ARHGAP4 is a spatially regulated RhoGAP that inhibits NIH/3T3 cell migration and dentate granule cell axon outgrowth.

摘要

Cell migration and axonal growth cone guidance are tightly regulated events that share many similarities. While some factors are not always shared between migrating cells and growth cones, the signaling events that are required for cell migration and growth guidance each utilize GTPases to regulate the actin and microtubule cytoskeletons. GTPases are expressed ubiquitously but signal in discrete subcellular locales to control directed cell migration and growth cone guidance. This strict control of GTPase signaling is controlled by GAPs, GEFs and GDIs, which can assemble signaling complexes and localize to unique regions due to an array of conserved functional domains. The Rho-family GAP ARHGAP4 contains FCH and SH3 domains, as well as other conserved domains of unknown function. The FCH domain has been attributed to binding actin, microtubules and lipids, but there is no consensus on its function. Here we show that ARHGAP4 localizes to the leading edges of NIH/3T3 fibroblasts and to growth cones of dentate granule neurons, via its FCH domain. Overall, ARHGAP4 inhibits NIH/3T3 cell migration and dentate granule cell axon outgrowth in a GAP dependent manner, and this inhibition is temporally and spatially regulated by ARHGAP4's conserved functional domains.