Circumventing embryonic lethality with Lcmt1 deficiency: generation of hypomorphic Lcmt1 mice with reduced protein phosphatase 2A methyltransferase expression and defects in insulin signaling.
Circumventing embryonic lethality with Lcmt1 deficiency: generation of hypomorphic Lcmt1 mice with reduced protein phosphatase 2A methyltransferase expression and defects in insulin signaling.
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DOI：
10.1371/journal.pone.0065967
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Clarke SG
中科院分区：
文献类型：
--
作者：
MacKay KB;Tu Y;Young SG;Clarke SG
蛋白磷酸酶2A（PP 2A）是真核细胞中主要的丝氨酸/苏氨酸磷酸酶，是由结构亚基、催化亚基和靶向亚基组成的异源三聚体蛋白。PP 2A组装受多种机制控制，其中之一是亮氨酸羧基甲基转移酶LCMT 1对催化亚基的羧基末端甲基化。PP 2A在胞质溶胶中几乎是化学计量甲基化的，尽管一些PP 2A靶向亚基独立于甲基化结合，但这种修饰是其他亚基结合所需的。为了研究这种甲基化反应在哺乳动物组织中的作用，我们在Lcmt 1的内含子1内产生了一个基因诱捕盒。由于插入周围的剪接，Lcmt 1转录和LCMT 1蛋白水平降低，但没有消除。LCMT 1活性和PP 2A甲基化以协调方式降低，表明LCMT 1是唯一的PP 2A甲基转移酶。这些小鼠表现出胰岛素抵抗表型，表明这种甲基转移酶在胰岛素敏感组织中的信号传导中的作用。来自这些动物的组织对于PP 2A的甲基化敏感底物的体内鉴定以及它们如何对不同的生理条件作出反应至关重要。
Protein phosphatase 2A (PP2A), the major serine/threonine phosphatase in eukaryotic cells, is a heterotrimeric protein composed of structural, catalytic, and targeting subunits. PP2A assembly is governed by a variety of mechanisms, one of which is carboxyl-terminal methylation of the catalytic subunit by the leucine carboxyl methyltransferase LCMT1. PP2A is nearly stoichiometrically methylated in the cytosol, and although some PP2A targeting subunits bind independently of methylation, this modification is required for the binding of others. To examine the role of this methylation reaction in mammalian tissues, we generated a mouse harboring a gene-trap cassette within intron 1 of Lcmt1. Due to splicing around the insertion, Lcmt1 transcript and LCMT1 protein levels were reduced but not eliminated. LCMT1 activity and methylation of PP2A were reduced in a coordinate fashion, suggesting that LCMT1 is the only PP2A methyltransferase. These mice exhibited an insulin-resistance phenotype, indicating a role for this methyltransferase in signaling in insulin-sensitive tissues. Tissues from these animals will be vital for the in vivo identification of methylation-sensitive substrates of PP2A and how they respond to differing physiological conditions.
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