Antagonism of p66shc by melanoma inhibitory activity

K. Kasuno, A. Naqvi, J. DeRicco, T. Yamamori, L. Santhanam, I. Mattagajasingh, S. Yang, F. L. Meyskens, A. K. Bosserhoff, K. Irani

Research output: Contribution to journalArticle

Abstract

The p66shc protein governs oxidant stress and mammalian lifespan. Here, we identify melanoma inhibitory activity (MIA), a protein secreted by melanoma cells, as a novel binding partner and antagonist of p66shc. The N-terminal collagen homology-2 (CH2) domain of p66shc binds to the Src Homology-3 (SH3)-like domain of MIA in vitro. In cells, ectopically expressed MIA and p66shc colocalize and co-precipitate. MIA also co-precipitates with the CH2 domain of p66shc in vivo. MIA expression in vivo suppresses p66shc-stimulated increase in endogenous hydrogen peroxide (H2O2), and inhibits basal and H2O2-induced phosphorylation of p66shc on serine 36 and H2O2-induced death. In human melanoma cells expressing MIA, endogenous MIA and p66shc co-precipitate. Downregulation of MIA in melanoma cells increases basal and ultraviolet radiation (UVR)-induced phosphorylation of p66shc on serine 36, augments endogenous H2O2 levels, and increases their susceptibility to UVR-induced death. These findings show that MIA binds to p66shc, and suggest that this interaction antagonizes phosphorylation and function of p66shc.

Original languageEnglish (US)
Pages (from-to)1414-1421
Number of pages8
JournalCell death and differentiation
Volume14
Issue number8
DOIs
StatePublished - Aug 1 2007

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ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Kasuno, K., Naqvi, A., DeRicco, J., Yamamori, T., Santhanam, L., Mattagajasingh, I., Yang, S., Meyskens, F. L., Bosserhoff, A. K., & Irani, K. (2007). Antagonism of p66shc by melanoma inhibitory activity. Cell death and differentiation, 14(8), 1414-1421. https://doi.org/10.1038/sj.cdd.4402131