More than just kinases: the scaffolding function of PI3K.

Recently, it has been reported that some members of the PI3K family might have a "double identity"; in other words, PI3K have been found to act not only as classical kinases, but also as scaffolding proteins. Until now, the use of knockout mice has been considered sufficient to model the effects of PI3K inhibition and to predict the outcome of anti-PI3K pharmacological treatments by observing the resulting phenotypes. These studies supported the view that PI3K may represent promising pharmacological targets for cancer and inflammation. However, in selected cases, different experimental strategies of gene targeting of the same locus have resulted in distinct phenotypes. This demonstrates that "knocking-out" a gene is not necessarily equivalent to "knocking-in" an inactivating point mutation (Vanhaesebroeck et al. in Cell 118:274-276, 2004). Specifically, knockout and kinase-dead models have led to the discovery that PI3Kγ and β may act independently of their kinase activity, likely as adaptor proteins.