Sprouty1 and Sprouty2 provide a control mechanism for the Ras/MAPK signalling pathway
Abstract
Sprouty (Spry) inhibits signalling by receptor tyrosine kinases; however, the molecular mechanism underlying this function has not been defined. Here we show that after stimulation by growth factors Spry1 and Spry2 translocate to the plasma membrane and become phosphorylated on a conserved tyrosine. Next, they bind to the adaptor protein Grb2 and inhibit the recruitment of the Grb2-Sos complex either to the fibroblast growth factor receptor (FGFR) docking adaptor protein FRS2 or to Shp2. Membrane translocation of Spry is necessary for its phosphorylation, which is essential for its inhibitor activity. A tyrosine-phosphorylated octapeptide derived from mouse Spry2 inhibits Grb2 from binding FRS2, Shp2 or mouse Spry2 in vitro and blocks activation of the extracellular-signal-regulated kinase (ERK) in cells stimulated by growth factor. A non-phosphorylated Spry mutant cannot bind Grb2 and acts as a dominant negative, inducing prolonged activation of ERK in response to FGF and promoting the FGF-induced outgrowth of neurites in PC12 cells. Our findings suggest that Spry functions in a negative feedback mechanism in which its inhibitor activity is controlled rapidly and reversibly by post-translational mechanisms.
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Four of the validated miR-21 target genes are known negative regulators of the Ras/MEK/ERK pathway: Spry1, Spry2, Btg2, and Pdcd4.
“Four of the validated miR-21 target genes are known negative regulators of the Ras/MEK/ERK pathway: sprouty 1 (Spry1), sprouty 2 (Spry2), B-cell translocation gene 2 (Btg2), and programmed cell death 4 (Pdcd4).”
From Modulation of K-Ras-Dependent Lung Tumorigenesis by MicroRNA-21 (2010) · cites this paper as Hanafusa et al., 2002
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- Authors
- Hanafusa, H., Torii, S., Yasunaga, T., & Nishida, E.
- Affiliations
- Kyoto University (JP)
- Corresponding author
- Nishida, Eisuke
- Venue
- Nature Cell Biology
- Published
- 2002-10-28
- Volume
- 4
- Issue
- 11
- Pages
- 850-858
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- OpenAlex
- W2020292268
- Cited by
- 566
- References
- 2
- Citations by year
- 2026: 11 · 2025: 17 · 2024: 13 · 2023: 22 · 2022: 19 · 2021: 20 · 2020: 26 · 2019: 26 · 2018: 23 · 2017: 21 · 2016: 25 · 2015: 34 · 2014: 17 · 2013: 29 · 2012: 23
- FWCI
- 10.41
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Keywords
- Sprouty1, Sprouty2, RAS/MAPK pathway, ERK activation, Grb2, FRS2, SHP2, receptor tyrosine kinase signaling, fibroblast growth factor receptor, tyrosine phosphorylation, membrane translocation, negative feedback regulation, neurite outgrowth, PC12 cells
- MeSH terms
- Amino Acid Sequence, Animals, Binding, Competitive, Cattle, Cell Line, Cell Membrane, Enzyme Activation, Genes, Dominant, HeLa Cells, Humans, Luciferases, Membrane Proteins, Microscopy, Fluorescence, Molecular Sequence Data, Mutation, Nerve Tissue Proteins, Neurons, Peptides, Phosphoproteins, Phosphorylation, Plasmids, Precipitin Tests, Protein Binding, Protein Processing, Post-Translational, Time Factors, Tyrosine, Xenopus, Immunoblotting, PC12 Cells, Protein Tyrosine Phosphatases, Sequence Homology, Amino Acid, Receptors, Fibroblast Growth Factor, DNA, Complementary, ras Proteins, Dimerization, COS Cells, Mitogen-Activated Protein Kinases, MAP Kinase Signaling System, Protein Transport, Intracellular Signaling Peptides and Proteins, Adaptor Proteins, Signal Transducing, Mice, Rats, Protein Tyrosine Phosphatase, Non-Receptor Type 11
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