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首页> 外文期刊>Cellular Signalling >Regulation of the CREB coactivator TORC by the dual leucine zipper kinase at different levels
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Regulation of the CREB coactivator TORC by the dual leucine zipper kinase at different levels

机译：双亮氨酸拉链激酶在不同水平上调节CREB共激活因子TORC

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摘要

CREB is a ubiquitously expressed transcription factor regulating gene expression via binding to a CRE DNA element. Previous work showed that the dual leucine zipper kinase (DLK) reduced CREB-dependent gene transcription at least in part via inhibition of the coactivator CBP. Here we demonstrate that DLK also inhibits CREB activity by affecting the interaction of CREB with its second coactivator TORC. DLK acted on TORC-dependent transcription by distinct mechanisms. An interaction between DLK and all three TORC isoforms was demonstrated by in vitro protein-protein interaction assays and in cells by coimmunoprecipitation that required the N-terminus of TORC and the leucine zipper of dimerized DLK. Overexpressed DLK induced the phosphorylation of TORC2 and TORC1 on Ser-171 and 167, respectively and on additional residues. Since a kinase-dead DLK mutant did not prevent the nuclear localization of TORC and did not reduce TORC transcriptional activity to the same extent as wild-type DLK, we suggest that DLK-induced phosphorylation of TORC contributes to DLK's inhibitory action. Both the interaction with and the phosphorylation of TORC by DLK might account for the reduced recruitment of TORC to a CRE containing promoter as revealed by chromatin immunoprecipitation assay. These results show for the first time the inhibition of TORC function by a mitogen-activated kinase. Given the dependence on TORC in CREB-directed gene transcription, DLK and its downstream kinases thus contribute to the finely tuned regulation of CREB-dependent effects.
机译：CREB是一种通过与CRE DNA元件结合来调节基因表达的普遍表达的转录因子。先前的研究表明，双亮氨酸拉链激酶（DLK）至少部分通过抑制共激活因子CBP降低了CREB依赖的基因转录。在这里，我们证明DLK还通过影响CREB及其第二个辅助活化剂TORC的相互作用来抑制CREB活性。 DLK通过不同的机制作用于TORC依赖性转录。 DLK与所有三种TORC亚型之间的相互作用已通过体外蛋白质-蛋白质相互作用测定得到证实，并通过共免疫沉淀法在细胞中得到了证明，这需要TORC的N端和二聚化DLK的亮氨酸拉链。过表达的DLK分别在Ser-171和167以及其他残基上诱导TORC2和TORC1的磷酸化。由于激酶死亡的DLK突变体不会阻止TORC的核定位，并且不会像野生型DLK一样降低TORC转录活性，因此我们建议DLK诱导的TORC磷酸化有助于DLK的抑制作用。染色质免疫沉淀试验表明，DLK与TORC的相互作用和磷酸化都可能解释了TORC向含有启动子的CRE募集的减少。这些结果首次显示了丝裂原激活的激酶对TORC功能的抑制。考虑到CREB指导的基因转录过程中对TORC的依赖性，DLK及其下游激酶因此有助于CREB依赖性效应的精细调节。

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