Phosphorylation of the tubulin-binding protein, stathmin, by Cdk5 and MAP kinases in the brain
Phosphorylation of the tubulin-binding protein, stathmin, by Cdk5 and MAP kinases in the brain
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DOI：
10.1111/j.1471-4159.2006.04113.x
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发表时间：
2006-10-01
影响因子：
4.7
通讯作者：
Bibb, James A.
中科院分区：
文献类型：
--
作者：
Hayashi, Kanehiro;Pan, Yong;Bibb, James A.
细胞骨架动力学的调节对发育和成年期神经元的可塑性至关重要。这些机制的失调可能导致神经精神和神经退行性疾病。神经元蛋白激酶，细胞周期蛋白依赖性激酶5（Cdk 5），参与神经元功能的多个方面，包括细胞骨架的调节。神经蛋白质组学搜索发现微管蛋白结合蛋白Stathmin是一种新型Cdk 5底物。Stathmin在体外被Cdk 5在Ser 25和Ser 38磷酸化，先前被鉴定为促分裂原活化蛋白激酶（MAPK）和p38 MAPK δ位点。Cdk 5主要磷酸化Ser 38，而MAPK和p38 MAPK δ主要磷酸化Ser 25。Stathmin在小鼠脑中的两个位点都被磷酸化，在皮质和纹状体中的水平更高。Cdk 5基因敲除小鼠表现出磷酸化Ser 38水平降低。在发展过程中，磷酸丝氨酸25和丝氨酸38水平在出生后第7天达到峰值，随后减少总stathmin。抑制纹状体切片中的蛋白磷酸酶导致磷酸丝氨酸25的增加和总stathmin的减少。有趣的是，精神分裂症患者的前额叶皮层磷酸化Ser 25水平增加。相比之下，总的和磷酸-Ser 25化学计量减少阿尔茨海默氏症患者的海马。因此，微管调节机制，涉及stathmin的磷酸化可能有助于发育突触修剪和结构可塑性，并可能参与神经精神和神经退行性疾病。
Regulation of cytoskeletal dynamics is essential to neuronal plasticity during development and adulthood. Dysregulation of these mechanisms may contribute to neuropsychiatric and neurodegenerative diseases. The neuronal protein kinase, cyclin-dependent kinase 5 (Cdk5), is involved in multiple aspects of neuronal function, including regulation of cytoskeleton. A neuroproteomic search identified the tubulin-binding protein, stathmin, as a novel Cdk5 substrate. Stathmin was phosphorylated by Cdk5 in vitro at Ser25 and Ser38, previously identified as mitogen-activated protein kinase (MAPK) and p38 MAPK delta sites. Cdk5 predominantly phosphorylated Ser38, while MAPK and p38 MAPK delta predominantly phosphorylated Ser25. Stathmin was phosphorylated at both sites in mouse brain, with higher levels in cortex and striatum. Cdk5 knockout mice exhibited decreased phospho-Ser38 levels. During development, phospho-Ser25 and -Ser38 levels peaked at post-natal day 7, followed by reduction in total stathmin. Inhibition of protein phosphatases in striatal slices caused an increase in phospho-Ser25 and a decrease in total stathmin. Interestingly, the prefrontal cortex of schizophrenic patients had increased phospho-Ser25 levels. In contrast, total and phospho-Ser25 stoichiometries were decreased in the hippocampus of Alzheimer's patients. Thus, microtubule regulatory mechanisms involving the phosphorylation of stathmin may contribute to developmental synaptic pruning and structural plasticity, and may be involved in neuropsychiatric and neurodegenerative disorders.