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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >LOK is a major ERM kinase in resting lymphocytes and regulates cytoskeletal rearrangement through ERM phosphorylation
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LOK is a major ERM kinase in resting lymphocytes and regulates cytoskeletal rearrangement through ERM phosphorylation

机译：LOK是静息淋巴细胞中的主要ERM激酶，并通过ERM磷酸化调节细胞骨架重排

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摘要

ERM (ezrin-radixin-moesin) proteins mediate linkage of actin cy-toskeleton to plasma membrane in many cells. ERM activity is regulated in part by phosphorylation at a C-terminal threonine, but the identity of ERM kinases is unknown in lymphocytes and incompletely defined in other mammalian cells. Our studies show that lymphocyte-oriented kinase (LOK) is an ERM kinase in vitro and in vivo. Mass spectrometric analysis indicates LOK is abundant at the lymphocyte plasma membrane and immunofluorescence studies show LOK enrichment at the plasma membrane near ERM. In vitro peptide specificity analyses characterize LOK as a basophilic kinase whose optimal substrate sequence resembles the ERM site, including unusual preference for tyrosine at P-2. LOK's activity on moesin peptide and protein was comparable to reported ERM kinases ROCK and PKC but unlike them LOK displayed preferential specificity for moesin compared to traditional basophilic kinase substrates. Two genetic approaches demonstrate a role for LOK in ERM phosphorylation: cell transfection with LOK kinase domain augments ERM phosphorylation and lymphocytes from LOK knockout mice have >50% reduction in ERM phosphorylation. The findings on localization and specificity argue that LOK is a direct ERM kinase. The knockout mice have normal hematopoietic cell development but notably lymphocyte migration and polarization in response to chemokine are enhanced. These functional alterations fit the current understanding of the role of ERM phosphorylation in regulating cortical reorganization. Thus, these studies identify a new ERM kinase of importance in lymphocytes and confirm the role of ERM phosphorylation in regulating cell shape and motility.
机译：ERM（ezrin-radixin-moesin）蛋白介导肌动蛋白cy骨架与许多细胞质膜的连接。 ERM活性部分受C端苏氨酸的磷酸化调节，但ERM激酶的身份在淋巴细胞中未知，在其他哺乳动物细胞中则不完全定义。我们的研究表明，体外和体内淋巴细胞定向激酶（LOK）是一种ERM激酶。质谱分析表明LOK在淋巴细胞质膜上很丰富，免疫荧光研究表明LOK在ERM附近的质膜上富集。体外肽特异性分析将LOK表征为嗜碱性激酶，其最佳底物序列类似于ERM位点，包括对P-2酪氨酸的异常偏爱。 LOK对肌动蛋白肽和蛋白质的活性与报道的ERM激酶ROCK和PKC相当，但与传统的嗜碱性激酶底物相比，LOK对肌动蛋白显示出优先的特异性。两种遗传学方法证明了LOK在ERM磷酸化中的作用：用LOK激酶结构域进行细胞转染可增强ERM磷酸化，而来自LOK敲除小鼠的淋巴细胞的ERM磷酸化降低了50％以上。关于定位和特异性的发现认为LOK是直接的ERM激酶。敲除小鼠的造血细胞发育正常，但淋巴细胞迁移和对趋化因子的极化作用明显增强。这些功能改变符合目前对ERM磷酸化在调节皮质重组中作用的理解。因此，这些研究确定了新的ERM激酶在淋巴细胞中的重要性，并证实了ERM磷酸化在调节细胞形状和运动性中的作用。

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  • 作者

    Natalya V. Belkina; Yin Liu; Jian-Jiang Hao; Hajime Karasuyama; Stephen Shaw;

  • 作者单位

    Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;

    Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;

    Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;

    Department of Immune Regulation, Tokyo Medical and Dental University Graduate School, Bunkyo-ku, Tokyo 113-8519, Japan;

    Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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  • 关键词

    ezrin; kinase specificity; knockout; migration; moesin;

    机译：ezrin;激酶特异性昏死;移民;肌动蛋白;

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