Identification of a novel serine/threonine kinase and a novel 15-kD protein as potential mediators of the gamma interferon-induced cell death.

Deiss, Louis P.; Feinstein, Elena; Berissi, Hanna; Cohen, Ofer; Kimchi, Adi

doi:10.1101/gad.9.1.15

Cited by 555 publications

(539 citation statements)

References 58 publications

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“…Therefore, this kinase was named ZIP kinase, for zipper interacting protein kinase. Moreover, these authors claimed that ectopic overexpression of ZIP kinase in NIH3T3 cells induced apoptosis, as might be expected from its homology to DAP kinase the latter of which is involved in interferon g-induced cell death (Deiss et al, 1995;Cohen et al, 1997). In our hands Dlk, when expressed as GFPfusion protein, did not exhibit apoptotic activity to a signi®cant extent.…”

Section: Introductionsupporting

confidence: 57%

Interaction partners of Dlk/ZIP kinase: co-expression of Dlk/ZIP kinase and Par-4 results in cytoplasmic retention and apoptosis

et al. 1999

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Dlk/ZIP kinase is a newly discovered serine/threonine kinase which, due to its homology to DAP kinase, was named DAP like kinase, Dlk. This kinase is tightly associated with nuclear structures, it undergoes extensive autophosphorylation and phosphorylates myosin light chain and core histones H3, H2A and H4 in vitro. Moreover, it possesses a leucine zipper which mediates interaction with transcription factor ATF-4, therefore it was called ZIP kinase. We employed the yeast twohybrid system to identify interaction partners of Dlk that might serve as regulators or targets. Besides ATF-4 and others we found Par-4, a modulator of transcription factor WT1 and mediator of apoptosis. Complex formation between Dlk and Par-4 was con®rmed by GST pull-down experiments and kinase reactions in vitro and coexpression experiments in vivo. The interaction domain within Dlk was mapped to an arginine-rich region between residues 338 ± 417, rather than to the leucine zipper. Strikingly, coexpression of Dlk and Par-4 lead to relocation of Dlk from the nucleus to the cytoplasm, particularly to actin ®laments. These interactions provoked a dramatic reorganization of the cytoskeleton and morphological symptoms of apoptosis, thus suggesting a functional relationship between Dlk and Par-4 in the control of apoptosis.

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Section: Introductionsupporting

confidence: 57%

Interaction partners of Dlk/ZIP kinase: co-expression of Dlk/ZIP kinase and Par-4 results in cytoplasmic retention and apoptosis

et al. 1999

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“…[1][2][3][4] Though a large number of physiological examples in which DAPk is pivotal for programmed cell death has accumulated over the years, only a few specific activating signals as well as relevant substrates and interacting proteins have been described. In this work, we demonstrate DAPk as a sensor of oxidative stress and describe PKD as a novel target of DAPk that mediates JNK activation and caspase-independent cell death under oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

“…1 It has since been characterized as a tumor suppressor protein whose expression is greatly reduced or lost in a significant number of human malignancies. 2,3 DAPk belongs to the family of Ca 2 þ -CAMregulated kinases and contains a Ca 2 þ -CAM binding domain proximal to the catalytic domain.…”

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confidence: 99%

DAP kinase regulates JNK signaling by binding and activating protein kinase D under oxidative stress

Eisenberg‐Lerner

Kimchi

2007

Cell Death Differ

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The stress-activated kinase JNK mediates key cellular responses to oxidative stress. Here we show that DAP kinase (DAPk), a cell death promoting Ser/Thr protein kinase, plays a main role in oxidative stress-induced JNK signaling. We identify protein kinase D (PKD) as a novel substrate of DAPk and demonstrate that DAPk physically interacts with PKD in response to oxidative stress. We further show that DAPk activates PKD in cells and that induction of JNK phosphorylation by ectopically expressed DAPk can be attenuated by knocking down PKD expression or by inhibiting its catalytic activity. Moreover, knockdown of DAPk expression caused a marked reduction in JNK activation under oxidative stress, indicating that DAPk is indispensable for the activation of JNK signaling under these conditions. Finally, DAPk is shown to be required for cell death under oxidative stress in a process that displays the characteristics of caspase-independent necrotic cell death. Taken together, these findings establish a major role for DAPk and its specific interaction with PKD in regulating the JNK signaling network under oxidative stress.

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“…DAP kinase is a member of the CaMK family that was originally identi®ed as an essential molecule in interferon (IFN) -g-induced apoptosis in HeLa cells (Deiss et al, 1995;Cohen et al, 1997). It was shown that the reduced expression of DAP kinase mediated by antisense mRNA protected HeLa cells from apoptosis induced by IFN-g, and overexpression of DAP kinase induced apoptosis .…”

Section: Introductionmentioning

confidence: 99%

Death-associated protein kinase 2 is a new calcium/calmodulin-dependent protein kinase that signals apoptosis through its catalytic activity

et al. 1999

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We have identi®ed and characterized a new calcium/ calmodulin (Ca 2+ /CaM) dependent protein kinase termed death-associated protein kinase 2 (DAPK2) that contains an N-terminal protein kinase domain followed by a conserved CaM-binding domain with signi®cant homologies to those of DAP kinase, a protein kinase involved in apoptosis. DAPK2 mRNA is expressed abundantly in heart, lung and skeletal muscle. The mapping results indicated that DAPK2 is located in the central region of mouse chromosome 9. In vitro kinase assay revealed that DAPK2 is autophosphorylated and phosphorylates myosin light chain (MLC) as an exogenous substrate. DAPK2 binds directly to CaM and is activated in a Ca 2+ /CaM-dependent manner. A constitutively active DAPK2 mutant is generated by removal of the CaMbinding domain (DCaM). Treatment of agonists that elevate intracellular Ca 2+ -concentration led to the activation of DAPK2 and transfection studies revealed that DAPK2 is localized in the cytoplasm. Overexpression of DAPK2, but not the kinase negative mutant, signi®cantly induced the morphological changes characteristic of apoptosis. These results indicate that DAPK2 is an additional member of DAP kinase family involved in apoptotic signaling.

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Identification of a novel serine/threonine kinase and a novel 15-kD protein as potential mediators of the gamma interferon-induced cell death.

Cited by 555 publications

References 58 publications

Interaction partners of Dlk/ZIP kinase: co-expression of Dlk/ZIP kinase and Par-4 results in cytoplasmic retention and apoptosis

Interaction partners of Dlk/ZIP kinase: co-expression of Dlk/ZIP kinase and Par-4 results in cytoplasmic retention and apoptosis

DAP kinase regulates JNK signaling by binding and activating protein kinase D under oxidative stress

Death-associated protein kinase 2 is a new calcium/calmodulin-dependent protein kinase that signals apoptosis through its catalytic activity

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