Selective role for RGS12 as a Ras/Raf/MEK scaffold in nerve growth factor-mediated differentiation

Abstract

Regulator of G‐protein signaling (RGS) proteins accelerate GTP hydrolysis by heterotrimeric G‐protein α subunits and thus inhibit signaling by many G protein‐coupled receptors. Several RGS proteins have a multidomain architecture that adds further complexity to their roles in cell signaling in addition to their GTPase‐accelerating activity. RGS12 contains a tandem repeat of Ras‐binding domains but, to date, the role of this protein in Ras‐mediated signal transduction has not been reported. Here, we show that RGS12 associates with the nerve growth factor (NGF) receptor tyrosine kinase TrkA, activated H‐Ras, B‐Raf, and MEK2 and facilitates their coordinated signaling to prolonged ERK activation. RGS12 is required for NGF‐mediated neurite outgrowth of PC12 cells, but not outgrowth stimulated by basic fibroblast growth factor. siRNA‐mediated knockdown of RGS12 expression also inhibits NGF‐induced axonal growth in dissociated cultures of primary dorsal root ganglia neurons. These data suggest that RGS12 may play a critical, and receptor‐selective, role in coordinating Ras‐dependent signals that are required for promoting and/or maintaining neuronal differentiation.