Kidins220/ARMS regulates Rac1-dependent neurite outgrowth by direct interaction with the RhoGEF Trio.

Neurite extension depends on extracellular signals that lead to changes in gene expression and rearrangement of the actin cytoskeleton. A factor that might orchestrate these signalling pathways with cytoskeletal elements is the integral membrane protein Kidins220/ARMS, a downstream target of neurotrophins. Here, we identified Trio, a RhoGEF for Rac1, RhoG and RhoA, which is involved in neurite outgrowth and axon guidance, as a binding partner of Kidins220. This interaction is direct and occurs between the N-terminus of Trio and the ankyrin repeats of Kidins220. Trio and Kidins220 colocalise at the tips of neurites in NGF-differentiated PC12 cells, where F-actin and Rac1 also accumulate. Expression of the ankyrin repeats of Kidins220 in PC12 cells inhibits NGF-dependent and Trio-induced neurite outgrowth. Similar results are seen in primary hippocampal neurons. Our data indicate that Kidins220 might localise Trio to specific membrane sites and regulate its activity, leading to Rac1 activation and neurite outgrowth.