Abstract:
Recent genetic knockin and pharmacological approaches have suggested that, of class-IA PI 3-kinases, it is the p110alpha isoform (PIK3CA)that plays the predominant role in insulin signalling. We have used isoform selective inhibitors of class-IA PI 3-kinase to further dissect the roles of individual p110 isoforms in insulin signalling. These include a p110±-specific inhibitor (PIK-75), a p110alpha-selective inhibitor (PI-103), a p110beta-specific inhibitor (TGX-221) and a p110delta specific inhibitor (IC87114). While we find that p110alpha is necessary for insulin stimulated phosphorylation of PKB in several cell lines, we find that this is not the case in HepG2 hepatoma cells. Inhibition of p110beta or p110delta alone was also not sufficient to block insulin signalling to PKB in these cells but when added in combination with p110alpha inhibitors they are able to significantly attenuate insulin signalling. Surprisingly, in J774.2 macrophage cells insulin signalling to PKB was inhibited to similar extent by inhibitors of p110alpha or p110beta or p110delta. These results provide evidence that p110beta and p110delta 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.
