Editors' ChoiceApoptosis

Inhibition of PIP5K by Apoptotic Stresses

Science's STKE  26 Sep 2006:
Vol. 2006, Issue 354, pp. tw332
DOI: 10.1126/stke.3542006tw332

Peroxide or ultraviolet radiation triggered cell death and stimulated the translocation of a reporter of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] to the cytosol, indicating that PI(4,5)P2 was depleted in the cells. When overexpressed in HeLa cells, murine phosphatidylinositol phosphate 5 kinase α (PIP5Kα, which is homologous to human PIP5Kβ) prevented the decrease in PI(4,5)P2 abundance and increase in apoptosis caused by oxidative stress. Overexpression of PIP5Kα was associated with an increase in extracellular signal–regulated kinase 1 and 2 (ERK1/2) phosphorylation. Pharmacological inhibition of ERK activation sensitized cells to peroxide-induced apoptosis and prevented overexpressed PIP5Kα from increasing cell survival. Peroxide transiently inhibited the activity of PIP5K; however, peroxide triggered a sustained translocation (lasting hours) of a green fluorescent protein (GFP)-tagged PIP5Kα away from the plasma membrane to the cytosol, which would take the enzyme away from its substrate. Peroxide stimulated the tyrosine phosphorylation of PIP5Kα, and this was prevented if the Src family of kinases was inhibited. The authors suggest that oxidative stress or ultraviolet radiation activates Src, which leads to the tyrosine phosphorylation of PIP5Kα and translocation of the enzyme away from the plasma membrane and thereby prevents the regeneration of PI(4,5)P2, which is necessary for activation of survival signals mediated by the ERK pathway.

J. R. Halstead, J. van Rheenen, M. H. J. Snel, S. Meeuws, S. Mohammed, C. S. D’Santos, A. J. Heck, K. Jalink, N. Divecha, A role for PtdIns(4,5)P2 and PIP5Kα in regulating stress-induced apoptosis. Curr. Biol. 16, 1850-1856 (2006). [Online Journal]

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