Regulation of dual leucine zipper kinase activity through its interaction with calcineurin

Escobar, Jorge Duque; Kutschenko, Anna; Schröder, Sabine; Blume, Roland; Köster, Kyra-Alexandra; Painer, Christina; Lemcke, Thomas; Maison, Wolfgang; Oetjen, Elke

doi:10.1016/j.cellsig.2021.109953

Cited by 3 publications

(10 citation statements)

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“…1A ). Taken into account that DLK V364A phosphorylated JNK to a higher degree than DLK WT, it was tested whether DLK V364A was more active than DLK WT to increase transcriptional activity (Duque Escobar et al 2021 ). Increasing amounts of expression vectors for DLK WT and the V364A were transiently co-transfected with the c-FOS promoter-luciferase gene.…”

Section: Resultsmentioning

confidence: 99%

“…All expression vectors for DLK wild-type (WT) and its diverse mutants (K185A, NLS, NES, V364A) have been described before (Wallbach et al 2016 ; Duque Escobar et al 2021 ). The luciferase reporter gene − 711 c-fosLuc has been described before (Eckert et al 1996 ), and the plasmid − 711 CREmut c-FOS Luc was generated by primerless PCR, destroying the CREB binding-site (kind gift of Annette Masuch, Göttingen).…”

Section: Methodsmentioning

confidence: 99%

“…Accordingly, phosphatases interfere with DLK activity as well (Asghari Adib et al 2018 ). Preventing the interaction of DLK with the calcium/calmodulin-dependent phosphatase calcineurin enforces DLK-dependent JNK activation (Duque Escobar et al 2021 ). Additionally, depending on its subcellular localization, DLK exerts distinct functions, thus contributing to compartmentalized signaling (Holland et al 2016 ; Wallbach et al 2016 ; Asghari Adib et al 2018 ).…”

Section: Introductionmentioning

confidence: 99%

“…In a rat beta-cell line, the transcription factor NK6 homeobox 1 (NKX6.1) increased c-Fos expression resulting in enhanced Nr4a1, Nr4a3, and VGF expression with beta-cell proliferation and glucose-induced insulin secretion (Ray et al 2016 ). Studies in the insulin-secreting beta-cell line HIT showed that DLK activated by diabetic risk factors reduces beta-cell function and mass, thereby contributing to the pathogenesis of diabetes mellitus (Plaumann et al 2008 ; Stahnke et al 2014 ; Wallbach et al 2016 ; Börchers et al 2017 ; Duque Escobar et al 2021 ). The inhibition of calcium-stimulated CRE/CRE binding protein (CREB)-dependent gene transcription by DLK might contribute to the apoptosis-inducing effect of the kinase (Oetjen et al 2006 ; Phu et al 2011 ; Wallbach et al 2016 ).…”

Section: Introductionmentioning

confidence: 99%

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Increase of c-FOS promoter transcriptional activity by the dual leucine zipper kinase

Köster

Escobar

Fietkau

et al. 2023

Naunyn-Schmiedeberg's Arch Pharmacol

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The dual leucine zipper kinase (DLK) and the ubiquitously expressed transcription factor c-FOS have important roles in beta-cell proliferation and function. Some studies in neuronal cells suggest that DLK can influence c-FOS expression. Given that c-FOS is mainly regulated at the transcriptional level, the effect of DLK on c-FOS promoter activity was investigated in the beta-cell line HIT. The methods used in this study are the following: Luciferase reporter gene assays, immunoblot analysis, CRISPR-Cas9-mediated genome editing, and real-time quantitative PCR. In the beta-cell line HIT, overexpressed DLK increased c-FOS promoter activity twofold. Using 5′-,3′-promoter deletions, the promoter regions from − 348 to − 339 base pairs (bp) and from a − 284 to − 53 bp conferred basal activity, whereas the promoter region from − 711 to − 348 bp and from − 53 to + 48 bp mediated DLK responsiveness. Mutation of the cAMP response element within the promoter prevented the stimulatory effect of DLK. Treatment of HIT cells with KCl and the adenylate cyclase activator forskolin increased c-FOS promoter transcriptional activity ninefold. Since the transcriptional activity of those promoter fragments activated by KCl and forskolin was decreased by DLK, DLK might interfere with KCl/forskolin-induced signaling. In a newly generated, genome-edited HIT cell line lacking catalytically active DLK, c-Fos mRNA levels were reduced by 80% compared to the wild-type cell line. DLK increased c-FOS promoter activity but decreased stimulated transcriptional activity, suggesting that DLK fine-tunes c-FOS promoter-dependent gene transcription. Moreover, at least in HIT cells, DLK is required for FOS mRNA expression.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Increase of c-FOS promoter transcriptional activity by the dual leucine zipper kinase

Köster

Escobar

Fietkau

et al. 2023

Naunyn-Schmiedeberg's Arch Pharmacol

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“…RGCs whose axons are undergoing ischemic stress rapidly upregulate cJun phosphorylation, likely via retrograde signaling through the double leucine zipper kinase (DLK), a member of the JNK signaling pathway [ 26 ]. One day post-rNAION induction, nearly all RGC nuclei express some degree of pJun signal, although the signal varies in intensity ( Figure 5 A).…”

Section: Resultsmentioning

confidence: 99%

Neuroprotection and Neuroregeneration Strategies Using the rNAION Model: Theory, Histology, Problems, Results and Analytical Approaches

Bernstein

Guo

Mehrabian

et al. 2022

IJMS

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Nonarteritic anterior ischemic optic neuropathy (NAION) is the most common cause of sudden optic nerve (ON)-related vision loss in humans. Study of this disease has been limited by the lack of available tissue and difficulties in evaluating both treatments and the window of effectiveness after symptom onset. The rodent nonarteritic anterior ischemic optic neuropathy model (rNAION) closely resembles clinical NAION in its pathophysiological changes and physiological responses. The rNAION model enables analysis of the specific responses to sudden ischemic axonopathy and effectiveness of potential treatments. However, there are anatomic and genetic differences between human and rodent ON, and the inducing factors for the disease and the model are different. These variables can result in marked differences in lesion development between the two species, as well as in the possible responses to various treatments. These caveats are discussed in the current article, as well as some of the species-associated differences that may be related to ischemic lesion severity and responses.

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Regulation of the Activity of the Dual Leucine Zipper Kinase by Distinct Mechanisms

Köster,

Dethlefs,

Duque Escobar

et al. 2024

Cells

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The dual leucine zipper kinase (DLK) alias mitogen-activated protein 3 kinase 12 (MAP3K12) has gained much attention in recent years. DLK belongs to the mixed lineage kinases, characterized by homology to serine/threonine and tyrosine kinase, but exerts serine/threonine kinase activity. DLK has been implicated in many diseases, including several neurodegenerative diseases, glaucoma, and diabetes mellitus. As a MAP3K, it is generally assumed that DLK becomes phosphorylated and activated by upstream signals and phosphorylates and activates itself, the downstream serine/threonine MAP2K, and, ultimately, MAPK. In addition, other mechanisms such as protein–protein interactions, proteasomal degradation, dephosphorylation by various phosphatases, palmitoylation, and subcellular localization have been shown to be involved in the regulation of DLK activity or its fine-tuning. In the present review, the diverse mechanisms regulating DLK activity will be summarized to provide better insights into DLK action and, possibly, new targets to modulate DLK function.

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Regulation of dual leucine zipper kinase activity through its interaction with calcineurin

Cited by 3 publications

References 75 publications

Increase of c-FOS promoter transcriptional activity by the dual leucine zipper kinase

Increase of c-FOS promoter transcriptional activity by the dual leucine zipper kinase

Neuroprotection and Neuroregeneration Strategies Using the rNAION Model: Theory, Histology, Problems, Results and Analytical Approaches

Regulation of the Activity of the Dual Leucine Zipper Kinase by Distinct Mechanisms

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