TrkA‐mediated Activation of the Rit GTPase

Abstract

Members of the Ras family of small GTP binding proteins (Ras GTPases) control numerous cellular processes including cell growth and differentiation. Rit (Ras-like protein in tissues) is a novel member of Ras GTPase superfamily that that is widely expressed in both the developing and adult nervous system and has been shown to play critical roles in controlling neuronal differentiation and promoting pro-survival signaling pathways. In pheochromocytoma 6 cells (PC6), nerve growth factor stimulation activates Rit, and RNAi-mediated silencing of Rit disrupts NGF-mediated stimulation of both ERK and p38 MAP kinase pathways, implicating Rit signaling in NGF-mediated neuronal differentiation. In the present study, we report the characterization of the molecular mechanism of linking NGF stimulation to Rit activation. Activation of the TrkA receptor tyrosine kinase is responsible for NGF-mediated Rit activation, and analysis of a series of TrkA mutant receptors has identified the phospho-tyrosine residue responsible for coupling TrkA to Rit activation. Ongoing studies are characterizing the role of both signaling adapter proteins and Rit guanine nucleotide exchange proteins in this process. Collectively, our studies suggest that Rit represents a regulator of neurotrophin signaling, required to couple NGF stimulation to neuronal development and survival. (Source of research NIH NINDS)