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

Abstract

Recent genetic knock-in and pharmacological approaches have suggested that, of class IA PI3Ks (phosphatidylinositol 3-kinases), it is the p110α 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 p110α-specific inhibitor (PIK-75), a p110α-selective inhibitor (PI-103), a p110β-specific inhibitor (TGX-221) and a p110δ-specific inhibitor (IC87114). Although we find that p110α is necessary for insulin-stimulated phosphorylation of PKB (protein kinase B) in several cell lines, we find that this is not the case in HepG2 hepatoma cells. Inhibition of p110β or p110δ alone was also not sufficient to block insulin signalling to PKB in these cells, but, when added in combination with p110α 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 p110α, p110β or p110δ. These results provide evidence that p110β and p110δ 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.