Specific Serine-Proline Phosphorylation and Glycogen Synthase Kinase 3β-directed Subcellular Targeting of Stathmin 3/Sclip in Neurons
Specific Serine-Proline Phosphorylation and Glycogen Synthase Kinase 3β-directed Subcellular Targeting of Stathmin 3/Sclip in Neurons
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DOI：
10.1074/jbc.m112.344044
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发表时间：
2012-06-22
影响因子：
4.8
通讯作者：
Sobel, Andre
中科院分区：
文献类型：
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作者：
Devaux, Sara;Poulain, Fabienne E.;Sobel, Andre
在神经系统发育过程中，神经元生长、迁移和功能形态发生依赖于对亚细胞骨架（包括微管动力学）的适当控制。 Stathmin 家族蛋白在神经元分化的各个阶段发挥重要作用，包括轴突生长和分支或树突发育。我们之前已经证明，stathmins 2 (SCG10) 和 3 (SCLIP) 在轴突形态发生中发挥独特、独立和互补的调节作用。尽管这两种蛋白被认为显示了最初在 stathmin 1 中鉴定的四个保守磷酸化位点，但我们在此表明，它们在其特定的富含脯氨酸结构域 (PRD) 内拥有不同的磷酸化位点，这些位点受到参与控制神经元分化的脯氨酸定向激酶的磷酸化的差异调节。 ERK2 或 CDK5 磷酸化这两种蛋白质，但具有不同的位点特异性。我们还首次证明，与 Stathmin 2 不同，stathmin 3 在体外和体内都是糖原合酶激酶 (GSK) 3 beta 的底物。有趣的是，在其 GSK-3 β 靶位点磷酸化的 Stathmin 3 在神经炎尖端和培养中分化海马神经元的生长锥富含肌动蛋白的外围区域内显示出特定的亚细胞定位。最后，GSK-3 beta 的药理抑制会诱导 stathmin 3（而非 stathmin 2）从神经元外周向高尔基体区域重新分布。因此，Stathmin 蛋白可以通过特异性磷酸化进行局部调节或局部靶向，Stathmin 家族的每种磷蛋白在控制神经元分化中发挥独特且特定的作用。
During nervous system development, neuronal growth, migration, and functional morphogenesis rely on the appropriate control of the subcellular cytoskeleton including microtubule dynamics. Stathmin family proteins play major roles during the various stages of neuronal differentiation, including axonal growth and branching, or dendritic development. We have shown previously that stathmins 2 (SCG10) and 3 (SCLIP) fulfill distinct, independent and complementary regulatory roles in axonal morphogenesis. Although the two proteins have been proposed to display the four conserved phosphorylation sites originally identified in stathmin 1, we show here that they possess distinct phosphorylation sites within their specific prolinerich domains (PRDs) that are differentially regulated by phosphorylation by proline-directed kinases involved in the control of neuronal differentiation. ERK2 or CDK5 phosphorylate the two proteins but with different site specificities. We also show for the first time that, unlike stathmin 2, stathmin 3 is a substrate for glycogen synthase kinase (GSK) 3 beta both in vitro and in vivo. Interestingly, stathmin 3 phosphorylated at its GSK-3 beta target site displays a specific subcellular localization at neuritic tips and within the actin-rich peripheral zone of the growth cone of differentiating hippocampal neurons in culture. Finally, pharmacological inhibition of GSK-3 beta induces a redistribution of stathmin 3, but not stathmin 2, from the periphery toward the Golgi region of neurons. Stathmin proteins can thus be either regulated locally or locally targeted by specific phosphorylation, each phosphoprotein of the stathmin family fulfilling distinct and specific roles in the control of neuronal differentiation.