Abstract
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.
Highlights
receptor tyrosine kinase (RTK) signaling pathways regulate many cellular and developmental events, including respiratory system branching and photoreceptor differentiation in Drosophila
The results demonstrate that Spry proteins are targets of Csw/SHP-2 tyrosine phosphatases in Drosophila and vertebrate RTK pathways, and explain how Csw/SHP-2 can enhance RTK signaling by inactivating a feedback inhibitor
Genetic experiments in developing Drosophila eye and trachea and human embryonic kidney 293 (HEK293) cells demonstrated that Csw/SHP-2 and Spry act in the same RTK signaling events but in opposite directions
Summary
RTK signaling pathways regulate many cellular and developmental events, including respiratory system branching and photoreceptor differentiation in Drosophila. Two of the best known but least well understood classes of regulators are the Corkscrew/SHP-2 family of tyrosine phosphatases that promote RTK signaling and the Sprouty family of RTK feedback inhibitors, whose genetic and molecular interactions we explore here. Corkscrew was identified by its requirement for development of the terminal regions of the embryo. It encodes an SH2 domaincontaining protein tyrosine phosphatase that functions downstream of, and promotes signaling through, the RTK Torso (Perkins et al, 1992). Further work demonstrated that Csw and SHP-2 promotes signaling downstream of many RTKs in a variety of Accepted 16 December 2005 systems (Perkins et al, 1996) (reviewed by Feng, 1999), and that this activity requires their tyrosine phosphate-binding SH2 domains and tyrosine phosphatase activity (Allard et al, 1998; Deb et al, 1998)
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