Article
- The EMBO Journal (2008) 27, 2305 - 2316
- doi:10.1038/emboj.2008.159
Published online: 7 August 2008
Subject Categories:
Phosphorylation-dependent binding of 14-3-3 terminates signalling by the Gab2 docking protein
Tilman Brummer1, Mark Larance2,3, Maria Teresa Herrera Abreu1, Ruth J Lyons1, Paul Timpson1, Christoph H Emmerich1, Emmy DG Fleuren1, Gillian M Lehrbach1, Daniel Schramek4, Michael Guilhaus3, David E James2 and Roger J Daly1
- Cancer Research Program, Garvan Institute of Medical Research, Sydney, New South Wales, Australia
- Diabetes and Obesity Research Program, Garvan Institute of Medical Research, Sydney, New South Wales, Australia
- Bioanalytical Mass Spectrometry Facility, University of New South Wales, Sydney, New South Wales, Australia
- Institute of Molecular Biotechnology, Vienna, Austria
Correspondence to:
Roger J Daly, Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Sydney, New South Wales 2010, Australia. Tel.: +61 2 92 95 8333; Fax: +61 2 92 95 8321; E-mail: r.daly@garvan.org.au
Received 10 January 2008; Accepted 18 July 2008
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 Gab2S210A/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.
Keywords:
- feedback phosphorylation,
- mammary epithelial cells,
- mass spectrometry,
- PI-3 kinase,
- transformation
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