Evidence for functional redundancy of class IA PI3K isoforms in insulin signalling

Recent genetic knock-in and pharmacological approaches have suggested that, of class IA PI13Ks (phosphatidylinositol 3-kinases), it is the p110 alpha isoform (PIK3CA) that plays the predominant role in insulin signalling. We have used isoform-selective inhibitors of class IA PI3K to dissect further the roles of individual p110 isoforms in insulin signalling. These include a p110 alpha-specific inhibitor (PIK-75), a p110 alpha-selective inhibitor (PI-103), a p110 beta-specific inhibitor (TGX-221) and a p110 delta-specific inhibitor (IC87114). Although we find that p110 alpha is necessary for insulin-stimulated phosphorylation of PKB (protein kinase 13) in several cell lines, we find that this is not the case in HepG2 hepatoma cells. Inhibition of p110 beta or p110 delta alone was also not sufficient to block insulin signalling to PKB in these cells, but, when added in combination with p110 alpha inhibitors, they are able to significantly attenuate insulin signalling. Surprisingly, in J774.2 macrophage cells, insulin signalling to PKB was inhibited to a similar extent by inhibitors of p110 alpha, p110 beta or p110 delta. These results provide evidence that p110 beta and p110 delta can play a role in insulin signalling and also provide the first evidence that there can be functional redundancy between p110 isoforms. Further, our results indicate that the degree of functional redundancy is linked to the relative levels of expression of each isoform in the target cells.