Interaction with Shc prevents aberrant Erk activation in the absence of extracellular stimuli

K.M. Suen, C.-C. Lin, R. George, F.A. Melo, Eleanor R. Biggs, Z. Ahmed, M.N. Drake, S. Arur, S.T. Arold, J.E. Ladbury

Research output: Contribution to journalArticle

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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.
Original languageEnglish
Pages (from-to)620-627
Number of pages8
JournalNature Structural and Molecular Biology
Volume20
Issue number5
Early online date13 Apr 2013
DOIs
Publication statusPublished - May 2013

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Shc Signaling Adaptor Proteins
Phosphotransferases
Receptor Protein-Tyrosine Kinases
Intercellular Signaling Peptides and Proteins
Homeostasis
Binding Sites
Growth
Genes
Neoplasms

Cite this

Suen, K. M., Lin, C-C., George, R., Melo, F. A., Biggs, E. R., Ahmed, Z., ... Ladbury, J. E. (2013). Interaction with Shc prevents aberrant Erk activation in the absence of extracellular stimuli. Nature Structural and Molecular Biology, 20(5), 620-627. https://doi.org/10.1038/nsmb.2557

Interaction with Shc prevents aberrant Erk activation in the absence of extracellular stimuli. / Suen, K.M.; Lin, C.-C.; George, R.; Melo, F.A.; Biggs, Eleanor R. ; Ahmed, Z.; Drake, M.N.; Arur, S.; Arold, S.T.; Ladbury, J.E.

In: Nature Structural and Molecular Biology, Vol. 20, No. 5, 05.2013, p. 620-627.

Research output: Contribution to journalArticle

Suen, KM, Lin, C-C, George, R, Melo, FA, Biggs, ER, Ahmed, Z, Drake, MN, Arur, S, Arold, ST & Ladbury, JE 2013, 'Interaction with Shc prevents aberrant Erk activation in the absence of extracellular stimuli', Nature Structural and Molecular Biology, vol. 20, no. 5, pp. 620-627. https://doi.org/10.1038/nsmb.2557
Suen, K.M. ; Lin, C.-C. ; George, R. ; Melo, F.A. ; Biggs, Eleanor R. ; Ahmed, Z. ; Drake, M.N. ; Arur, S. ; Arold, S.T. ; Ladbury, J.E. / Interaction with Shc prevents aberrant Erk activation in the absence of extracellular stimuli. In: Nature Structural and Molecular Biology. 2013 ; Vol. 20, No. 5. pp. 620-627.
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