Mammalian Sprouty4 suppresses Ras-independent ERK activation by binding to Raf1.
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.
Mesh Terms:
Animals, Cell Membrane, Endothelial Growth Factors, Epidermal Growth Factor, Eukaryotic Cells, Fibroblast Growth Factors, Growth Substances, Humans, Immunohistochemistry, Intercellular Signaling Peptides and Proteins, Intracellular Signaling Peptides and Proteins, Lymphokines, MAP Kinase Signaling System, Mitogen-Activated Protein Kinases, Mutation, Nerve Tissue Proteins, Protein Binding, Protein Structure, Tertiary, Proto-Oncogene Proteins c-raf, Receptor Protein-Tyrosine Kinases, Signal Transduction, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factors, ras Proteins
Animals, Cell Membrane, Endothelial Growth Factors, Epidermal Growth Factor, Eukaryotic Cells, Fibroblast Growth Factors, Growth Substances, Humans, Immunohistochemistry, Intercellular Signaling Peptides and Proteins, Intracellular Signaling Peptides and Proteins, Lymphokines, MAP Kinase Signaling System, Mitogen-Activated Protein Kinases, Mutation, Nerve Tissue Proteins, Protein Binding, Protein Structure, Tertiary, Proto-Oncogene Proteins c-raf, Receptor Protein-Tyrosine Kinases, Signal Transduction, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factors, ras Proteins
Nat. Cell Biol.
Date: May. 01, 2003
PubMed ID: 12717443
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