Chu, KME; Minogue, S; Hsuan, JJ; Waugh, MG; (2010) Differential effects of the phosphatidylinositol 4-kinases, PI4KII alpha and PI4KIII beta, on Akt activation and apoptosis. Cell Death & Disease , 1 , Article e106. 10.1038/cddis.2010.84.

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Abstract

In this study, we investigated the role of PI4P synthesis by the phosphatidylinositol 4-kinases, PI4KII alpha and PI4KIII beta, in epidermal growth factor (EGF)-stimulated phosphoinositide signaling and cell survival. In COS-7 cells, knockdown of either isozyme by RNA interference reduced basal levels of PI4P and PI(4,5)P-2, without affecting receptor activation. Only knockdown of PI4KII alpha inhibited EGF-stimulated Akt phosphorylation, indicating that decreased PI(4,5)P-2 synthesis observed by loss of either isoform could not account for this PI4KII alpha-specific effect. Phospholipase Cc activation was also differentially affected by knockdown of either PI4K isozyme. Overexpression of kinase-inactive PI4KII alpha, which induces defective endosomal trafficking without reducing PI(4,5)P-2 levels, also reduced Akt activation. Furthermore, PI4KII alpha knockdown profoundly inhibited cell proliferation and induced apoptosis as evidenced by the cleavage of caspase-3 and its substrate poly(ADP-ribose) polymerase. However, in MDA-MB-231 breast cancer cells, apoptosis was observed subsequent to knockdown of either PI4KII alpha or PI4KIII beta and this correlated with enhanced proapoptotic Akt phosphorylation. The differential effects of phosphatidylinositol 4-kinase knockdown in the two cell lines lead to the conclusion that phosphoinositide turnover is inhibited through PI4P substrate depletion, whereas impaired antiapoptotic Akt signaling is an indirect consequence of dysfunctional endosomal trafficking.

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