RGS14 is a multifunctional scaffold that integrates G protein and Ras/Raf MAPkinase signalling pathways

• Type of Material: Article
• Authors: Feng-jue Shu, Emory University; Suneela Ramineni, Emory University; John R Hepler, Emory University
• Language: English
• Date: 2010-03
• Publisher: Elsevier: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2009 Elsevier Inc. All rights reserved.
• License: Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported
• Final Published Version (URL): http://ac.els-cdn.com/S0898656809003222/1-s2.0-S0898656809003222-main.pdf?_tid=4cbcd512-97e7-11e3-a5fa-00000aacb361&acdnat=1392650723_7a2f235bcf2dd3e011f3d39cccc2fcaf
• Title of Journal or Parent Work: Cellular Signalling
• ISSN: 0898-6568
• Volume: 22
• Issue: 3
• Start Page: 366
• End Page: 376
• Grant/Funding Information: This work is supported by grants from the National Institutes of Health awarded to J.R.H. (R01NS37112 and R01NS049195).
• Keywords: Raf kinases; H-Ras; RGS proteins; MAPkiase signalling; RGS14; scaffolds; GoLoco proteins; GPR proteins
• Research Categories: Health Sciences, Pharmacology; Biology, Cell

Abstract

MAPkinase signalling is essential for cell growth, differentiation and cell physiology. G proteins and tyrosine kinase receptors each modulate MAPkinase signalling through distinct pathways. We report here that RGS14 is an integrator of G protein and MAPKinase signalling pathways. RGS14 contains a GPR/GoLoco (GL) domain that forms a stable complex with inactive Giα1/3-GDP, and a tandem (R1, R2) Ras binding domain (RBD). We find that RGS14 binds and regulates the subcellular localization and activities of H-Ras and Raf kinases in cells. Activated H-Ras binds RGS14 at the R1 RBD to form a stable complex at cell membranes. RGS14 also co-localizes with and forms a complex with Raf kinases in cells. The regulatory region of Raf-1 binds the RBD region of RGS14, and H-Ras and Raf each facilitate one another’s binding to RGS14. RGS14 selectively inhibits PDGF-, but not EGF- or serum-stimulated Erk phosphorylation. This inhibition is dependent on H-Ras binding to RGS14 and is reversed by co-expression of Giα1, which binds and recruits RGS14 to the plasma membrane. Giα1 binding to RGS14 inhibits Raf binding, indicating that Giα1 and Raf binding to RGS14 are mutually exclusive. Taken together, these findings indicate that RGS14 is a newly appreciated integrator of G protein and Ras/Raf signalling pathways.