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Mol. Biol. Cell 15 (5): 2176-2188

Copyright © 2004 by The American Society for Cell Biology.

Tyrosine Phosphorylation of Sprouty Proteins Regulates Their Ability to Inhibit Growth Factor Signaling: A Dual Feedback Loop

Jacqueline M. Mason *, Debra J. Morrison *, Bhramdeo Bassit *, Manjari Dimri {dagger}, Hamid Band {dagger}, Jonathan D. Licht * {ddagger}, and Isabelle Gross * {ddagger} §

* Division of Hematology/Oncology, Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029
{dagger} Evanston Northwestern Healthcare Research Institute, Evanston, Illinois 60201

Received for publication July 18, 2003. Revision received December 22, 2003. Accepted for publication January 26, 2004.

Monitoring Editor: Richard Assoian

Abstract: Sprouty proteins are recently identified receptor tyrosine kinase (RTK) inhibitors potentially involved in many developmental processes. Here, we report that Sprouty proteins become tyrosine phosphorylated after growth factor treatment. We identified Tyr55 as a key residue for Sprouty2 phosphorylation and showed that phosphorylation was required for Sprouty2 to inhibit RTK signaling, because a mutant Sprouty2 lacking Tyr55 augmented signaling. We found that tyrosine phosphorylation of Sprouty2 affected neither its subcellular localization nor its interaction with Grb2, FRS2/SNT, or other Sprouty proteins. In contrast, Sprouty2 tyrosine phosphorylation was necessary for its binding to the Src homology 2-like domain of c-Cbl after fibroblast growth factor (FGF) stimulation. To determine whether c-Cbl was required for Sprouty2-dependent cellular events, Sprouty2 was introduced into c-Cbl-wild-type and -null fibroblasts. Sprouty2 efficiently inhibited FGF-induced phosphorylation of extracellular signal-regulated kinase 1/2 in c-Cbl-null fibroblasts, thus indicating that the FGF-dependent binding of c-Cbl to Sprouty2 was dispensable for its inhibitory activity. However, c-Cbl mediates polyubiquitylation/proteasomal degradation of Sprouty2 in response to FGF. Last, using Src-family pharmacological inhibitors and dominant-negative Src, we showed that a Src-like kinase was required for tyrosine phosphorylation of Sprouty2 by growth factors. Thus, these data highlight a novel negative and positive regulatory loop that allows for the controlled, homeostatic inhibition of RTK signaling.


Article published online ahead of print. Mol. Biol. Cell 10.1091/mbc.E03–07–0503. Article and publication date are available at www.molbiolcell.org/cgi/doi/10.1091/mbc.E03–07–0503.

§ Present address: INSERM U381, 3 Avenue Molière, 67000 Strasbourg, France.

{ddagger} Corresponding authors. E-mail addresses: jonathan.licht{at}mssm.edu or isabelle.gross{at}inserm.u-strasbg.fr.


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