Protein kinase Cδ selectively regulates protein kinase D-dependent activation of NF-κB in oxidative stress signaling
Protein kinase Cδ selectively regulates protein kinase D-dependent activation of NF-κB in oxidative stress signaling
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DOI：
10.1128/mcb.24.7.2614-2626.2004
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发表时间：
2004-04-01
影响因子：
5.3
通讯作者：
Toker, A
中科院分区：
文献类型：
--
作者：
Storz, P;Döppler, H;Toker, A
蛋白激酶D（PKD）参与激活暴露于氧化应激的细胞中的转录因子NF-κ B（核因子κ B），导致细胞存活增加。我们先前证明，PKD在PH（普列克底物蛋白同源性）结构域中Tyr 463处的磷酸化是由Src-Abl途径介导的，并且它是PKD活化和随后的NF-κ B诱导所必需的。在这里，我们表明，PKD在氧化应激反应中的激活需要两个连续的信号传导事件，即，通过Abl对Tyr 463的磷酸化，其继而促进第二步，PKD活化环（Ser 738/Ser 742）的磷酸化。我们表明，这是介导的PKC 8（蛋白激酶C8），一种激酶，被激活Src在氧化应激反应。我们还表明，其他PKC，包括PKCzeta和PKCzeta不参与PKD激活或NF-κ B诱导。我们提出了一个模型，其中两个协调的信号事件所需的PKD激活。由Src-Abl途径介导的PH结构域中Tyr 463处的酪氨酸磷酸化，其进而促进由Src-PKC δ途径介导的活化环中的Ser 738/Ser 742的磷酸化。一旦激活，信号被传递到氧化应激反应中的NF-κ B的激活。
Protein kinase D (PKD) participates in activation of the transcription factor NF-kappaB (nuclear factor kappaB) in cells exposed to oxidative, stress, leading to increased cellular survival. We previously demonstrated that phosphorylation of PKD at Tyr463 in the PH (pleckstrin homology) domain is mediated by the Src-Abl pathway and that it is necessary for PKD activation and subsequent NF-kappaB induction. Here we show that activation of PKD in response to oxidative stress requires two sequential signaling events, i.e., phosphorylation of Tyr463 by Abl, which in turn promotes a second step, phosphorylation of the PKD activation loop (Ser738/Ser742). We show that this is mediated by PKC8 (protein kinase C8), a kinase that is activated by Src in response to oxidative stress. We also show that other PKCs, including PKCzeta and PKCzeta do not participate in PKD activation or NF-kappaB induction. We propose a model in which two coordinated signaling events are required for PKD activation. Tyrosine phosphorylation in the PH domain at Tyr463, mediated by the Src-Abl pathway, which in turn facilitates the phosphorylation of Ser738/Ser742 in the activation loop, mediated by the Src-PKCdelta pathway. Once active, the signal is relayed to the activation of NF-kappaB in oxidative stress responses.