Cdk5-mediated JIP1 phosphorylation regulates axonal outgrowth through Notch1 inhibition.
Cdk5-mediated JIP1 phosphorylation regulates axonal outgrowth through Notch1 inhibition.
复制标题
DOI：
10.1186/s12915-022-01312-4
复制
发表时间：
2022-05-17
期刊：
影响因子：
5.4
通讯作者：
Qu, Dianbo
中科院分区：
文献类型：
--
作者：
Im, Doo Soon;Joselin, Alvin;Svoboda, Devon;Takano, Tesuya;Rousseaux, Maxime W. C.;Callaghan, Steve;Slack, Ruth S.;Hisanaga, Shin-ichi;Davis, Roger J.;Park, David S.;Qu, Dianbo
激活的 Cdk5 调节神经系统形成过程中的许多过程，包括神经元分化、生长锥稳定和轴突生长。 Cdk5 磷酸化其位于轴突生长锥中的下游底物，其中高表达的 c-Jun N 末端激酶 (JNK) 相互作用蛋白 1 (JIP1) 被认为是轴突生长的另一个重要调节因子。此外，对Notch1 (Notch1-IC)胞内结构域水平的严格控制在神经元分化过程中轴突生长中发挥调节作用。然而，Cdk5-JIP1-Notch1 是否合作调节轴突生长，以及这种共同贡献该通路的机制目前尚不清楚，在这里我们探讨它们潜在的相互作用。我们的相互作用组筛选确定 JIP1 是 p35（一种 Cdk5 激活剂）的相互作用子，我们试图探索 Cdk5 和 JIP1 在轴突生长调节中的关系。我们证明，Cdk5 在 Thr205 处磷酸化的 JIP1 可增强轴突生长，而拟磷化的 JIP1 可挽救 JIP1−/− 和 p35−/− 神经元中的轴突生长缺陷。由 JIP1−/− 神经元中 Notch1 的特异性增加引起的轴突生长缺陷可通过 Numb 介导的 Notch1 抑制来挽救。最后，我们证明 JIP1 的 Cdk5 磷酸化进一步放大了另一种 Cdk5 底物 E3-泛素连接酶 Itch 的磷酸化状态，导致 Notch1 泛素化增加。我们的研究结果确定了一个涉及 Cdk5-JIP1-Itch-Notch1 的潜在关键信号轴，该轴在中枢神经系统发育的调节中发挥着重要作用。未来对该通路与调节轴突生长的其他通路整合方式的研究将进一步加深我们对正常中枢神经系统发育和病理状况的了解。在线版本包含可在 10.1186/s12915-022-01312-4 获取的补充材料。
Activated Cdk5 regulates a number of processes during nervous system formation, including neuronal differentiation, growth cone stabilization, and axonal growth. Cdk5 phosphorylates its downstream substrates located in axonal growth cones, where the highly expressed c-Jun N-terminal kinase (JNK)-interacting protein1 (JIP1) has been implicated as another important regulator of axonal growth. In addition, stringent control of the level of intracellular domain of Notch1 (Notch1-IC) plays a regulatory role in axonal outgrowth during neuronal differentiation. However, whether Cdk5-JIP1-Notch1 cooperate to regulate axonal outgrowth, and the mechanism of such joint contribution to this pathway, is presently unknown, and here we explore their potential interaction. Our interactome screen identified JIP1 as an interactor of p35, a Cdk5 activator, and we sought to explore the relationship between Cdk5 and JIP1 on the regulation of axonal outgrowth. We demonstrate that JIP1 phosphorylated by Cdk5 at Thr205 enhances axonal outgrowth and a phosphomimic JIP1 rescues the axonal outgrowth defects in JIP1−/− and p35−/− neurons. Axonal outgrowth defects caused by the specific increase of Notch1 in JIP1−/− neurons are rescued by Numb-mediated inhibition of Notch1. Finally, we demonstrate that Cdk5 phosphorylation of JIP1 further amplifies the phosphorylation status of yet another Cdk5 substrate E3-ubiquitin ligase Itch, resulting in increased Notch1 ubiquitination. Our findings identify a potentially critical signaling axis involving Cdk5-JIP1-Itch-Notch1, which plays an important role in the regulation of CNS development. Future investigation into the way this pathway integrates with additional pathways regulating axonal growth will further our knowledge of normal central nervous system development and pathological conditions. The online version contains supplementary material available at 10.1186/s12915-022-01312-4.
登录
查看更多内容
影响因子：
16.6
作者：
Huang E;Qu D;Huang T;Rizzi N;Boonying W;Krolak D;Ciana P;Woulfe J;Klein C;Slack RS;Figeys D;Park DS
通讯作者：
Park DS
影响因子：
9.2
作者：
Dajas-Ballador, Federico;Jones, Emma V.;Whitmarsh, Alan J.
通讯作者：
Whitmarsh, Alan J.
影响因子：
4
作者：
Dajas-Bailador, Federico;Bantounas, Ioannis;Whitmarsh, Alan J.
通讯作者：
Whitmarsh, Alan J.
影响因子：
3
作者：
Ferrari-Toninelli, Giulia;Bonini, Sara Anna;Memo, Maurizio
通讯作者：
Memo, Maurizio
影响因子：
4.8
作者：
McGill, Melanie A.;Dho, Sascha E.;McGlade, C. Jane
通讯作者：
McGlade, C. Jane