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

• Published in: Cellular signalling Vol. 22; no. 3; pp. 366 - 376
• Main Authors: Shu, Feng-jue, Ramineni, Suneela, Hepler, John R.
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 01.03.2010
• Subjects: Extracellular Signal-Regulated MAP Kinases - metabolism; GoLoco proteins; GPR proteins; GTP-Binding Protein alpha Subunits, Gi-Go - genetics; GTP-Binding Protein alpha Subunits, Gi-Go - metabolism; H-Ras; HeLa Cells; Humans; MAP Kinase Signaling System; MAPkinase signalling; Phosphorylation; Platelet-Derived Growth Factor - metabolism; Protein Binding; Protein Structure, Tertiary; Raf kinases; raf Kinases - metabolism; ras Proteins - metabolism; RGS proteins; RGS Proteins - analysis; RGS Proteins - metabolism; RGS14; Scaffolds; Signal Transduction; RGS14; RGS proteins; MAPkinase signalling; CFP; GDI; GFP; GPR proteins; MAGUK; RBD; NMDA; MAPkinase; NuMA; GPR/GoLoco (GL); PSD; BDNF; EGF; Raf kinases; GΑP; Ric-8A; GEF; AGS; Frmpd1; SDS-PAGE; LGN; H-Ras; PDGF; GoLoco proteins; GPCR; Scaffolds; RGS
• ISSN: 0898-6568; 1873-3913
• DOI: 10.1016/j.cellsig.2009.10.005

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.