The C. elegans Discoidin Domain Receptor DDR-2 Modulates the Met-like RTK-JNK Signaling Pathway in Axon Regeneration.
The C. elegans Discoidin Domain Receptor DDR-2 Modulates the Met-like RTK-JNK Signaling Pathway in Axon Regeneration.
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DOI：
10.1371/journal.pgen.1006475
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发表时间：
2016-12
期刊：
影响因子：
4.5
通讯作者：
Matsumoto K
中科院分区：
文献类型：
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作者：
Hisamoto N;Nagamori Y;Shimizu T;Pastuhov SI;Matsumoto K
损伤后特定神经元轴突再生的能力受细胞内在再生途径的支配。然而，调控轴突再生的信号通路尚不清楚。在秀丽隐杆线虫中，SVH-2 met样生长因子受体酪氨酸激酶（RTK）信号通过JNK - MAPK途径正向调节轴突再生的启动。在这里，我们发现SVH-4/DDR-2（一种含有被胶原激活的盘状蛋白结构域的RTK）和EMB-9 IV型胶原调节轴突损伤后神经元的再生。支架蛋白SHC-1与DDR-2和SVH-2相互作用。此外，我们发现在ddr-2突变体中，svh-2和shc-1的过表达抑制了轴突再生的延迟，这表明ddr-2的功能在svh-2和shc-1的上游。这些结果表明，DDR-2通过SHC-1调节SVH-2-JNK通路。因此，我们确定了两种不同的RTK信号网络，它们在轴突再生的调节中发挥协调作用。损伤后轴突的再生能力受细胞内在再生途径的支配。秀丽隐杆线虫JNK MAP激酶通路是损伤后神经元再生所必需的。之前，我们发现了几个参与jnk介导的信号传导的svh基因。其中，svh-1和svh-2基因分别编码生长因子及其受体酪氨酸激酶（RTK）。这种SVH-1-SVH-2信号级联通过JNK途径正向调节轴突再生。在本研究中，我们研究了svh-4/ddr-2基因的作用，该基因编码含有被胶原活化的盘状蛋白结构域的RTK。事实上，DDR-2在EMB-9型胶原的下游发挥作用。在这里，我们发现DDR-2和EMB-9突变延迟了轴突损伤后再生的启动。此外，我们证明DDR-2通过支架蛋白SHC-1调节SVH-1-SVH-2-JNK通路。因此，两种不同的RTK信号网络在轴突再生调控中发挥协同作用。
The ability of specific neurons to regenerate their axons after injury is governed by cell-intrinsic regeneration pathways. However, the signaling pathways that orchestrate axon regeneration are not well understood. In Caenorhabditis elegans, initiation of axon regeneration is positively regulated by SVH-2 Met-like growth factor receptor tyrosine kinase (RTK) signaling through the JNK MAPK pathway. Here we show that SVH-4/DDR-2, an RTK containing a discoidin domain that is activated by collagen, and EMB-9 collagen type IV regulate the regeneration of neurons following axon injury. The scaffold protein SHC-1 interacts with both DDR-2 and SVH-2. Furthermore, we demonstrate that overexpression of svh-2 and shc-1 suppresses the delay in axon regeneration observed in ddr-2 mutants, suggesting that DDR-2 functions upstream of SVH-2 and SHC-1. These results suggest that DDR-2 modulates the SVH-2–JNK pathway via SHC-1. We thus identify two different RTK signaling networks that play coordinated roles in the regulation of axonal regeneration. An axon’s ability to regenerate after injury is governed by cell-intrinsic regeneration pathways. The C. elegans JNK MAP kinase pathway is required for the regrowth of neurons after injury. Previously, we identified several svh genes involved in JNK-mediated signaling. Among them, the svh-1 and svh-2 genes encode a growth factor and its receptor tyrosine kinase (RTK), respectively. This SVH-1–SVH-2 signaling cascade positively regulates axon regeneration through the JNK pathway. In the present study, we investigate the role of the svh-4/ddr-2 gene, which encodes an RTK containing a discoidin domain that is activated by collagen. Indeed, DDR-2 functions downstream of EMB-9 collagen type IV. Here, we show that the ddr-2 and emb-9 mutations delay initiation of regeneration after axon injury. Furthermore, we demonstrate that DDR-2 modulates the SVH-1–SVH-2–JNK pathway through the scaffold protein SHC-1. Thus, two different RTK signaling networks play coordinated roles in the regulation of axonal regeneration.