TY - JOUR
T1 - Antagonism of p66shc by melanoma inhibitory activity
AU - Kasuno, K.
AU - Naqvi, A.
AU - DeRicco, J.
AU - Yamamori, T.
AU - Santhanam, L.
AU - Mattagajasingh, I.
AU - Yang, S.
AU - Meyskens, F. L.
AU - Bosserhoff, A. K.
AU - Irani, K.
PY - 2007/8
Y1 - 2007/8
N2 - 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.
AB - 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.
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U2 - 10.1038/sj.cdd.4402131
DO - 10.1038/sj.cdd.4402131
M3 - Article
C2 - 17431427
AN - SCOPUS:34447627712
SN - 1350-9047
VL - 14
SP - 1414
EP - 1421
JO - Cell death and differentiation
JF - Cell death and differentiation
IS - 8
ER -