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Rac GTPase signaling through the PP5 protein phosphatase

机译：Rac GTPase通过PP5蛋白磷酸酶的信号转导

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摘要

We have investigated the Rac-dependent mechanism of KCNH2 channel stimulation by thyroid hormone in a rat pituitary cell line, GH(4)C(1), with the patch-clamp technique. Here we present physiological evidence for the protein serine/threonine phosphatase, PP5, as an effector of Rac GTPase signaling. We also propose and test a specific molecular mechanism for PP5 stimulation by Rac-GTP. Inhibition of PP5 with the microbial toxin, okadaic acid, blocked channel stimulation by thyroid hormone and by Rac, but signaling was restored by expression of a toxin-insensitive mutant of PP5, Y451A, which we engineered. PP5 is unique among protein phosphatases in that it contains an N-terminal regulatory domain with three tetratricopeptide repeats (TPR) that inhibit its activity. Expression of the TPR domain coupled to GFP blocked channel stimulation by the thyroid hormone. We also show that the published structures of the PP5 TPR domain and the TPR domain of p67, the Rac-binding subunit of NADPH oxidase, superimpose over 92 a carbons. Mutation of the PP5 TPR domain at two predicted contact points with Rac-GTP prevents the TPR domain from functioning as a dominant negative and blocks the ability of Y451A to rescue signaling in the presence of okadaic acid. PP5 stimulation by Rac provides a unique molecular mechanism for the antagonism of Rho-dependent signaling through protein kinases in many cellular processes, including metastasis, immune cell chemotaxis, and neuronal development.
机译：我们用膜片钳技术研究了大鼠垂体细胞系GH（4）C（1）中甲状腺激素对KCNH2通道刺激的Rac依赖性机制。在这里，我们为丝氨酸/苏氨酸磷酸酶，PP5，作为Rac GTPase信号转导的效应物提供生理证据。我们还提出并测试了Rac-GTP刺激PP5的特定分子机制。用微生物毒素冈田酸抑制PP5可阻止甲状腺激素和Rac刺激通道，但通过我们设计的对毒素不敏感的PP5突变体Y451A的表达恢复了信号传导。 PP5在蛋白质磷酸酶中是独特的，因为它包含一个N末端调节域和三个抑制其活性的四肽重复（TPR）。 TPR结构域与GFP偶联的表达阻断了甲状腺激素对通道的刺激。我们还显示，PP5 TPR域和p67（NADPH氧化酶的Rac结合亚基）的TPR域的已发布结构重叠了92个碳原子。 PP5 TPR结构域在两个与Rac-GTP的预期接触点处发生突变，可防止TPR结构域起显性负性作用，并在冈田酸存在下阻止Y451A挽救信号的能力。 Rac对PP5的刺激提供了独特的分子机制，可在许多细胞过程（包括转移，免疫细胞趋化和神经元发育）中通过蛋白激酶拮抗Rho依赖性信号传导。

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