The C. elegans Discoidin Domain Receptor DDR-2 Modulates the Met-like RTK–JNK Signaling Pathway in Axon Regeneration

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. © 2016 hisamoto et al.