Protein Kinase Cδ Selectively Regulates Protein Kinase D-Dependent Activation of NF-κB in Oxidative Stress Signaling

Störz, Peter; Döppler, Heike; Toker, Alex

doi:10.1128/mcb.24.7.2614-2626.2004

Cited by 217 publications

(253 citation statements)

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“…Multiple lines of evidence suggest PKD as a sensor of oxidative stress involved in several signaling pathways. [15][16][17] Therefore, we asked whether the interaction of PKD with DAPk might be regulated by oxidative stress. To induce oxidative stress, cells were treated with hydrogen peroxide (H 2 O 2 ) for 2min.…”

Section: Resultsmentioning

confidence: 99%

“…Phosphorylation of tyrosine 463 in PKD by Src, in concert with phosphorylation of the PKD activation loop by PKC-d, were shown to induce the activation of NF-kB by PKD leading to increased cellular survival. 16,17 More recently, Zhang et al, 15 demonstrated a PKC-independent activation mode of PKD under oxidative stress, which stimulates JNK phosphorylation via the activation of ASK1, consequently leading to cell death. However, how PKD is regulated in the latter cellular setting was not described.…”

Section: Discussionmentioning

confidence: 99%

“…Protein kinase D 1 (PKD 1, also known as PKC-m), 13,14 a kinase classified within the CAM kinase family, has been identified as one of the upstream regulators of this pathway, required for JNK activation and induction of cell death under oxidative stress conditions. 15 In general, two modes of PKD activation have been reported to function under oxidative stress, one depending on PKC activation 16,17 and the second, shown to be wired to the induction of JNK activity through ASK1, being PKC-independent. 15,18 Yet, the mechanism of the latter PKC-independent activation of PKD, initiating the induction of JNK signaling, remains undefined.…”

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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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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…After ruling out a number of putative Src substrates to interfere with IB degradation [28][29][30][31][32][33][34] Ser/Thr phosphatase PP2A was found to be the critical component. PP2A is known to modulate NFB activity [47].…”

Section: Discussionmentioning

confidence: 99%

Tyrosine phosphatase inhibition triggers sustained canonical serine-dependent NFκB activation via Src-dependent blockade of PP2A

Barisic

Schmidt

Walczak

et al. 2010

Biochemical Pharmacology

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Activation status of Tyr-kinase Src as well as of the transcription factor NFB is a decisive criterion for the onset of cancer and in conveying radio-resistance. While the activation status of Src is Tyr-phosphorylation dependent, NFB activation requires Ser phosphorylation of its cytosolic inhibitor, IBSince constitutive NFB activation was linked to tumor maintenance, its tight regulation is mandatory.We provide evidence that inhibition of pan-Try phosphatase activity by orthovanadate is translated via Src to inhibition of Ser phosphatase PP2A, thereby changing the physiologic response of the cell. In particular we unravelled a new sequence of molecular interactions linking initial activating Tyr416 phosphorylation of Src not to Tyr42-dependent phosphorylation and degradation of IB, but to sustained Ser177/181 phosphorylation of IB kinase IKK following IL-1 stimulation. Consequently, sustained IKK activation provides for chronic canonical IB degradation, thereby eliciting constitutive NFB activation. As the critical translator of Tyr to Ser phosphorylation we identified Ser/Thr phosphatase PP2A. We show that the catalytic subunit PP2Ac serves as a Src substrate with Tyr307 phosphorylation leading to its catalytic inhibition. Additionally to the known survival pathways triggered by Src, Src-mediated canonical and persistent NFB activation may fortify its tumorigenic effects.

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“…Previously, it was shown that in response to mROS PKD1 can be activated via Src-mediated phosphorylation events. [23][24][25] Src is a redox-regulated kinase and its activation involves the oxidation of cysteine residues which then results in intramolecular disulfide bond formation and increased kinase activity. 26 This can be further potentiated by ROS-mediated oxidation and inactivation of regulatory phosphotyrosine phosphatases.…”

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confidence: 99%

KRas, ROS and the initiation of pancreatic cancer

Störz

2016

Small GTPases

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Oncogenic mutations of KRAS are the most frequent driver mutations in pancreatic cancer. Expression of an oncogenic allele of KRAS leads to metabolic changes and altered cellular signaling that both can increase the production of intracellular reactive oxygen species (ROS). Increases in ROS have been shown to drive the formation and progression of pancreatic precancerous lesions by upregulating survival and growth factor signaling. A key issue for precancerous and cancer cells is to keep ROS at levels where they are beneficial for tumor development and progression, but below the threshold that leads to induction of senescence or cell death. In KRas-driven neoplasia aberrantly increased ROS levels are therefore balanced by an upregulation of antioxidant genes. KEYWORDSKRas; mitochondria; oxidative stress; pancreatic cancer; PanIN; ROS Epidemiological and animal studies suggest that supplementation of dietary antioxidants decreases cancer risk, which implies that increased ROS may play a role in carcinogenesis. 1 Approximately 95% of all pancreatic ductal adenocarcinoma (PDA) show acquisition of activating KRAS mutations, 2 which, due to oncogene-mediated alterations in the cell's metabolism, goes along with increased cellular oxidative stress levels. [3][4][5][6] In mouse models for development of PDA, KRas-caused formation of ROS already is induced in acinar cells and gradually increased during ADM and PanIN formation and progression 5 (Fig. 1).In pancreatic cancer, oncogenic KRas induces the generation of ROS through multiple mechanisms. Typical metabolic changes initiated by tumor cells are, for example, an increase in aerobic glycolysis (Warburg effect) to support growth under hypoxic conditions 7 or altered mitochondrial metabolic activity. 5,6,[8][9][10] Oncogenic KRas can modulate mitochondrial metabolism and ROS generation by regulating hypoxia-inducible factors (HIFs) HIF-1a and HIF-2a, 8 or through regulation of the transferrin receptor (TfR1), which is highly expressed in pancreatic cancers. 11 In addition, KRas can induce suppression of respiratory chain complex I and III to cause mitochondrial dysfunction. 6,12 Decreased mitochondrial efficiency then results in an increased production of ROS. 5 A possible cause is the ROS-mediated occurrence of 4-hydroxy-2-nonenal (4HNE) and 4HNE-adduct formation with macromolecules, which can lead to inhibition of mitochondrial proteins or damage of mtDNA. 5 KRas-induced increases in intracellular ROS levels can also occur via altered NADPH oxidase activities, 1 i.e. due to activation of Rac1-NOX4 signaling. 13 For example, Rac1 in Kras G12D -expressing PanIN1B/PanIN2 is increasingly active when the tumor protein p53-induced nuclear protein 1 (TP53INP1) is knocked out or decreasingly expressed. 14 Other mechanisms by which increases in intracellular ROS can be achieved include enhanced growth factor signaling, 15,16 KRas G12D -induced induction of autophagy-specific genes 5 and 7 (ATG5, ATG7), 17 repression of SESN3, which controls the regeneration of peroxi...

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Protein Kinase Cδ Selectively Regulates Protein Kinase D-Dependent Activation of NF-κB in Oxidative Stress Signaling

Cited by 217 publications

References 58 publications

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

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

Tyrosine phosphatase inhibition triggers sustained canonical serine-dependent NFκB activation via Src-dependent blockade of PP2A

KRas, ROS and the initiation of pancreatic cancer

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