Reference - Detail
| RRC ID | 76047 |
|---|---|
| Author | Sakai Y, Tsunekawa M, Ohta K, Shimizu T, Pastuhov S 4th, Hanafusa H, Hisamoto N, Matsumoto K. |
| Title | The Integrin Signaling Network Promotes Axon Regeneration via the Src-Ephexin-RhoA GTPase Signaling Axis. |
| Journal | J Neurosci |
| Abstract |
Axon regeneration is an evolutionarily conserved process essential for restoring the function of damaged neurons. In Caenorhabditis elegans hermaphrodites, initiation of axon regeneration is regulated by the RhoA GTPase-ROCK (Rho-associated coiled-coil kinase)-regulatory nonmuscle myosin light-chain phosphorylation signaling pathway. However, the upstream mechanism that activates the RhoA pathway remains unknown. Here, we show that axon injury activates TLN-1/talin via the cAMP-Epac (exchange protein directly activated by cAMP)-Rap GTPase cascade and that TLN-1 induces multiple downstream events, one of which is integrin inside-out activation, leading to the activation of the RhoA-ROCK signaling pathway. We found that the nonreceptor tyrosine kinase Src, a key mediator of integrin signaling, activates the Rho guanine nucleotide exchange factor EPHX-1/ephexin by phosphorylating the Tyr-568 residue in the autoinhibitory domain. Our results suggest that the C. elegans integrin signaling network regulates axon regeneration via the Src-RhoGEF-RhoA axis.SIGNIFICANCE STATEMENT The ability of axons to regenerate after injury is governed by cell-intrinsic regeneration pathways. We have previously demonstrated that the Caenorhabditis elegans RhoA GTPase-ROCK (Rho-associated coiled-coil kinase) pathway promotes axon regeneration by inducing MLC-4 phosphorylation. In this study, we found that axon injury activates TLN-1/talin through the cAMP-Epac (exchange protein directly activated by cAMP)-Rap GTPase cascade, leading to integrin inside-out activation, which promotes axonal regeneration by activating the RhoA signaling pathway. In this pathway, SRC-1/Src acts downstream of integrin activation and subsequently activates EPHX-1/ephexin RhoGEF by phosphorylating the Tyr-568 residue in the autoinhibitory domain. Our results suggest that the C. elegans integrin signaling network regulates axon regeneration via the Src-RhoGEF-RhoA axis. |
| Volume | 41(22) |
| Pages | 4754-4767 |
| Published | 2021-6-2 |
| DOI | 10.1523/JNEUROSCI.2456-20.2021 |
| PII | JNEUROSCI.2456-20.2021 |
| PMID | 33963050 |
| PMC | PMC8260174 |
| MeSH | Animals Axons / metabolism Caenorhabditis elegans Guanine Nucleotide Exchange Factors / metabolism* Integrins / metabolism* Nerve Regeneration / physiology* Signal Transduction / physiology rhoA GTP-Binding Protein / metabolism* src-Family Kinases / metabolism* |
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| The most frequently cited source | X(Twitter) |
| Total number of mentions | 9 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| C.elegans | tm3203 |