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首页> 外文期刊>American Journal of Physiology >Protein kinase C-{delta} regulates the subcellular localization of Shc in H2O2-treated cardiomyocytes.
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Protein kinase C-{delta} regulates the subcellular localization of Shc in H2O2-treated cardiomyocytes.

机译：蛋白激酶C-δ调节HcO2处理过的心肌细胞中Shc的亚细胞定位。

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摘要

Protein kinase C-delta (PKCdelta) exerts important cardiac actions as a lipid-regulated kinase. There is limited evidence that PKCdelta also might exert an additional kinase-independent action as a regulator of the subcellular compartmentalization of binding partners such as Shc (Src homologous and collagen), a family of adapter proteins that play key roles in growth regulation and oxidative stress responses. This study shows that native PKCdelta forms complexes with endogenous Shc proteins in H(2)O(2)-treated cardiomyocytes; H(2)O(2) treatment also leads to the accumulation of PKCdelta and Shc in a detergent-insoluble cytoskeletal fraction and in mitochondria. H(2)O(2)-dependent recruitment of Shc isoforms to cytoskeletal and mitochondrial fractions is amplified by wild-type-PKCdelta overexpression, consistent with the notion that PKCdelta acts as a signal-regulated scaffold to anchor Shc in specific subcellular compartments. However, overexpression studies with kinase-dead (KD)-PKCdelta-K376R (an ATP-binding mutant of PKCdelta that lacks catalytic activity) are less informative, since KD-PKCdelta-K376R aberrantly localizes as a constitutively tyrosine-phosphorylated enzyme to detergent-insoluble and mitochondrial fractions of resting cardiomyocytes; relatively little KD-PKCdelta-K376R remains in the cytosolic fraction. The aberrant localization and tyrosine phosphorylation patterns for KD-PKCdelta-K376R do not phenocopy the properties of native PKCdelta, even in cells chronically treated with GF109203X to inhibit PKCdelta activity. Hence, while KD-PKCdelta-K376R overexpression increases Shc localization to the detergent-insoluble and mitochondrial fractions, the significance of these results is uncertain. Our studies suggest that experiments using KD-PKCdelta-K376R overexpression as a strategy to competitively inhibit the kinase-dependent actions of native PKCdelta or to expose the kinase-independent scaffolding functions of PKCdelta should be interpreted with caution.
机译：蛋白激酶C-δ（PKCdelta）作为脂质调节激酶发挥重要的心脏作用。有限的证据表明，PKCdelta还可能发挥额外的激酶非依赖性作用，作为结合伴侣如Shc（Src同源和胶原蛋白）的亚细胞区室化的调节剂，Shc是一种在生长调节和氧化应激中起关键作用的衔接蛋白回应。这项研究表明，天然PKCdelta与H（2）O（2）处理过的心肌细胞中的内源性Shc蛋白形成复合体。 H（2）O（2）处理还导致去污剂不溶性细胞骨架部分和线粒体中PKCdelta和Shc的积累。 H（2）O（2）依赖Shc亚型向细胞骨架和线粒体部分的募集被野生型PKCdelta过表达放大，这与PKCdelta充当信号调节支架将Shc锚定在特定亚细胞区室中的观点一致。但是，激酶死亡（KD）-PKCdelta-K376R（缺乏催化活性的PKCdelta的ATP结合突变体）的过表达研究信息较少，因为KD-PKCdelta-K376R异常地定位为去污剂-酪氨酸的磷酸化酪氨酸。静息心肌细胞的不溶和线粒体部分;相对较少的KD-PKCdelta-K376R保留在胞质级分中。即使在长期用GF109203X处理以抑制PKCdelta活性的细胞中，KD-PKCdelta-K376R的异常定位和酪氨酸磷酸化模式也不能表象天然PKCdelta的特性。因此，尽管KD-PKCdelta-K376R过表达增加了Shc对去污剂不溶和线粒体部分的定位，但这些结果的意义尚不确定。我们的研究表明，使用KD-PKCdelta-K376R过表达作为竞争性抑制天然PKCdelta的激酶依赖性作用或暴露PKCdelta的激酶非依赖性支架功能的策略的实验应谨慎解释。

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