Mammalian Sprouty4 suppresses Ras-independent ERK activation by binding to Raf1

Atsuo Sasaki, Takaharu Taketomi, Reiko Kato, Kazuko Saeki, Atsushi Nonami, Mika Sasaki, Masamitsu Kuriyama, Naoaki Saito, Masabumi Shibuya, Akihiko Yoshimura

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183 Citations (Scopus)

Abstract

The signalling cascade including Raf, mitogen-activated protein kinase (MAPK) kinase and extracellular-signal-regulated kinase (ERK) is important in many facets of cellular regulation1-3. Raf is activated through both Ras-dependent and Ras-independent mechanisms4-6, but the regulatory mechanisms of Raf activation remain unclear7-9. Two families of membrane-bound molecules, Sprouty and Sprouty-related EVH1-domain-containing protein (Spred) have been identified10-13 and characterized as negative regulators of growth-factor-induced ERK activation14-25. But the molecular functions of mammalian Sproutys have not been clarified. Here we show that mammalian Sprouty4 suppresses vascular epithelial growth factor (VEGF)-induced, Ras-independent activation of Raf1 but does not affect epidermal growth factor (EGF)-induced, Ras-dependent activation of Raf1. Sprouty4 binds to Raf1 through its carboxy-terminal cysteine-rich domain, and this binding is necessary for the inhibitory activity of Sprouty4. In addition, Sprouty4 mutants of the amino-terminal region containing the conserved tyrosine residue, which is necessary for suppressing fibroblast growth factor signalling19,25, still inhibit the VEGF-induced ERK pathway. Our results show that receptor tyrosine kinases use distinct pathways for Raf and ERK activation and that Sprouty4 differentially regulates these pathways.

Original languageEnglish
Pages (from-to)427-432
Number of pages6
JournalNature Cell Biology
Volume5
Issue number5
DOIs
Publication statusPublished - May 1 2003

All Science Journal Classification (ASJC) codes

  • Cell Biology

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    Sasaki, A., Taketomi, T., Kato, R., Saeki, K., Nonami, A., Sasaki, M., Kuriyama, M., Saito, N., Shibuya, M., & Yoshimura, A. (2003). Mammalian Sprouty4 suppresses Ras-independent ERK activation by binding to Raf1. Nature Cell Biology, 5(5), 427-432. https://doi.org/10.1038/ncb978