CDK14 Promotes Axon Regeneration by Regulating the Noncanonical Wnt Signaling Pathway in a Kinase-Independent Manner
| Autor: | Tatsuhiro Shimizu, Hiroshi Hanafusa, Naoki Hisamoto, Yoshiki Sakai, Kunihiro Matsumoto, Kohei Ohta, Chun Li |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Frizzled
GTPase macromolecular substances Animals Genetically Modified Chlorocebus aethiops medicine Animals Axon Caenorhabditis elegans Caenorhabditis elegans Proteins noncanonical Wnt signaling pathway Wnt Signaling Pathway Research Articles Chemistry General Neuroscience Regeneration (biology) Wnt signaling pathway axon regeneration Axons Cyclin-Dependent Kinases Cell biology Nerve Regeneration medicine.anatomical_structure cdk14 COS Cells C. elegans Phosphorylation Guanine nucleotide exchange factor Signal transduction Cellular/Molecular |
| Zdroj: | The Journal of Neuroscience |
| ISSN: | 1529-2401 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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