title: 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 alpha 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.
authors: Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599-7365, USA.
authors: Melinda D
authors: MD
authors: Willard
authors: Francis S
authors: FS
authors: Willard
authors: Xiaoyan
authors: X
authors: Li
authors: Steven D
authors: SD
authors: Cappell
authors: William D
authors: WD
authors: Snider
authors: David P
authors: DP
authors: Siderovski
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D045744:Cell Line, Tumor; D048370:MAP Kinase Kinase 2 / Q000378:metabolism; D009474:Neurons / Q000166:cytology*; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism; D020710:RGS Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D020917:Receptor, trkA / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D018631:ras Proteins / Q000378:metabolism
chemical_list: D020710:RGS Proteins; D034741:RNA, Small Interfering; C491401:Rgs12 protein, rat; D020917:Receptor, trkA; C482123:Braf protein, rat; D048493:Proto-Oncogene Proteins B-raf; D048370:MAP Kinase Kinase 2; D018631:ras Proteins