Phosphorylation of synaptic GTPase-activating protein (synGAP) by polo-like kinase (Plk2) alters the ratio of its GAP activity toward HRas, Rap1 and Rap2 GTPases.
Phosphorylation of synaptic GTPase-activating protein (synGAP) by polo-like kinase (Plk2) alters the ratio of its GAP activity toward HRas, Rap1 and Rap2 GTPases.
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DOI：
10.1016/j.bbrc.2018.07.087
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发表时间：
2018-09-10
影响因子：
3.1
通讯作者：
Kennedy MB
中科院分区：
文献类型：
--
作者：
Walkup WG 4th;Sweredoski MJ;Graham RL;Hess S;Kennedy MB
SynGAP 是一种 Ras 和 Rap GTP 酶激活蛋白 (GAP)，在哺乳动物前脑的突触后密度 (PSD) 部分中以高浓度存在，并与 PSD-95 的 PDZ 结构域结合。 Ca2+/钙调蛋白依赖性蛋白激酶 II (CaMKII) 对纯重组 synGAP 进行磷酸化，使 synGAP 的 GAP 活性平衡向 Rap1 失活方向转变；而细胞周期蛋白依赖性激酶 5 (CDK5) 的磷酸化则具有相反的作用，将平衡转向 HRas 失活。这些平衡的变化有助于调节表面 AMPA 受体的数量，这些受体在突触增强 (CaMKII) 过程中增加，在突触缩放 (CDK5) 过程中下降。 Polo 样激酶 2 (Plk2/SNK) 与 CDK5 一样，有助于突触缩放。这两种激酶协同作用，通过标记脊柱相关的 Rap 特异性 GAP 蛋白 (SPAR) 进行降解，从而在神经元活动升高后减少表面 AMPA 受体的数量，从而提高激活的 Rap 水平。在这里，我们表明 Plk2 还磷酸化并调节 synGAP。 Plk2 对 synGAP 的磷酸化可刺激其对 HRas 的 GAP 活性增加 65%，对 Rap1 的 GAP 活性增加 16%。 Plk2 和 CDK5 在不同位点同时磷酸化 synGAP，导致 GAP 对 HRas 的活性加性增加 (~230%)，并对 Rap1 的活性产生较小的非加性增加 (~15%)。双磷酸化还会导致 Rap2 的 GAP 活性增加 (~40-50%)，这是任一激酶单独无法产生的效果。正如我们之前对 CDK5 观察到的那样，Ca2+/CaM 的添加会导致 Plk2 对 synGAP 磷酸化的速率和化学计量进行底物定向加倍，靶向也被 CaMKII 磷酸化的残基。总之，Plk2 的磷酸化（如 CDK5）改变了 synGAP 的 GAP 活性比率，从而导致活性 Ras 比活性 Rap 产生更大的减少，这将导致神经元树突中表面 AMPA 受体数量的减少。
SynGAP is a Ras and Rap GTPase-activating protein (GAP) found in high concentration in the postsynaptic density (PSD) fraction from mammalian forebrain where it binds to PDZ domains of PSD-95. Phosphorylation of pure recombinant synGAP by Ca2+/calmodulin-dependent protein kinase II (CaMKII) shifts the balance of synGAP’s GAP activity toward inactivation of Rap1; whereas phosphorylation by cyclin-dependent kinase 5 (CDK5) has the opposite effect, shifting the balance toward inactivation of HRas. These shifts in balance contribute to regulation of the numbers of surface AMPA receptors, which rise during synaptic potentiation (CaMKII) and fall during synaptic scaling (CDK5). Polo-like kinase 2 (Plk2/SNK), like CDK5, contributes to synaptic scaling. These two kinases act in concert to reduce the number of surface AMPA receptors following elevated neuronal activity by tagging spine-associated Rap-specific GAP protein (SPAR) for degradation, thus raising the level of activated Rap. Here we show that Plk2 also phosphorylates and regulates synGAP. Phosphorylation of synGAP by Plk2 stimulates its GAP activity toward HRas by 65%, and toward Rap1 by 16%. Simultaneous phosphorylation of synGAP by Plk2 and CDK5 at distinct sites produces an additive increase in GAP activity toward HRas (~230%) and a smaller, non-additive increase in activity toward Rap1 (~15%). Dual phosphorylation also produces an increase in GAP activity toward Rap2 (~40–50%), an effect not produced by either kinase alone. As we previously observed for CDK5, addition of Ca2+/CaM causes a substrate-directed doubling of the rate and stoichiometry of phosphorylation of synGAP by Plk2, targeting residues also phosphorylated by CaMKII. In summary, phosphorylation by Plk2, like CDK5, shifts the ratio of GAP activity of synGAP to produce a greater decrease in active Ras than in active Rap, which would produce a shift toward a decrease in the number of surface AMPA receptors in neuronal dendrites.
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