Department of Pharmacology, Georgetown University Medical Center, Washington, DC 20057-1464, USA.
Neuron. 2011 Mar 10;69(5):957-73. doi: 10.1016/j.neuron.2011.02.004.
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.
Ras 和 Rap 小 GTPases 对突触可塑性和记忆很重要。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，丝氨酸/苏氨酸激酶 2（Plk2），一种过度兴奋的内稳态抑制因子，通过协调其调节蛋白来控制 Ras 和 Rap 的活性。Plk2 通过磷酸化依赖性泛素-蛋白酶体降解来指导 Ras 激活因子 RasGRF1 和 Rap 抑制剂 SPAR 的消除。相反，Plk2 磷酸化刺激 Ras 抑制剂 SynGAP 和 Rap 激活因子 PDZGEF1。这些 Ras/Rap 调节剂在活性升高后执行互补的功能来下调树突棘和 AMPA 受体，并且它们被 Plk2 集体调节可显著刺激 Rap 并抑制 Ras。此外，Plk2 的扰动会破坏 Ras 和 Rap 信号转导，防止稳态收缩和树突棘丢失，并损害适当的记忆形成。我们的研究表明 Plk2 在 Ras 和 Rap 的同步调谐中起着关键作用，并强调了这种调节在稳态突触可塑性中的功能重要性。
