Distinct functions of the dual leucine zipper kinase depending on its subcellular localization

Cellular Signalling
Manuel WallbachE Oetjen

Abstract

The dual leucine zipper kinase DLK induces β-cell apoptosis by inhibiting the transcriptional activity conferred by the β-cell protective transcription factor cAMP response element binding protein CREB. This action might contribute to β-cell loss and ultimately diabetes. Within its kinase domain DLK shares high homology with the mixed lineage kinase (MLK) 3, which is activated by tumor necrosis factor (TNF) α and interleukin (IL)-1β, known prediabetic signals. In the present study, the regulation of DLK in β-cells by these cytokines was investigated. Both, TNFα and IL-1β induced the nuclear translocation of DLK. Mutations within a putative nuclear localization signal (NLS) prevented basal and cytokine-induced nuclear localization of DLK and binding to the importin receptor importin α, thereby demonstrating a functional NLS within DLK. DLK NLS mutants were catalytically active as they phosphorylated their down-stream kinase c-Jun N-terminal kinase to the same extent as DLK wild-type but did neither inhibit CREB-dependent gene transcription nor transcription conferred by the promoter of the anti-apoptotic protein BCL-xL. In addition, the β-cell apoptosis-inducing effect of DLK was severely diminished by mutation of its NLS. In a ...Continue Reading

References

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Citations

Apr 5, 2016·Expert Opinion on Therapeutic Patents·Elke Oetjen, Thomas Lemcke
Jul 29, 2016·Microbiology and Molecular Biology Reviews : MMBR·András ZekeMarie A Bogoyevitch
Oct 9, 2019·Annual Review of Cell and Developmental Biology·Yishi Jin, Binhai Zheng
Mar 20, 2020·Cellular and Molecular Life Sciences : CMLS·Mathie TenenbaumAmar Abderrahmani
May 28, 2017·Naunyn-Schmiedeberg's Archives of Pharmacology·Svenja BörchersElke Oetjen
Feb 19, 2021·Cellular Signalling·J Duque EscobarElke Oetjen
Apr 21, 2021·Molecular and Cellular Biology·Srimathi KasturiranganDeborah N Chadee

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