Selective role for RGS12 as a Ras/Raf/MEK scaffold in nerve growth factor-mediated differentiation.
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.
Willard
Melinda D
MD
Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599-7365, USA.
Willard
Francis S
FS
Li
Xiaoyan
X
Cappell
Steven D
SD
Snider
William D
WD
Siderovski
David P
DP
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
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