The novel function of cyclin-dependent kinase 5, a role in long term potentiation

细胞周期蛋白依赖性激酶 5 的新功能，在长时程增强中的作用

• 批准号: 14580703
• 负责人: HISANAGA Shin-ichi
• 金额: $ 2.3万
• 依托单位: Tokyo Metropolitan University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14580703/
• 关键词: Cdk5; Phosphorylation; Protein kinase; Neuron; Alzheimer; Proteasome; Calpain; Siganal transduction; p35; タンパク分解; 長期増強; グルタミン酸受容体; シナプ; 神経細胞; カルシウム; NMDA; 記憶

Cdk5, a cdc2-related kinase expressed in postmitotic neurons, is activated by association with a brain-specific activator, p35. It has been suggested the conversion of p35 to p25 by the protease calpain is involved in neuronal cell death. On the other hand, p35 protein is rapidly turned over via proteasomal degradation in living neurons. In this study, we found that the phosphorylation of p35 is involved in the control of its proteolytic degradation, and that the phosphorylation status of p35 changes in a developmental manner. The phosphorylated from of p35 is resistant to cleavage by calpain and is more susceptible to proteasomal degradation. The unphosphorylated form of p35 is more resistant to proteasomal degradation but is more susceptible to calpain-dependent cleavage to produce p25. Autophosphorylation of p35 by Cdk5 suppresses the cleavage to p25 by calpain, whereas autophosphorylation facilitates the proteasomal degradation of p35. A phosphorylated form of p35 is more prevalent in the fetal brain, whereas the unphosphorylated form of p35 occurs in the adult brain. These results suggest that the autophosphorylation of p35 serves as a protective mechanism that suppresses the generation of p25 in developing brains.

Cdk5是一种表达于有丝分裂后神经元的cdc2相关激酶，通过与脑特异性激活因子p35的结合而被激活。有研究表明，蛋白酶calpain将p35转化为p25与神经元细胞死亡有关。另一方面，p35蛋白在活神经元中通过蛋白酶体降解而快速翻转。在本研究中，我们发现p35的磷酸化参与了其蛋白水解降解的控制，并且p35的磷酸化状态以发育方式发生变化。p35的磷酸化片段抗钙蛋白酶裂解，更容易被蛋白酶体降解。p35的未磷酸化形式对蛋白酶体降解更有抵抗力，但更容易被calpain依赖性裂解产生p25。Cdk5对p35的自磷酸化抑制calpain对p25的裂解，而自磷酸化促进p35的蛋白酶体降解。p35的磷酸化形式在胎儿大脑中更为普遍，而p35的未磷酸化形式则出现在成人大脑中。这些结果表明p35的自磷酸化是抑制发育中的大脑中p25生成的一种保护机制。

项目成果

Sasaki, T., et al.: "In vivo and in vitro phosphorylation at Ser493 in the E-segment of neurofilament-H subunit by GSK3b"J. Biol. Chem.. 277. 36032-36039 (2002)

Sasaki, T. 等人：“GSK3b 对神经丝 H 亚基 E 段中 Ser493 的体内和体外磷酸化”J。

Takahashi, S.et al.: "Tau phosphorylation by cyclin-dependent kinase 5/p39 during brain development reduces its affinity for microtubules."J.Biol.Chem.. 278. 10506-10515 (2003)

Takahashi, S.et al.：“大脑发育过程中细胞周期蛋白依赖性激酶 5/p39 的 Tau 磷酸化降低了其对微管的亲和力。”J.Biol.Chem.. 278. 10506-10515 (2003)

Takahashi, S., et al.: "Tau phosphorylation by cyclin-dependent-kinase 5/p39 during brain development reduces its affinity for microtubules"J. Biol. Chem.. (in press). (2003)

Takahashi, S. 等人：“大脑发育过程中细胞周期蛋白依赖性激酶 5/p39 的 Tau 磷酸化降低了其对微管的亲和力”J.

Saito et al.: "Developmental regulation of the proteolysis of the p35 Cdk5 activator by phosphorylation."J. Neurosci. 23. 1189-1197 (2003)

Saito 等人：“通过磷酸化对 p35 Cdk5 激活剂的蛋白水解进行发育调节。”J.

Takahashi et al.: "Tau phosphorylation by cyclin-dependent kinase 5/p39 during brain development reduces its affinity for microtubules."J.Biol.Chem.. 278. 10506-10515 (2003)

Takahashi 等人：“大脑发育过程中细胞周期蛋白依赖性激酶 5/p39 的 Tau 磷酸化降低了其对微管的亲和力。”J.Biol.Chem.. 278. 10506-10515 (2003)