Abstract
Control mechanisms that prevent aberrant signaling are necessary to maintain cellular homeostasis. We describe a new mechanism by which the adaptor protein Shc directly binds the MAP kinase Erk, thus preventing its activation in the absence of extracellular stimuli. The Shc–Erk complex restricts Erk nuclear translocation, restraining Erk-dependent transcription of genes, including those responsible for oncogenic growth. The complex forms through unique binding sites on both the Shc PTB domain and the N-terminal lobe of Erk. Upon receptor tyrosine kinase stimulation, a conformational change within Shc—induced through interaction with the phosphorylated receptor—releases Erk, allowing it to fulfill its role in signaling. Thus, in addition to its established role in promoting MAP kinase signaling in stimulated cells, Shc negatively regulates Erk activation in the absence of growth factors and thus could be considered a tumor suppressor in human cells.
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Acknowledgements
J.E.L. is funded by the G. Harold and Leila Y. Mathers Charitable Foundation and the University of Texas MD Anderson Cancer Center Trust. S.A. is funded through US National Institutes of Health GM98200. C. elegans strains were obtained through the Center for Caenorhabditis elegans consortium funded by the US National Institutes of Health National Center for Research Resources. We thank A. Radhakrishnan for the preparation of protein samples used in SAXS analysis and A.C. Schüller for assistance with western blots. MKN28 cells and MCF7 cells were kind gifts from R.M. Peek (Division of Gastroenterology, Vanderbilt University Medical Center, Nashville, Tennessee, USA) and P.H. Brown (Department of Clinical Cancer Prevention, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA), respectively. We thank the Berkeley Laboratory Advanced Light Source and SIBYLS beamline staff at bl12.3.1 for assistance with collection of SAXS data.
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K.M.S., C.-C.L., R.G., F.A.M., E.R.B., Z.A. and S.T.A. carried out experiments and analyzed data. K.M.S., M.N.D. and S.A. performed the C. elegans experiments and analyzed the data. K.M.S., S.A., S.T.A. and J.E.L. conceived of the experiments and wrote the manuscript.
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Suen, K., Lin, CC., George, R. et al. Interaction with Shc prevents aberrant Erk activation in the absence of extracellular stimuli. Nat Struct Mol Biol 20, 620–627 (2013). https://doi.org/10.1038/nsmb.2557
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DOI: https://doi.org/10.1038/nsmb.2557
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