Novel ZIP kinase isoform lacks leucine zipper

Takamoto, Norio; Komatsu, Setsuko; Komaba, Shigeru; Niiro, Naohisa; Ikebe, Mitsuo

doi:10.1016/j.abb.2006.09.026

Cited by 8 publications

(8 citation statements)

References 38 publications

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“…At least in ferrets, for which the protein sequence of Dlk is not known yet, Dlk was shown to colocalize with endogenous Par-4 on actin filaments in differentiated vascular smooth muscle cells (Vetterkind and Morgan, 2009). Even in human ARPE19 cells that have a much more pronounced microfilament system than the HeLa cells investigated (Shoval et al, 2007), an association of ZIPK with the microfilament system was observed (Takamoto et al, 2006). Taken together, these data suggest that in different species ZIPK protein recruitment to the microfilament system is achieved by different proteins: Although Par-4 functions as the predominant recruitment factor for Dlk in murine cells, human ZIPK may be targeted to microfilaments via different proteins, yet to be identified.…”

Section: Discussionmentioning

confidence: 89%

Par-4 Is an Essential Downstream Target of DAP-like Kinase (Dlk) in Dlk/Par-4–mediated Apoptosis

Boosen

Vetterkind

Kubíček³

et al. 2009

MBoC

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Prostate apoptosis response-4 (Par-4) was initially identified as a gene product up-regulated in prostate cancer cells undergoing apoptosis. In rat fibroblasts, coexpression of Par-4 and its interaction partner DAP-like kinase (Dlk, which is also known as zipper-interacting protein kinase [ZIPK]) induces relocation of the kinase from the nucleus to the actin filament system, followed by extensive myosin light chain (MLC) phosphorylation and induction of apoptosis. Our analyses show that the synergistic proapoptotic effect of Dlk/Par-4 complexes is abrogated when either Dlk/Par-4 interaction or Dlk kinase activity is impaired. In vitro phosphorylation assays employing Dlk and Par-4 phosphorylation mutants carrying alanine substitutions for residues S154, T155, S220, or S249, respectively, identified T155 as the major Par-4 phosphorylation site of Dlk. Coexpression experiments in REF52.2 cells revealed that phosphorylation of Par-4 at T155 by Dlk was essential for apoptosis induction in vivo. In the presence of the Par-4 T155A mutant Dlk was partially recruited to actin filaments but resided mainly in the nucleus. Consequently, apoptosis was not induced in Dlk/Par-4 T155A-expressing cells. In vivo phosphorylation of Par-4 at T155 was demonstrated with a phospho-specific Par-4 antibody. Our results demonstrate that Dlk-mediated phosphorylation of Par-4 at T155 is a crucial event in Dlk/Par-4-induced apoptosis.

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Section: Discussionmentioning

confidence: 89%

Par-4 Is an Essential Downstream Target of DAP-like Kinase (Dlk) in Dlk/Par-4–mediated Apoptosis

Boosen

Vetterkind

Kubíček³

et al. 2009

MBoC

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“…A mutation in the leucine zipper domain (V422A, V429A, and L436A) resulted in the drastic decrease in homodimerization and autophosphorylation of DAPK3 . Despite that, an isoform that lacks the leucine zipper domain retained the ability to bind myosin, indicating that myosin binding is mediated by the catalytic domain of DAPK3 …”

Section: Dapk Family Structurementioning

confidence: 99%

Death‐associated protein kinase (DAPK) family modulators: Current and future therapeutic outcomes

Farag

Roh

2018

Medicinal Research Reviews

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Serine/threonine kinases (STKs) represent the majority of discovered kinases to date even though a few Food and Drug Administration approved STKs inhibitors are reported. The third millennium came with the discovery of an important group of STKs that reshaped our understanding of several biological signaling pathways. This family was named death-associated protein kinase family (DAPK family). DAPKs comprise five members (DAPK1, DAPK2, DAPK3, DRAK1, and DRAK2) and belong to the calcium/calmodulin-dependent kinases domain. As time goes on, the list of biological functions of this family is constantly updated. The most extensively studied member is DAPK1 (based on the publications number and Protein Data Bank reported crystal structures) that plays fundamental biological roles depending on the cellular context. DAPK1 regulates apoptosis, autophagy, contributes to the pathogenesis of Alzheimer's disease, acts as a tumor suppressor, inhibits metastasis, mediates the body responses to viral infections, and regulates the synaptic plasticity and depression. For their biological roles, several DAPKs' modulators have been reported for treatment of many diseases as well as acting as probe compounds to facilitate the understanding of the biological functions elicited by this family. Despite that, the number of reported modulators is still limited and more research needs to be conducted on the discovery of novel strategies to activate or inhibit this family. In this report, we aim at drawing more attention to this family by reviewing the recent updates regarding the structure, biological roles, and regulation of this family. In addition, the small-molecule modulators of this family are reviewed in details with their potential therapeutic outcomes evaluated to help medicinal chemists develop more potent and selective possible drug candidates.

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“…Others argued that the differences were species specific, and depended on whether the human or mouse/rat orthologs were used in these studies [6,14]. Since the latter possibility has not been studied in a direct manner, we have undertaken integrated bioinformatics and experimental analyses of ZIPK orthologs to test this hypothesis.…”

Section: Introductionmentioning

confidence: 99%

ZIPK: A Unique Case of Murine-Specific Divergence of a Conserved Vertebrate Gene

2007

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Zipper interacting protein kinase (ZIPK, also known as death-associated protein kinase 3 [DAPK3]) is a Ser/Thr kinase that functions in programmed cell death. Since its identification eight years ago, contradictory findings regarding its intracellular localization and molecular mode of action have been reported, which may be attributed to unpredicted differences among the human and rodent orthologs. By aligning the sequences of all available ZIPK orthologs, from fish to human, we discovered that rat and mouse sequences are more diverged from the human ortholog relative to other, more distant, vertebrates. To test experimentally the outcome of this sequence divergence, we compared rat ZIPK to human ZIPK in the same cellular settings. We found that while ectopically expressed human ZIPK localized to the cytoplasm and induced membrane blebbing, rat ZIPK localized exclusively within nuclei, mainly to promyelocytic leukemia oncogenic bodies, and induced significantly lower levels of membrane blebbing. Among the unique murine (rat and mouse) sequence features, we found that a highly conserved phosphorylation site, previously shown to have an effect on the cellular localization of human ZIPK, is absent in murines but not in earlier diverging organisms. Recreating this phosphorylation site in rat ZIPK led to a significant reduction in its promyelocytic leukemia oncogenic body localization, yet did not confer full cytoplasmic localization. Additionally, we found that while rat ZIPK interacts with PAR-4 (also known as PAWR) very efficiently, human ZIPK fails to do so. This interaction has clear functional implications, as coexpression of PAR-4 with rat ZIPK caused nuclear to cytoplasm translocation and induced strong membrane blebbing, thus providing the murine protein a possible adaptive mechanism to compensate for its sequence divergence. We have also cloned zebrafish ZIPK and found that, like the human and unlike the murine orthologs, it localizes to the cytoplasm, and fails to bind the highly conserved PAR-4 protein. This further supports the hypothesis that murine ZIPK underwent specific divergence from a conserved consensus. In conclusion, we present a case of species-specific divergence occurring in a specific branch of the evolutionary tree, accompanied by the acquisition of a unique protein–protein interaction that enables conservation of cellular function.

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Novel ZIP kinase isoform lacks leucine zipper

Cited by 8 publications

References 38 publications

Par-4 Is an Essential Downstream Target of DAP-like Kinase (Dlk) in Dlk/Par-4–mediated Apoptosis

Par-4 Is an Essential Downstream Target of DAP-like Kinase (Dlk) in Dlk/Par-4–mediated Apoptosis

Death‐associated protein kinase (DAPK) family modulators: Current and future therapeutic outcomes

ZIPK: A Unique Case of Murine-Specific Divergence of a Conserved Vertebrate Gene

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