibitor treatment

Martínez-González

Rodríguez‐Cueto

Cabezudo

et al. 2020

Sci Rep

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Pathogenesis of amyotrophic lateral sclerosis (ALS), a devastating disease where no treatment exists, involves the compartmentalization of the nuclear protein TDP-43 (TAR DNA-binding protein 43) in the cytoplasm which is promoted by its aberrant phosphorylation and others posttranslational modifications. Recently, it was reported that CK-1δ (protein casein kinase-1δ) is able to phosphorylate TDP-43. Here, the preclinical efficacy of a benzothiazole-based CK-1δ inhibitor IGS-2.7, both in a TDP-43 (A315T) transgenic mouse and in a human cell-based model of ALS, is shown. Treatment with IGS-2.7 produces a significant preservation of motor neurons in the anterior horn at lumbar level, a decrease in both astroglial and microglial reactivity in this area, and in TDP-43 phosphorylation in spinal cord samples. Furthermore, the recovery of TDP-43 homeostasis (phosphorylation and localization) in a human-based cell model from ALS patients after treatment with IGS-2.7 is also reported. Moreover, we have shown a trend to increase in CK-1δ mRNA in spinal cord and significantly in frontal cortex of sALS cases. All these data show for the first time the in vivo modulation of TDP-43 toxicity by CK-1δ inhibition with IGS-2.7, which may explain the benefits in the preservation of spinal motor neurons and point to the relevance of CK-1δ inhibitors in a future disease-modifying treatment for ALS.

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Section: Discussionmentioning

confidence: 99%

Motor neuron preservation and decrease of in vivo TDP-43 phosphorylation by protein CK-1δ kinase inhibitor treatment

Martínez-González

Rodríguez‐Cueto

Cabezudo

et al. 2020

Sci Rep

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“…As shown in higher eukaryotes, localisation of CK1 is linked to its functions and regulates its specificity towards its substrates. Thus, the localisation of Leishmania CK1.2 provides insights into its functions [26], especially since the localisation or functions of CK1.2 orthologs in other parasites is largely unknown. In Plasmodium falciparum , the localisation of PfCK1 depends on the life cycle and is mainly at the surface of the red blood cells in early stages of infection and restricted to the parasite in mature trophozoites and merozoites [12].…”

Section: Discussionmentioning

confidence: 99%

“…and the most closely related to its human orthologs, suggesting that it might have been selected by the host cell rather than by the parasite. Lastly, Leishmania CK1.2, released in the host cell as free protein or via exosomes was shown to phosphorylate the host IFNAR1 (a receptor for alpha/beta interferon), leading to its degradation and the attenuation of the cellular responses to IFN-α, mimicking human CK1α [22, 24, 25] [26]. These data suggest that Leishmania CK1.2 phosphorylates host proteins to subvert macrophages and favours parasite survival, making this kinase a key player in host-pathogen interactions.…”

Section: Introductionmentioning

confidence: 99%

The low complexity regions in the C-terminus are essential for the subcellular localisation of Leishmania casein kinase 1 but not for its activity

Martel

Pine

Bartsch

et al. 2020

Preprint

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Casein Kinase 1 (CK1) family members are serine/threonine protein kinases ubiquitously expressed in eukaryotic organisms. They are involved in a wide range of important cellular processes, such as membrane trafficking, or vesicular transport in organisms from yeast to humans. Due to its broad spectrum of action, CK1 activity and expression is tightly regulated by a number of mechanisms, including subcellular sequestration. Defects in CK1 regulation, localisation or the introduction of mutations in the CK1 coding sequence are often associated with important diseases such as cancer. Increasing evidence suggest that the manipulation of host cell CK1 signalling pathways by intracellular pathogens, either by exploiting the host CK1 or by exporting the CK1 of the pathogen into the host cell may play an important role in infectious diseases. Leishmania CK1.2 is essential for parasite survival and released into the host cell, playing an important role in host pathogen interactions. Although Leishmania CK1.2 has dual role in the parasite and in the host cell, nothing is known about its parasitic localisation and organelle-specific functions. In this study, we show that CK1.2 is a ubiquitous kinase, which is present in the cytoplasm, associated to the cytoskeleton and localised to various organelles, indicating potential roles in kinetoplast and nuclear segregation, as well as ribosomal processing and motility. Furthermore, using truncated mutants, we show for the first time that the two low complexity regions (LCR) present in the C-terminus of CK1.2 are essential for the subcellular localisation of CK1.2 but not for its kinase activity, whereas the deletion of the N-terminus leads to a dramatic decrease in CK1.2 abundance. In conclusion, our data on the localisation and regulation of Leishmania CK1.2 contribute to increase the knowledge on this essential kinase and get insights into its role in the parasite.

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“…Mutations located in the C-terminus of CK1δ (ranging from amino acid 296 to 415 for human CK1δ transcription variant 1 [33]) resulted in different effects on phosphorylation of α-casein in kinetic analysis. While increased activity was determined for GST-CK1δ R299Q and GST-CK1δ Q399* , decreased activity was observed for GST-CK1δ R316G and GST-CK1δ H414Y .…”

Section: Discussionmentioning

confidence: 99%

Newly Developed CK1-Specific Inhibitors Show Specifically Stronger Effects on CK1 Mutants and Colon Cancer Cell Lines

Liu

Witt

Ianes

et al. 2019

IJMS

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Protein kinases of the CK1 family can be involved in numerous physiological and pathophysiological processes. Dysregulated expression and/or activity as well as mutation of CK1 isoforms have previously been linked to tumorigenesis. Among all neoplastic diseases, colon and rectal cancer (CRC) represent the fourth leading cause of cancer related deaths. Since mutations in CK1δ previously found in CRC patients exhibited increased oncogenic features, inhibition of CK1δ is supposed to have promising therapeutic potential for tumors, which present overexpression or mutations of this CK1 isoform. Therefore, it is important to develop new small molecule inhibitors exhibiting higher affinity toward CK1δ mutants. In the present study, we first characterized the kinetic properties of CK1δ mutants, which were detected in different tumor entities. Subsequently, we characterized the ability of several newly developed IWP-based inhibitors to inhibit wild type and CK1δ mutants and we furthermore analyzed their effects on growth inhibition of various cultured colon cancer cell lines. Our results indicate, that these compounds represent a promising base for the development of novel CRC therapy concepts.

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Structure, regulation, and (patho-)physiological functions of the stress-induced protein kinase CK1 delta (CSNK1D)

Cited by 61 publications

References 340 publications

Motor neuron preservation and decrease of in vivo TDP-43 phosphorylation by protein CK-1δ kinase inhibitor treatment

Motor neuron preservation and decrease of in vivo TDP-43 phosphorylation by protein CK-1δ kinase inhibitor treatment

The low complexity regions in the C-terminus are essential for the subcellular localisation of Leishmania casein kinase 1 but not for its activity

Newly Developed CK1-Specific Inhibitors Show Specifically Stronger Effects on CK1 Mutants and Colon Cancer Cell Lines

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