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J. Biol. Chem. 277 (5): 3195-3201

© 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

Sprouty2 Inhibits the Ras/MAP Kinase Pathway by Inhibiting the Activation of Raf*

Permeen Yusoff, Dieu-Hung Lao, Siew Hwa OngDagger , Esther Sook Miin Wong, Jormay Lim, Ting Ling Lo, Hwei Fen Leong, Chee Wai Fong, and Graeme R. Guy§

From the Signal Transduction Laboratory, Institute of Molecular and Cell Biology, National University of Singapore, Singapore 117609, Singapore

Several genetic studies in Drosophila have shown that the dSprouty (dSpry) protein inhibits the Ras/mitogen-activated protein (MAP) kinase pathway induced by various activated receptor tyrosine kinase receptors, most notably those of the epidermal growth factor receptor (EGFR) and fibroblast growth factor receptor (FGFR). Currently, the mode of action of dSpry is unknown, and the point of inhibition remains controversial. There are at least four mammalian Spry isoforms that have been shown to co-express preferentially with FGFRs as compared with EGFRs. In this study, we investigated the effects of the various mammalian Spry isoforms on the Ras/MAP kinase pathway in cells overexpressing constitutively active FGFR1. hSpry2 was significantly more potent than mSpry1 or mSpry4 in inhibiting the Ras/MAP kinase pathway. Additional experiments indicated that full-length hSpry2 was required for its full potency. hSpry2 had no inhibitory effect on either the JNK or the p38 pathway and displayed no inhibition of FRS2 phosphorylation, Akt activation, and Ras activation. Constitutively active mutants of Ras, Raf, and Mek were employed to locate the prospective point of inhibition of hSpry2 downstream of activated Ras. Results from this study indicated that hSpry2 exerted its inhibitory effect at the level of Raf, which was verified in a Raf activation assay in an FGF signaling context.

* This work was supported by funding from the National Science and Technology Board of Singapore.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger Present address: Program in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Ontario, M5G 1X5, Toronto, Canada.

§ To whom correspondence should be addressed: Signal Transduction Laboratory, Institute of Molecular and Cell Biology, National University of Singapore, 30 Medical Dr., Singapore 117609. Tel.: 65-874-3737; Fax: 65-779-1117; E-mail: mcbgg@imcb.nus.edu.sg.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

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