Cloning and characterization of Dlk, a novel serine/threonine kinase that is tightly associated with chromatin and phosphorylates core histones

Kögel, Donat; Plöttner, Oliver; Landsberg, G; Christian, Sven; Scheidtmann, Karl Heinz

doi:10.1038/sj.onc.1202204

Cited by 109 publications

(116 citation statements)

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“…Yet, within the DAPk family itself, DRP-1 and ZIP-kinase are also capable of phosphorylating the purified regulatory light chain. 2,3,5,6 In fact, ZIPk phosphorylates the RLC on Thr18 and Ser19 in vivo, leading to membrane protrusions that are reminiscent of those observed with DAPk. 37 In addition, introduction of RLC mutated at Thr18 and Ser19 blocked ZIPk-induced protrusions.…”

Section: Discussionmentioning

confidence: 96%

“…1 It is the prototype for a family of death-inducing kinases, which includes DRP-1 and ZIP-kinase (ZIPk). [2][3][4][5][6] In addition to the conserved catalytic module, DAPk harbors multiple functional domains, including eight ankyrin repeats, a cytoskeletal interacting region, and a C-terminal death domain. 1 DAPk activity is necessary for the induction of cell death by ceramide, matrix detachment, oncogene expression, TNF-a, Fas, TGF-b, and IFN-g, and overexpression leads to pronounced death-associated cellular changes, which include membrane blebbing, cell rounding, and the formation of autophagic vesicles.…”

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confidence: 99%

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DAP-kinase-mediated morphological changes are localization dependent and involve myosin-II phosphorylation

2004

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DAP-kinase (DAPk) is a Ser/Thr kinase that regulates cytoplasmic changes associated with programmed cell death. It is shown here that a GFP-DAPk fusion, which partially localized to actin stress fibers, induced extensive membrane protrusions. This phenotype correlated with changes in myosin-II distribution and with increased phosphorylation of the myosin-II regulatory light chain (RLC). A mutant lacking the cytoskeletal-interacting region (GFP-DAPkDCyto) displayed diffuse cytoplasmic localization, and induced peripheral membrane blebbing, instead of the extensive protrusions. In contrast, deletion of the ankyrin repeats led to mislocalization of the kinase to focal contacts, where it failed to elicit any changes in cell morphology. While both wild-type DAPk and DAPkDCyto induced RLC phosphorylation independently of the Rho-activated kinase ROCK, only the wild type led to increases in stress-fiber associated phospho-RLC. Thus, the precise intracellular localization of DAPk is critical for exposure to its substrates, including the RLC, which mediate varying morphologic changes.

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Section: Discussionmentioning

confidence: 96%

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confidence: 99%

DAP-kinase-mediated morphological changes are localization dependent and involve myosin-II phosphorylation

2004

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“…It displays apoptotic functions which like in the case of DAP-kinase depend on its intrinsic kinase activity. Its rat counterpart was also independently cloned and characterized by Kogel et al (1998). DAP-5 belongs to the extended eIF4G family consisting of the aforementioned eIFGI, and the recently cloned eIF4GII (Gradi et al, 1998), and PAIP (Craig et al, 1998).…”

Section: Conclusion and Prospects For The Futurementioning

confidence: 99%

Death associated proteins (DAPs): from gene identification to the analysis of their apoptotic and tumor suppressive functions

1998

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The process of apoptosis (programmed cell death) has become the subject of intensive and extensive research over the past few years. Various approaches are being used to identify and study genes which function as positive mediators of apoptosis. Here, we address a novel approach of gene cloning aimed at isolating intracellular death promoting genes by utilizing a functional screen. This method, called TKO, was based on transfection of cells with an anti-sense cDNA library, followed by the selection of transfectants which survived in the continuous presence of a killing cytokine ± interferon-g. It led to the identi®cation of ®ve novel apoptotic genes and to the ®nding that a known protease ± cathepsin D, is actively recruited to the death process. The ®ve novel apoptotic genes (named DAP genes for: Death Associated Proteins) code for proteins which display a diverse spectrum of biochemical activities. The list comprises a novel type of calcium/calmodulin-regulated kinase which carries ankyrin repeats and a death domain (DAPkinase), a nucleotide-binding protein (DAP-3), a small proline-rich cytoplasmic protein (DAP-1), and a novel homolog of the eIF4G translation initiation factor (DAP-5). Extensive studies proved that these genes are critical for mediating cell death initiated by interferon-g, and in some of the tested cases also cell death induced by Fas/APO-1, TNF-a, and a detachment from extracellular matrix. Moreover, one of these genes, DAP-kinase, was recently found to display strong tumor suppressive activities, coupling the control of apoptosis to metastasis.The advantage of functional approaches of gene cloning is that they select the relevant rate limiting genes along the death pathways in a complete unbiased manner. As a consequence, novel targets and unpredicted mechanisms emerged. A few examples illustrating this important point will be discussed. One relates to the calcium/calmodulin-dependent DAP-kinase, which is localized to the actin micro®laments. It was found that the correct localization of DAP-kinase to the micro®la-ment network was critical for the execution of the apoptotic process, and more speci®cally for the disruption of the stress ®bers ± a typical hallmark of apoptosis. Another important breakthrough step in our understanding of apoptotic processes relates to the identi®ca-tion and analysis of the DAP-5 gene. The structure/ function features of this novel translation regulator resemble the proteolytically cleaved eIF4G which appears in cells upon infection with some RNA viruses and which directs cap-independent translation. Thus, the rescue of DAP-5 highlighted the importance of regulation of protein translation in certain apoptotic systems. Finally, the isolation of cathespin D by our method suggests that lysosomal proteases are recruited during apoptosis, in addition to the well known caspase family of proteases, and that a unique pattern of regulation a ecting the processing of this protease takes place. The major challenge now is to analyse how these diverse DAP gene activities co...

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“…Zipper-interacting protein kinase (ZIP) kinase, also termed death-associated protein kinase like kinase (DLK), was originally identified by two different groups and classified as a subfamily of the death-associated protein kinase (DAPK) [1,2]. ZIP kinase is a serine/threonine-specific protein kinase that contains a high homology to the kinase domain of the DAPK at the Nterminus and leucine zipper domain at the C-terminus [1,2].…”

Section: Introductionmentioning

confidence: 99%

“…ZIP kinase is a serine/threonine-specific protein kinase that contains a high homology to the kinase domain of the DAPK at the Nterminus and leucine zipper domain at the C-terminus [1,2]. Previous studies suggested that ZIP kinase is oligomerized through its C-terminal leucine zipper structure and it has been thought that the oligomerization is critical for the activation of the enzyme [1].…”

Section: Introductionmentioning

confidence: 99%

Novel ZIP kinase isoform lacks leucine zipper

Takamoto¹,

Komatsu²,

Komaba³

et al. 2006

Archives of Biochemistry and Biophysics

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Zipper-interacting protein kinase (ZIP kinase) has been thought to be involved in apoptosis and the C-terinal leucine zipper motif is important for its function. Recent studies have revealed that ZIP kinase also plays a role in regulating myosin phosphorylation. Here we found novel ZIP kinase isoform in which the C-terminal non-kinase domain containing a leucine zipper is eliminated (hZIPK-S). hZIPK-S binds to myosin phosphatase targeting subunit 1(MYPT1) similar to the long isoform (hZIPK-L). In addition, we found that hZIPK-S as well as hZIPK-L binds to myosin. These results indicate that a leucine zipper is not critical for the binding of ZIP kinase to MYPT1 and myosin. Consistently, hZIPK-S localized with stress-fibers where they co-localized with myosin. The residues 278-311, the C-terminal side of the kinase domain common to the both isoforms, is involved in the binding to MYPT1, while the myosin binding domain is within the kinase domain. These results suggest that the newly found hZIPK-S as well as the long isoform plays an important role in the regulation of myosin phosphorylation.

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Cloning and characterization of Dlk, a novel serine/threonine kinase that is tightly associated with chromatin and phosphorylates core histones

Cited by 109 publications

References 20 publications

DAP-kinase-mediated morphological changes are localization dependent and involve myosin-II phosphorylation

DAP-kinase-mediated morphological changes are localization dependent and involve myosin-II phosphorylation

Death associated proteins (DAPs): from gene identification to the analysis of their apoptotic and tumor suppressive functions

Novel ZIP kinase isoform lacks leucine zipper

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