Department of Neurology and Neurosurgery, Montreal Neurological Institute, Montreal, Quebec, Canada.
PLoS One. 2010 Dec 15;5(12):e14345. doi: 10.1371/journal.pone.0014345.
Glycogen Synthase Kinase 3 (GSK3) has been implicated in regulating chromosomal alignment and mitotic progression but the physiological substrates mediating these GSK3-dependent effects have not been identified. Collapsin Response Mediator Protein 4 (CRMP4) is a cytosolic phosphoprotein known to regulate cytoskeletal dynamics and is a known physiological substrate of GSK3. In this study, we investigate the role of CRMP4 during mitosis.
Here we demonstrate that during mitosis CRMP4 phosphorylation is regulated in a GSK3-dependent manner. We show that CRMP4 localizes to spindle microtubules during mitosis and loss of CRMP4 disrupts chromosomal alignment and mitotic progression. The effect of CRMP4 on chromosomal alignment is dependent on phosphorylation by GSK3 identifying CRMP4 as a critical GSK3 substrate during mitotic progression. We also provide mechanistic data demonstrating that CRMP4 regulates spindle microtubules consistent with its known role in the regulation of the microtubule cytoskeleton.
Our findings identify CRMP4 as a key physiological substrate of GSK3 in regulating chromosomal alignment and mitotic progression through its effect on spindle microtubules.
糖原合成酶激酶 3（GSK3）被认为参与调节染色体排列和有丝分裂进程，但介导这些 GSK3 依赖性效应的生理底物尚未确定。 collapsin 反应介质蛋白 4（CRMP4）是一种已知调节细胞骨架动态的细胞质磷酸蛋白，是 GSK3 的已知生理底物。在这项研究中，我们研究了 CRMP4 在有丝分裂中的作用。
在这里，我们证明 CRMP4 的磷酸化在有丝分裂过程中受到 GSK3 的调节。我们表明，CRMP4 在有丝分裂期间定位于纺锤体微管上，而 CRMP4 的缺失会破坏染色体排列和有丝分裂进程。CRMP4 对染色体排列的影响依赖于 GSK3 的磷酸化，这表明 CRMP4 是有丝分裂进程中 GSK3 的关键底物。我们还提供了机制数据，证明 CRMP4 通过调节微管骨架来调节纺锤体微管，这与其在微管细胞骨架调节中的已知作用一致。
我们的发现确定了 CRMP4 作为 GSK3 的关键生理底物，通过其对纺锤体微管的影响，调节染色体排列和有丝分裂进程。
