Requirement for Plk2 in orchestrated ras and rap signaling, homeostatic structural plasticity, and memory.
Requirement for Plk2 in orchestrated ras and rap signaling, homeostatic structural plasticity, and memory.
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DOI：
10.1016/j.neuron.2011.02.004
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发表时间：
2011-03-10
期刊：
影响因子：
16.2
通讯作者：
Pak, Daniel T. S.
中科院分区：
文献类型：
--
作者：
Lee, Kea Joo;Lee, Yeunkum;Rozeboom, Aaron;Lee, Ji-Yun;Udagawa, Noriko;Hoe, Hyang-Sook;Pak, Daniel T. S.
Ras和Rap小GTP酶对于突触可塑性和记忆是重要的。然而，它们在稳态可塑性中的作用尚不清楚。在这里，我们报告说，马球样激酶2（Plk 2），一个稳态抑制过度兴奋，通过协调其调节蛋白的Ras和Rap的活动。Plk 2通过磷酸化依赖的泛素-蛋白酶体降解指导Ras激活剂RasGRF 1和Rap抑制剂SPAR的消除。相反，Plk 2磷酸化刺激Ras抑制剂SynGAP和Rap激活剂PDZGEF 1。这些Ras/Rap调节子执行互补功能，以在活性升高后下调树突棘和AMPA受体，并且Plk 2对其的集体调节深刻地刺激Rap并抑制Ras。此外，Plk 2的扰动破坏Ras和Rap信号传导，防止树突棘的稳态收缩和丢失，并损害适当的记忆形成。我们的研究表明，在Ras和Rap的同步调谐Plk 2的关键作用，并强调了这种调节在稳态突触可塑性的功能重要性。
Ras and Rap small GTPases are important for synaptic plasticity and memory. However, their roles in homeostatic plasticity are unknown. Here, we report that polo-like kinase 2 (Plk2), a homeostatic suppressor of overexcitation, governs the activity of Ras and Rap via coordination of their regulatory proteins. Plk2 directs elimination of Ras activator RasGRF1 and Rap inhibitor SPAR via phosphorylation-dependent ubiquitin-proteasome degradation. Conversely, Plk2 phosphorylation stimulates Ras inhibitor SynGAP and Rap activator PDZGEF1. These Ras/Rap regulators perform complementary functions to downregulate dendritic spines and AMPA receptors following elevated activity, and their collective regulation by Plk2 profoundly stimulates Rap and suppresses Ras. Furthermore, perturbation of Plk2 disrupts Ras and Rap signaling, prevents homeostatic shrinkage and loss of dendritic spines, and impairs proper memory formation. Our study demonstrates a critical role of Plk2 in the synchronized tuning of Ras and Rap, and underscores the functional importance of this regulation in homeostatic synaptic plasticity.
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