The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism

Abstract

Phosphatidylinositol 3-kinases (PI3Ks) are members of a unique and conserved family of intracellular lipid kinases that phosphorylate the 3′-hydroxyl group of phosphatidylinositols. This reaction leads to the activation of many intracellular signalling pathways that regulate functions as diverse as cell metabolism, survival and polarity, and vesicle trafficking. PI3Ks are grouped into three classes (I–III) according to their substrate preference and sequence homology. Different classes of PI3K have distinct roles in cellular signal transduction, as do the different isoforms that can exist within each class. Studies using mouse models have shown the importance of class IA PI3K signalling in regulating growth and metabolism. Attenuated PI3K signalling downstream of the insulin receptor is a main contributor towards type-2 diabetes, whereas mutations that lead to the amplification of PI3K signalling are among the most common mutations in human cancers. Many types of human cancer harbour mutations in key proteins that regulate the amount of phosphatidylinositol-3,4,5-trisphosphate (PIP₃) generated at the membrane. The two most commonly mutated genes are the mammalian phosphatase and tensin homologue (PTEN) and phosphoinositide-3-kinase, catalytic, α polypeptide (PIK3CA). In normal cells, negative-feedback loops function to attenuate PI3K signalling. One such pathway is the mammalian target of rapamycin (mTOR)–raptor-dependent pathway that disrupts insulin receptor substrate (IRS)-mediated PI3K activation. As isoform-specific inhibitors of the PI3K pathway are developed as potential therapeutics, careful pre-clinical studies using floxed alleles, RNA interference and mutated inhibitor-resistant kinases will be required to distinguish between their on- and off-target effects.