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PNAS 104 (36): 14348-14353

Copyright © 2007 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / CELL BIOLOGY

Spatial regulation of Raf kinase signaling by RKTG

Lin Feng, Xiaoduo Xie, Qiurong Ding, Xiaolin Luo, Jing He, Fengjuan Fan, Weizhong Liu, Zhenzhen Wang, and Yan Chen*

Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai 200031, China

Edited by Melanie H. Cobb, University of Texas Southwestern Medical Center, Dallas, TX, and approved July 18, 2007

Received for publication February 12, 2007.

Abstract: Subcellular compartmentalization has become an important theme in cell signaling such as spatial regulation of Ras by RasGRP1 and MEK/ERK by Sef. Here, we report spatial regulation of Raf kinase by RKTG (Raf kinase trapping to Golgi). RKTG is a seven-transmembrane protein localized at the Golgi apparatus. RKTG expression inhibits EGF-stimulated ERK and RSK phosphorylation, blocks NGF-mediated PC12 cell differentiation, and antagonizes Ras- and Raf-1-stimulated Elk-1 transactivation. Through interaction with Raf-1, RKTG changes the localization of Raf-1 from cytoplasm to the Golgi apparatus, blocks EGF-stimulated Raf-1 membrane translocation, and reduces the interaction of Raf-1 with Ras and MEK1. In RKTG-null mice, the basal ERK phosphorylation level is increased in the brain and liver. In RKTG-deleted mouse embryonic fibroblasts, EGF-induced ERK phosphorylation is enhanced. Collectively, our results reveal a paradigm of spatial regulation of Raf kinase by RKTG via sequestrating Raf-1 to the Golgi apparatus and thereby inhibiting the ERK signaling pathway.

Key Words: EGF • ERK • Golgi • Raf-1 • Ras • PAQR3

Author contributions: L.F. and Y.C. designed research; L.F., X.X., Q.D., X.L., J.H., F.F., and W.L. performed research; L.F., Z.W., and Y.C. analyzed data; and L.F. and Y.C. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/cgi/content/full/0701298104/DC1.

*To whom correspondence should be addressed at: Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 294 Taiyuan Road, Shanghai 200031, China. E-mail: ychen3{at}sibs.ac.cn

© 2007 by The National Academy of Sciences of the USA

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