NMDA-mediated activation of the tyrosine phosphatase STEP regulates the duration of ERK signaling
NMDA-mediated activation of the tyrosine phosphatase STEP regulates the duration of ERK signaling
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DOI：
10.1038/nn989
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发表时间：
2003-01-01
影响因子：
25
通讯作者：
Lombroso, PJ
中科院分区：
文献类型：
--
作者：
Paul, S;Nairn, AC;Lombroso, PJ
细胞决定细胞外信号调节激酶（ERK）激活持续时间的细胞内机制尚不清楚。我们研究了 STEP（一种富含纹状体的酪氨酸磷酸酶）在调节大鼠神经元 ERK 活性中的作用。谷氨酸介导的 NMDA 受体激活导致培养神经元中 ERK 快速但短暂的磷酸化。在这里，我们发现 NMDA 受体的激活导致 STEP 的激活，这限制了 ERK 活性的持续时间及其向细胞核的易位及其随后的下游核信号传导。在神经元中，STEP 被磷酸化并且在基础条件下失活。 NMDA 介导的 Ca2+ 流入，但不会增加其他来源的细胞内 Ca2+，导致 Ca2+ 依赖性磷酸酶钙调神经磷酸酶的激活以及 STEP 的去磷酸化和激活。我们已经确定了参与神经元 ERK 活性调节的重要机制，该机制强调了丝氨酸/苏氨酸与酪氨酸激酶和磷酸酶之间复杂的相互作用。
The intracellular mechanism(s) by which a cell determines the duration of extracellular signal-regulated kinase (ERK) activation is not well understood. We have investigated the role of STEP, a striatal-enriched tyrosine phosphatase, in the regulation of ERK activity in rat neurons. Glutamate-mediated activation of NMDA receptors leads to the rapid but transient phosphorylation of ERK in cultured neurons. Here we show that activation of NMDA receptors led to activation of STEP, which limited the duration of ERK activity as well as its translocation to the nucleus and its subsequent downstream nuclear signaling. In neurons, STEP is phosphorylated and inactive under basal conditions. NMDA-mediated influx of Ca2+, but not increased intracellular Ca2+ from other sources, leads to activation of the Ca2+-dependent phosphatase calcineurin and the dephosphorylation and activation of STEP. We have identified an important mechanism involved in the regulation of ERK activity in neurons that highlights the complex interplay between serine/threonine and tyrosine kinases and phosphatases.