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

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.

Coordinated regulation by Shp2 tyrosine phosphatase of signaling events controlling insulin biosynthesis in pancreatic β-cells

“…3F). Prior studies have shown that Shp2 promotes receptor tyrosine kinase signaling by inactivating Sprouty 1, a feedback inhibitor of the Erk pathway, in Drosophila (21,22). To test whether Sprouty 1 is an Shp2 target in INS-1 832/13 cells, we first determined whether Shp2 associated with Sprouty 1 protein by coimmunoprecipitation.…”

A Mass Action Model of a Fibroblast Growth Factor Signaling Pathway and Its Simplification

“…Also commonly noted is the binding of SOS to FRS2 via GRB2 and the subsequent activation of the RAS-MAP kinase pathway (ibid) together with CBL induced degradation (Dailey et al, 2005). It is also known that SHP2 can induce a dephosphorylation of SPRY (Jarvis et al, 2006;Hanafusa et al, 2004) and that SPRY associates with GRB2 (Thisse and Thisse, 2005) plus CBL (Wong et al, 2001). Signal attenuation due to SRC binding FRS2 has also been reported, along with the observation that SPRY is a direct physiological substrate for SRC (Li et al, 2004).…”

Sprouty2 expression controls endothelial monolayer integrity and quiescence

“…The Src family of kinases is likely responsible for phosphorylation of SPRY at this conserved tyrosine, while Shp2 phosphatase is involved in dephosphorylating this critical residue [119][120][121][122] (Fig. 10).…”