Phosphorylation of Carboxyl-terminal Tyrosines Modulates the Specificity of Sprouty-2 Inhibition of Different Signaling Pathways

• Published in: The Journal of biological chemistry Vol. 280; no. 10; pp. 9735 - 9744
• Main Authors: Rubin, Chanan, Zwang, Yaara, Vaisman, Nora, Ron, Dina, Yarden, Yosef
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11-03-2005; American Society for Biochemistry and Molecular Biology
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Animals; Cell Line; Chlorocebus aethiops; CHO Cells; COS Cells; Cricetinae; Cysteine; GRB2 Adaptor Protein; Humans; MAP Kinase Signaling System - physiology; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Phosphorylation; Phosphotyrosine - metabolism; Protein Binding; Rats; Recombinant Proteins - metabolism; RNA Interference; Signal Transduction - physiology; Transfection
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M408308200

Sprouty proteins are evolutionarily conserved negative feedback regulators of multiple receptor tyrosine kinases. Mammalian versions of these proteins differentially regulate signaling induced by the fibroblast and the epidermal growth factors (FGF and EGF, respectively). Herein we show that, although both growth factors elevate expression of Sprouty-2, FGF- and not EGF-induced activation of the Erk/MAPK pathway is inhibited by Sprouty-2. Attenuation of FGF-signaling is accompanied by the induction of Sprouty-2 phosphorylation on the amino-terminal as well as carboxyl-terminal tyrosine residues, which are less effectively modified upon EGF treatment. Mutagenesis of carboxyl-terminal tyrosines, especially a newly identified phosphorylation site, tyrosine 227, impaired the inhibitory activity of Sprouty-2. These results attribute a novel role for carboxyl-terminal tyrosine residues and yet unidentified phosphotyrosine-binding proteins in the differential regulation of Sprouty-2 activity.