The Integrin Signaling Network Promotes Axon Regeneration via the Src-Ephexin-RhoA GTPase Signaling Axis.
The Integrin Signaling Network Promotes Axon Regeneration via the Src-Ephexin-RhoA GTPase Signaling Axis.
复制标题
整合素信号网络通过Src-Ephexin-RhoA GTdR信号轴促进轴突再生。
DOI：
10.1523/jneurosci.2456-20.2021
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发表时间：
2021-06-02
期刊：
影响因子：
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通讯作者：
Matsumoto K
中科院分区：
文献类型：
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作者：
Sakai Y;Tsunekawa M;Ohta K;Shimizu T;Pastuhov S 4th;Hanafusa H;Hisamoto N;Matsumoto K
轴突再生是一个进化上保守的过程，对于恢复受损神经元的功能至关重要。在秀丽隐杆线虫雌雄同体中，轴突再生的起始受RhoA GTP酶-ROCK（Rho相关卷曲螺旋激酶）调节非肌肉肌球蛋白轻链磷酸化信号通路的调节。然而，激活RhoA通路的上游机制仍然未知。在这里，我们表明，轴突损伤激活TLN-1/talin通过cAMP-Epac（交换蛋白直接激活cAMP）-Rap GT3级联和TLN-1诱导多个下游事件，其中之一是整合素由内而外激活，导致RhoA-ROCK信号通路的激活。我们发现，非受体酪氨酸激酶Src，整合素信号的关键介质，激活Rho鸟嘌呤核苷酸交换因子EPHX-1/ephexin的磷酸化的Tyr-568残基的自抑制结构域。我们的研究结果表明，C。线虫整联蛋白信号网络通过Src-RhoGEF-RhoA轴调节轴突再生。损伤后轴突再生的能力由细胞内源性再生途径控制。我们先前已经证明，秀丽隐杆线虫RhoA GTP酶-ROCK（Rho相关卷曲螺旋激酶）途径通过诱导MLC-4磷酸化促进轴突再生。在这项研究中，我们发现轴突损伤通过cAMP-Epac（由cAMP直接激活的交换蛋白）-Rap GT3级联激活TLN-1/talin，导致整合素由内而外激活，其通过激活RhoA信号通路促进轴突再生。在该途径中，SRC-1/Src在整合素活化的下游起作用，随后通过磷酸化自身抑制结构域中的Tyr-568残基来活化EPHX-1/ephexin RhoGEF。我们的研究结果表明，C。线虫整联蛋白信号网络通过Src-RhoGEF-RhoA轴调节轴突再生。
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.