Distinct functions of the dual leucine zipper kinase depending on its subcellular localization
Standard
Distinct functions of the dual leucine zipper kinase depending on its subcellular localization. / Wallbach, Manuel; Duque Escobar, Jorge; Babaeikelishomi, Rohollah; Stahnke, Marie-Jeannette; Blume, Roland; Schröder, Sabine; Kruegel, Jenny; Maedler, Kathrin; Kluth, Oliver; Kehlenbach, Ralph H; Miosge, Nicolai; Oetjen, Elke.
In: CELL SIGNAL, Vol. 28, No. 4, 04.2016, p. 272-83.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - Distinct functions of the dual leucine zipper kinase depending on its subcellular localization
AU - Wallbach, Manuel
AU - Duque Escobar, Jorge
AU - Babaeikelishomi, Rohollah
AU - Stahnke, Marie-Jeannette
AU - Blume, Roland
AU - Schröder, Sabine
AU - Kruegel, Jenny
AU - Maedler, Kathrin
AU - Kluth, Oliver
AU - Kehlenbach, Ralph H
AU - Miosge, Nicolai
AU - Oetjen, Elke
N1 - Copyright © 2016 Elsevier Inc. All rights reserved.
PY - 2016/4
Y1 - 2016/4
N2 - 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 murine model of prediabetes, enhanced nuclear DLK was found. These data demonstrate that DLK exerts distinct functions, depending on its subcellular localization and thus provide a novel level of regulating DLK action. Furthermore, the prevention of the nuclear localization of DLK as induced by prediabetic signals with consecutive suppression of β-cell apoptosis might constitute a novel target in the therapy of diabetes mellitus.
AB - 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 murine model of prediabetes, enhanced nuclear DLK was found. These data demonstrate that DLK exerts distinct functions, depending on its subcellular localization and thus provide a novel level of regulating DLK action. Furthermore, the prevention of the nuclear localization of DLK as induced by prediabetic signals with consecutive suppression of β-cell apoptosis might constitute a novel target in the therapy of diabetes mellitus.
KW - Animals
KW - Apoptosis
KW - Cell Line
KW - Cell Nucleus
KW - Cyclic AMP Response Element-Binding Protein
KW - Diabetes Mellitus, Experimental
KW - Insulin-Secreting Cells
KW - Interleukin-1beta
KW - JNK Mitogen-Activated Protein Kinases
KW - MAP Kinase Kinase Kinases
KW - Mice
KW - Mutation
KW - Protein Transport
KW - Tumor Necrosis Factor-alpha
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1016/j.cellsig.2016.01.002
DO - 10.1016/j.cellsig.2016.01.002
M3 - SCORING: Journal article
C2 - 26776303
VL - 28
SP - 272
EP - 283
JO - CELL SIGNAL
JF - CELL SIGNAL
SN - 0898-6568
IS - 4
ER -