Phosphorylation-dependent binding of 14-3-3 terminates signalling by the Gab2 docking protein

Tilman Brummer, Mark Larance, Maria Teresa Herrera Abreu, Ruth J. Lyons, Paul Timpson, Christoph H. Emmerich, Emmy D. G. Fleuren, Gillian M. Lehrbach, Daniel Schramek, Michael Guilhaus, David E. James, Roger J. Daly (Lead / Corresponding author)

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    43 Citations (Scopus)

    Abstract

    Grb2-associated binder (Gab)2 functions downstream of a variety of receptor and cytoplasmic tyrosine kinases as a docking platform for specific signal transducers and performs important functions in both normal physiology and oncogenesis. Gab2 signalling is promoted by its association with specific receptors through the adaptor Grb2. However, the molecular mechanisms that attenuate Gab2 signals have remained unclear. We now demonstrate that growth factor-induced phosphorylation of Gab2 on two residues, S210 and T391, leads to recruitment of 14-3-3 proteins. Together, these events mediate negative-feedback regulation, as Gab2(S210A/T391A) exhibits sustained receptor association and signalling and promotes cell proliferation and transformation. Importantly, introduction of constitutive 14-3-3-binding sites into Gab2 renders it refractory to receptor activation, demonstrating that site-selective binding of 14-3-3 proteins is sufficient to terminate Gab2 signalling. Furthermore, this is associated with reduced binding of Grb2. This leads to a model where signal attenuation occurs because 14-3-3 promotes dissociation of Gab2 from Grb2, and thereby uncouples Gab2 from the receptor complex. This represents a novel regulatory mechanism with implications for diverse tyrosine kinase signalling systems.
    Original languageEnglish
    Pages (from-to)2305-2316
    Number of pages12
    JournalEMBO Journal
    Volume27
    Issue number17
    DOIs
    Publication statusPublished - 3 Sep 2008

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    Keywords

    • 14-3-3 Proteins
    • Recombinant Proteins
    • Humans
    • Amino Acid Sequence
    • Feedback, Physiological
    • Models, Biological
    • Protein Binding
    • Binding Sites
    • Mutagenesis, Site-Directed
    • Multiprotein Complexes
    • Phosphorylation
    • Adaptor Proteins, Signal Transducing
    • Molecular Sequence Data
    • Sequence Homology, Amino Acid
    • Signal Transduction
    • Cell Line

    Cite this

    Brummer, T., Larance, M., Herrera Abreu, M. T., Lyons, R. J., Timpson, P., Emmerich, C. H., Fleuren, E. D. G., Lehrbach, G. M., Schramek, D., Guilhaus, M., James, D. E., & Daly, R. J. (2008). Phosphorylation-dependent binding of 14-3-3 terminates signalling by the Gab2 docking protein. EMBO Journal, 27(17), 2305-2316. https://doi.org/10.1038/emboj.2008.159