A novel FERM domain including guanine nucleotide exchange factor is involved in Rac signaling and regulates neurite remodeling

Abstract

The Rho family of small GTPases, key regulators of the actin cytoskeleton in eukaryotic cells from yeast to human, is implicated in the control of neuronal morphology. Guanine nucleotide exchange factors (GEFs) are upstream positive regulators of Rho GTPases and integrate extracellular signaling for appropriate activation of Rho GTPases at specific subcellular regions. Here we describe the identification of a novel Dbl family GEF for Rho GTPases in Homo sapiens and Mus musculus. It contains a tandem Dbl homology-pleckstrin homology domain and FERM domain, characteristic of the plasma membrane proteins linker. This gene, termed FERM domain including RhoGEF (FIR), was abundantly expressed in brain, lung, and testis, as well as embryonic hippocampal and cortical neurons. FIR was found to activate the biochemical pathway specific for Rac1 but not for RhoA or Cdc42. Ectopic expression of FIR in the cortical neurons resulted in significantly shortened neurites and excessive growth cones, presumably mediated by Rac1. These results suggest that FIR may regulate neurite remodeling by mediating the signaling pathways from membrane proteins to Rac.