1. Academic Validation
  2. Mammalian Sprouty4 suppresses Ras-independent ERK activation by binding to Raf1

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

  • Nat Cell Biol. 2003 May;5(5):427-32. doi: 10.1038/ncb978.
Atsuo Sasaki 1 Takaharu Taketomi Reiko Kato Kazuko Saeki Atsushi Nonami Mika Sasaki Masamitsu Kuriyama Naoaki Saito Masabumi Shibuya Akihiko Yoshimura
Affiliations

Affiliation

  • 1 Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
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 regulation. Raf is activated through both Ras-dependent and Ras-independent mechanisms, but the regulatory mechanisms of Raf activation remain unclear. Two families of membrane-bound molecules, Sprouty and Sprouty-related EVH1-domain-containing protein (Spred) have been identified and characterized as negative regulators of growth-factor-induced ERK activation. 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 signalling, 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.

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