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

Melinda D. Willard, Francis S. Willard, Xiaoyan Li, Steven D. Cappell, William D. Snider, David P. Siderovski

Research output: Contribution to journalArticlepeer-review

58 Scopus citations

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.

Original languageEnglish
Pages (from-to)2029-2040
Number of pages12
JournalEMBO Journal
Volume26
Issue number8
DOIs
StatePublished - 18 Apr 2007

Keywords

  • MEK
  • RGS12
  • Raf
  • Ras
  • TrkA

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