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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176 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 - 2003 May 1
Externally publishedYes

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Extracellular Signal-Regulated MAP Kinases
Intercellular Signaling Peptides and Proteins
Blood Vessels
Fibroblast Growth Factors
Mitogen-Activated Protein Kinase Kinases
Receptor Protein-Tyrosine Kinases
Epidermal Growth Factor
Cysteine
Tyrosine
Membranes

ASJC Scopus subject areas

  • Cell Biology

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Mammalian Sprouty4 suppresses Ras-independent ERK activation by binding to Raf1. / Sasaki, Atsuo; Taketomi, Takaharu; Kato, Reiko; Saeki, Kazuko; Nonami, Atsushi; Sasaki, Mika; Kuriyama, Masamitsu; Saito, Naoaki; Shibuya, Masabumi; Yoshimura, Akihiko.

In: Nature Cell Biology, Vol. 5, No. 5, 01.05.2003, p. 427-432.

Research output: Contribution to journalArticle

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, vol. 5, no. 5, pp. 427-432. https://doi.org/10.1038/ncb978
Sasaki A, Taketomi T, Kato R, Saeki K, Nonami A, Sasaki M et al. Mammalian Sprouty4 suppresses Ras-independent ERK activation by binding to Raf1. Nature Cell Biology. 2003 May 1;5(5):427-432. https://doi.org/10.1038/ncb978
Sasaki, Atsuo ; Taketomi, Takaharu ; Kato, Reiko ; Saeki, Kazuko ; Nonami, Atsushi ; Sasaki, Mika ; Kuriyama, Masamitsu ; Saito, Naoaki ; Shibuya, Masabumi ; Yoshimura, Akihiko. / Mammalian Sprouty4 suppresses Ras-independent ERK activation by binding to Raf1. In: Nature Cell Biology. 2003 ; Vol. 5, No. 5. pp. 427-432.
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