Protein kinase Cdelta selectively regulates protein kinase D-dependent activation of NF-kappaB in oxidative stress signaling.
Protein kinase Cdelta selectively regulates protein kinase D-dependent activation of NF-kappaB in oxidative stress signaling.
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发表时间：
2004
影响因子：
5.3
通讯作者：
P. Storz;Heike R. Döppler;A. Toker
中科院分区：
文献类型：
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作者：
P. Storz;Heike R. Döppler;A. Toker
蛋白激酶 D (PKD) 参与氧化应激细胞中转录因子 NF-kappaB（核因子 kappaB）的激活，从而提高细胞存活率。我们之前证明了 PH（pleckstrin 同源）结构域中 Tyr463 处的 PKD 磷酸化是由 Src-Abl 途径介导的，并且它对于 PKD 激活和随后的 NF-kappaB 诱导是必需的。在这里，我们表明，响应氧化应激而激活 PKD 需要两个连续的信号传导事件，即 Abl 对 Tyr463 的磷酸化，这反过来又促进第二步，即 PKD 激活环 (Ser738/Ser742) 的磷酸化。我们证明这是由 PKCdelta（蛋白激酶 Cdelta）介导的，PKCdelta 是一种由 Src 响应氧化应激而激活的激酶。我们还表明其他 PKC，包括 PKCepsilon 和 PKCzeta，不参与 PKD 激活或 NF-kappaB 诱导。我们提出了一个模型，其中 PKD 激活需要两个协调的信号事件。 Tyr463 的 PH 结构域中的酪氨酸磷酸化由 Src-Abl 途径介导，反过来又促进激活环中 Ser738/Ser742 的磷酸化，由 Src-PKCdelta 途径介导。一旦激活，信号就会被传递到氧化应激反应中 NF-kappaB 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 PKCdelta (protein kinase Cdelta), a kinase that is activated by Src in response to oxidative stress. We also show that other PKCs, including PKCepsilon 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.