Protein Kinase Inhibitors CK59 and CID755673 Alter Primary Human NK Cell Effector Functions

Scheiter, Maxi; Bulitta, Björn; Ham, Marco van; Klawonn, Frank; König, Sebastian; Jänsch, Lothar

doi:10.3389/fimmu.2013.00066

Cited by 8 publications

(7 citation statements)

References 57 publications

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“…Further experimentation is needed to clarify this point. Recent studies have shown that different PKC isoforms are acting upstream of PKD1 (Scheiter et al, 2013). For example, PKCδ is upstream of PKD1 in reactive oxygen species-mediated mitochondrial depolarization (Zhang et al, 2015), and PKCδ knockdown effectively attenuates PKD1 activation (Asaithambi et al, 2011).…”

Section: Discussionmentioning

confidence: 98%

Subtilase cytotoxin produced by locus of enterocyte effacement‐negative Shiga‐toxigenic Escherichia coli induces stress granule formation

Tsutsuki

Yahiro

Ogura

et al. 2016

Cellular Microbiology

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Subtilase cytotoxin (SubAB) is mainly produced by locus of enterocyte effacement (LEE)-negative strains of Shiga-toxigenic Escherichia coli (STEC). SubAB cleaves an endoplasmic reticulum (ER) chaperone, BiP/Grp78, leading to induction of ER stress. This stress causes activation of ER stress sensor proteins and induction of caspase-dependent apoptosis. We found that SubAB induces stress granules (SG) in various cells. Aim of this study was to explore the mechanism by which SubAB induced SG formation. Here, we show that SubAB-induced SG formation is regulated by activation of double-stranded RNA-activated protein kinase (PKR)-like endoplasmic reticulum kinase (PERK). The culture supernatant of STEC O113:H21 dramatically induced SG in Caco2 cells, although subAB knockout STEC O113:H21 culture supernatant did not. Treatment with phorbol 12-myristate 13-acetate (PMA), a protein kinase C (PKC) activator, and lysosomal inhibitors, NH4 Cl and chloroquine, suppressed SubAB-induced SG formation, which was enhanced by PKC and PKD inhibitors. SubAB attenuated the level of PKD1 phosphorylation. Depletion of PKCδ and PKD1 by siRNA promoted SG formation in response to SubAB. Furthermore, death-associated protein 1 (DAP1) knockdown increased basal phospho-PKD1(S916) and suppressed SG formation by SubAB. However, SG formation by an ER stress inducer, Thapsigargin, was not inhibited in PMA-treated cells. Our findings show that SubAB-induced SG formation is regulated by the PERK/DAP1 signalling pathway, which may be modulated by PKCδ/PKD1, and different from the signal transduction pathway that results in Thapsigargin-induced SG formation.

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Section: Discussionmentioning

confidence: 98%

Subtilase cytotoxin produced by locus of enterocyte effacement‐negative Shiga‐toxigenic Escherichia coli induces stress granule formation

Tsutsuki

Yahiro

Ogura

et al. 2016

Cellular Microbiology

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“…To verify our hypothesis, by using a specific inhibitor CID755673, we disrupted PKD activity and assessed the polar body extrusion as well as the meiotic procession. Previous study indicated that the treatment with 5 μM CID755673 resulted in significant inhibition of NK cells [22]. Additionally, the phosphorylation levels of PKD were completely blocked at 50 μM CID755673 treatment [23].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of protein kinase D disrupts spindle formation and actin assembly during porcine oocyte maturation

Wang

Wan

et al. 2018

Aging

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Protein kinase D (PKD) subfamily which includes PKD1, PKD2 and PKD3 is a novel family of serine/threonine kinases. PKD has been widely implicated in the regulation of multiple physiological effects including immune responses, apoptosis and cell proliferation. However, the roles of PKD in oocytes have not been fully clarified. In this study we investigated the regulatory functions of PKD during porcine oocyte maturation. Our results indicated that PKD expressed in porcine oocytes and the inhibition of PKD family activity led to the failure of meiosis resumption and the first polar body extrusion. Further analysis indicated that the spindle assembly and chromosome alignment were disrupted after PKD family inhibition, and this might be through its regulatory role on MAPK phosphorylation. We also found that PKD phosphorylated cofilin for actin assembly, which further affected cortical actin distribution, indicating the roles of PKD family on cytoskeleton. In addition, a decreased expression of PKD in postovulatory aging porcine oocytes was observed, which might connect PKD with cytoskeleton defects in aged oocytes. Taken together, these results suggest that PKD possesses important functions in porcine oocyte maturation by regulating spindle organization and actin assembly.

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“…PKD has been extensively studied in multiple cancer relevant pathological processes. Our review will focus on the impact of PKD in pathways pertinent to several hallmarks of cancer, including enhanced growth, proliferative capacity [ 6 , 7 , 39 , 41 , 42 ], evasion of cell death [ 6 , 43 , 44 , 45 ], migration and invasion [ 41 , 42 ], angiogenesis [ 46 , 47 ], and immune modulation [ 6 , 48 , 49 , 50 ]. The role of each PKD isoforms in each of the pathological process will be reviewed and discussed (see a summary on the contributary roles of PKD isoforms in cancer in Table 1 ).…”

Section: Pkd In Pathological Processes and Human Diseasesmentioning

confidence: 99%

Multifaceted Functions of Protein Kinase D in Pathological Processes and Human Diseases

et al. 2021

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Protein kinase D (PKD) is a family of serine/threonine protein kinases operating in the signaling network of the second messenger diacylglycerol. The three family members, PKD1, PKD2, and PKD3, are activated by a variety of extracellular stimuli and transduce cell signals affecting many aspects of basic cell functions including secretion, migration, proliferation, survival, angiogenesis, and immune response. Dysregulation of PKD in expression and activity has been detected in many human diseases. Further loss- or gain-of-function studies at cellular levels and in animal models provide strong support for crucial roles of PKD in many pathological conditions, including cancer, metabolic disorders, cardiac diseases, central nervous system disorders, inflammatory diseases, and immune dysregulation. Complexity in enzymatic regulation and function is evident as PKD isoforms may act differently in different biological systems and disease models, and understanding the molecular mechanisms underlying these differences and their biological significance in vivo is essential for the development of safer and more effective PKD-targeted therapies. In this review, to provide a global understanding of PKD function, we present an overview of the PKD family in several major human diseases with more focus on cancer-associated biological processes.

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Protein Kinase Inhibitors CK59 and CID755673 Alter Primary Human NK Cell Effector Functions

Cited by 8 publications

References 57 publications

Subtilase cytotoxin produced by locus of enterocyte effacement‐negative Shiga‐toxigenic Escherichia coli induces stress granule formation

Subtilase cytotoxin produced by locus of enterocyte effacement‐negative Shiga‐toxigenic Escherichia coli induces stress granule formation

Inhibition of protein kinase D disrupts spindle formation and actin assembly during porcine oocyte maturation

Multifaceted Functions of Protein Kinase D in Pathological Processes and Human Diseases

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