Mechanisms for redox-regulation of protein kinase C.
Mechanisms for redox-regulation of protein kinase C.
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DOI：
10.3389/fphar.2015.00128
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发表时间：
2015
影响因子：
5.6
通讯作者：
Steinberg SF
中科院分区：
文献类型：
--
作者：
Steinberg SF
蛋白激酶C(PKC)由一系列信号调节酶组成，在许多生理和病理反应的调控中起着多效性的作用。PKC亚型传统上被认为是变构激活的酶，被生长因子受体产生的脂辅因子招募到膜上。这种传统的PKC异构体激活模型的一个固有假设是，PKC仅作用于膜分隔的底物，并且PKC催化活性是每个酶的固有属性，不会因激活过程而改变。这种传统的PKC激活模型不能很好地解释PKC酶在线粒体、核和心肌肌节(非肌膜)亚细胞间隔中的许多已有文献记载的作用。最近的研究通过确定生长因子激活过程中PKC亚型激活与氧化应激过程中PKC亚型激活机制的特定差异来解决这一困境。这篇综述讨论了一些非典型的氧化还原触发的机制，它们可以改变PKC酶的催化性质和亚细胞划分模式。虽然一些氧化还原激活机制作用于所有PKC共同的结构决定因素，但氧化还原依赖的PKCδ激活机制需要该酶上一个独特的磷酸化基序的Src依赖的酪氨酸磷酸化，并且是异构体特异性的。由于氧化应激参与了一系列临床疾病的发病机制，因此，在PKC激活的对照和后果方面的这些刺激特异性差异对于PKC靶向治疗的设计和评估具有重要意义。
Protein kinase C (PKC) is comprised of a family of signal-regulated enzymes that play pleiotropic roles in the control of many physiological and pathological responses. PKC isoforms are traditionally viewed as allosterically activated enzymes that are recruited to membranes by growth factor receptor-generated lipid cofactors. An inherent assumption of this conventional model of PKC isoform activation is that PKCs act exclusively at membrane-delimited substrates and that PKC catalytic activity is an inherent property of each enzyme that is not altered by the activation process. This traditional model of PKC activation does not adequately explain the many well-documented actions of PKC enzymes in mitochondrial, nuclear, and cardiac sarcomeric (non-sarcolemmal) subcellular compartments. Recent studies address this dilemma by identifying stimulus-specific differences in the mechanisms for PKC isoform activation during growth factor activation versus oxidative stress. This review discusses a number of non-canonical redox-triggered mechanisms that can alter the catalytic properties and subcellular compartmentation patterns of PKC enzymes. While some redox-activated mechanisms act at structural determinants that are common to all PKCs, the redox-dependent mechanism for PKCδ activation requires Src-dependent tyrosine phosphorylation of a unique phosphorylation motif on this enzyme and is isoform specific. Since oxidative stress contributes to pathogenesis of a wide range of clinical disorders, these stimulus-specific differences in the controls and consequences of PKC activation have important implications for the design and evaluation of PKC-targeted therapeutics.
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DOI：
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发表时间：
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影响因子：
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作者：
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通讯作者：
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