期刊
CELLULAR SIGNALLING
卷 22, 期 3, 页码 366-376出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2009.10.005
关键词
RGS14; RGS proteins; GoLoco proteins; GPR proteins; Scaffolds; H-Ras; Raf kinases; MAPkinase signalling
类别
资金
- National Institutes of Health [1101 NS37112, R01 NS049195]
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS049195, R01NS037112] Funding Source: NIH RePORTER
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 CPR/GoLoco (GL) domain that forms a stable complex with inactive Gi alpha 1/3-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 colocalizes 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 Gi alpha 1, which binds and recruits RGS14 to the plasma membrane. Gi alpha 1 binding to RGS14 inhibits Raf binding, indicating that Gi alpha 1 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. (C) 2009 Elsevier Inc. All rights reserved.
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