CDK14 Promotes Axon Regeneration by Regulating the Noncanonical Wnt Signaling Pathway in a Kinase-Independent Manner.
CDK14 Promotes Axon Regeneration by Regulating the Noncanonical Wnt Signaling Pathway in a Kinase-Independent Manner.
复制标题
CDK14通过以激酶非依赖性方式调节非经典Wnt信号通路促进轴突再生
DOI：
10.1523/jneurosci.0711-21.2021
复制
发表时间：
2021-10-06
期刊：
影响因子：
--
通讯作者：
Matsumoto K
中科院分区：
文献类型：
--
作者：
Hisamoto N;Sakai Y;Ohta K;Shimizu T;Li C;Hanafusa H;Matsumoto K
神经元损伤后的再生能力被认为是由内在再生途径和外部信号的复杂相互作用所调节的。在秀丽线虫中，轴突再生的启动受非肌肉肌球蛋白轻链-4(MLC-4)磷酸化信号通路的调控。在本研究中，我们发现哺乳动物CDK14同源基因SVH-16/CDK-14是运动神经元轴突再生的正向调节因子。然后我们分离了CDK-14结合蛋白MIG-5/Disheveled(Dsh)，发现EGL-20/Wnt和MIG-1/Frizzleed受体(FZ)是有效的轴突再生所必需的。此外，我们证明CDK-14以一种不依赖于激酶的方式激活EPHX-1，它是哺乳动物Ephexin Rho型GTP酶鸟嘌呤核苷酸交换因子(Egf)的线虫同源物。EPHX-1作为CDC-42 GTP酶的全球环境基金，抑制维持MLC-4磷酸化的肌球蛋白磷酸酶。这些结果表明，CDK14在促进轴突再生的非典范Wnt信号通路中激活了Rhogef-CDc42-MLC磷酸化轴。意义陈述非典型的Wnt信号是由FrizzledR(Fz)、Disheveled(Dsh)、Rho-type GTPase和非肌肉肌球蛋白轻链(MLC)磷酸化介导的。本研究证实编码哺乳动物CDK14同源基因的SVH-16/CDK-14是秀丽线虫运动神经元轴突再生的调节因子。我们发现CDK-14与MIG-5/Dsh结合，而EGL-20/Wnt、MIG-1/FZ和EPHX-1/Rhogef是轴突再生所必需的。模拟磷酸化的MLC-4抑制了MiG-1、CDK-14和EPHX-1突变体中的轴突再生缺陷。CDK-14介导EPHX-1的非依赖性激活，EPHX-1是CDC-42 GTP酶的鸟嘌呤核苷酸交换因子。激活的CDC-42使肌球蛋白磷酸酶失活，从而维持MLC的磷酸化。因此，非典型的Wnt信号通路通过CDK-14-EPHX-1-CDC-42-MLC磷酸化轴控制轴突再生。
The postinjury regenerative capacity of neurons is known to be mediated by a complex interaction of intrinsic regenerative pathways and external cues. In Caenorhabditis elegans, the initiation of axon regeneration is regulated by the nonmuscle myosin light chain-4 (MLC-4) phosphorylation signaling pathway. In this study, we have identified svh-16/cdk-14, a mammalian CDK14 homolog, as a positive regulator of axon regeneration in motor neurons. We then isolated the CDK-14-binding protein MIG-5/Disheveled (Dsh) and found that EGL-20/Wnt and the MIG-1/Frizzled receptor (Fz) are required for efficient axon regeneration. Further, we demonstrate that CDK-14 activates EPHX-1, the C. elegans homolog of the mammalian ephexin Rho-type GTPase guanine nucleotide exchange factor (GEF), in a kinase-independent manner. EPHX-1 functions as a GEF for the CDC-42 GTPase, inhibiting myosin phosphatase, which maintains MLC-4 phosphorylation. These results suggest that CDK14 activates the RhoGEF–CDC42–MLC phosphorylation axis in a noncanonical Wnt signaling pathway that promotes axon regeneration. SIGNIFICANCE STATEMENT Noncanonical Wnt signaling is mediated by Frizzled receptor (Fz), Disheveled (Dsh), Rho-type GTPase, and nonmuscle myosin light chain (MLC) phosphorylation. This study identified svh-16/cdk-14, which encodes a mammalian CDK14 homolog, as a regulator of axon regeneration in Caenorhabditis elegans motor neurons. We show that CDK-14 binds to MIG-5/Dsh, and that EGL-20/Wnt, MIG-1/Fz, and EPHX-1/RhoGEF are required for axon regeneration. The phosphorylation-mimetic MLC-4 suppressed axon regeneration defects in mig-1, cdk-14, and ephx-1 mutants. CDK-14 mediates kinase-independent activation of EPHX-1, which functions as a guanine nucleotide exchange factor for CDC-42 GTPase. Activated CDC-42 inactivates myosin phosphatase and thereby maintains MLC phosphorylation. Thus, the noncanonical Wnt signaling pathway controls axon regeneration via the CDK-14–EPHX-1–CDC-42–MLC phosphorylation axis.