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First published online 15 February 2006
doi: 10.1242/dev.02255

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Sprouty proteins are in vivo targets of Corkscrew/SHP-2 tyrosine phosphatases

Lesley A. Jarvis^1,*,, Stephanie J. Toering^1,*,, Michael A. Simon², Mark A. Krasnow^1,¶ and Rachel K. Smith-Bolton^2,*,

¹ Department of Biochemistry and Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305-5307 USA.
² Department of Biological Sciences, Stanford University, Stanford, CA 94305-5020 USA.

^¶ Author for correspondence (e-mail: krasnow{at}cmgm.stanford.edu)

Accepted 16 December 2005

Drosophila Corkscrew protein and its vertebrate ortholog SHP-2 (now known as Ptpn11) positively modulate receptor tyrosine kinase (RTK) signaling during development, but how these tyrosine phosphatases promote tyrosine kinase signaling is not well understood. Sprouty proteins are tyrosine-phosphorylated RTK feedback inhibitors, but their regulation and mechanism of action are also poorly understood. Here, we show that Corkscrew/SHP-2 proteins control Sprouty phosphorylation and function. Genetic experiments demonstrate that Corkscrew/SHP-2 and Sprouty proteins have opposite effects on RTK-mediated developmental events in Drosophila and an RTK signaling process in cultured mammalian cells, and the genes display dose-sensitive genetic interactions. In cultured cells, inactivation of SHP-2 increases phosphorylation on the critical tyrosine of Sprouty 1. SHP-2 associates in a complex with Sprouty 1 in cultured cells and in vitro, and a purified SHP-2 protein dephosphorylates the critical tyrosine of Sprouty 1. Substrate-trapping forms of Corkscrew bind Sprouty in cultured Drosophila cells and the developing eye. These results identify Sprouty proteins as in vivo targets of Corkscrew/SHP-2 tyrosine phosphatases and show how Corkscrew/SHP-2 proteins can promote RTK signaling by inactivating a feedback inhibitor. We propose that this double-negative feedback circuit shapes the output profile of RTK signaling events.

Key words: Sprouty (Spry), Corkscrew (Csw), Ptpn11 (SHP-2), Tyrosine phosphatase, Receptor tyrosine kinase (RTK) signaling, Drosophila

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