Phosphoinositide 3-kinase (PI3K) is an enzyme that participates in a myriad of cellular processes and whose activity has been linked to cell growth and transformation, differentiation, motility, insulin action, and cell survival to name a few. Direct links between PI3K action and human diseases have also been made, most notably in cancer. Thus it is not surprising that considerable effort has gone into understanding the mechanisms by which PI3K mediates these responses. PI3K comprises a family of agonist-stimulated lipid signaling enzymes that initiate signaling cascades by generating three distinct membrane lipids, the polyphosphoinositides PtdIns-3-P, PtdIns-3, 4-P2, and PtdIns-3, 4, 5-P3. Virtually all eukaryotic cells studied to date, including yeasts, have been found to contain one or more PI3K lipid products. In mammalian cells, three distinct classes of PI3Ks have been discovered, characterized, and cloned, and found to differ in their activation mechanisms by extracellular agonists, substrate specificity, and subcellular and tissue distribution. Type III PI3Ks are responsible for the synthesis of PtdIns-3-P in yeasts and higher eukaryotes. PtdIns-3-P is constitutively present in all cells, and its levels do not dramatically change following agonist stimulation. Conversely, PtdIns-3, 4-P2 and PtdIns-3, 4, 5-P3, generated by type II and type I enzymes, are nominally absent in most cells and their levels rapidly accumulate on agonist stimulation (for a recent review on the PI3K family of enzymes, see Vanhaesebroeck and Waterfield, 1999). Thus, the accumulation of these two lipids at the plasma membrane, in particular PtdIns-3, 4, 5-P3, has been extensively studied with respect to initiation of PI3K-dependent signaling cascades. Molecular genetic and biochemical studies in the last decade of the second millennium resulted in the identification of a multitude of PI3K effector molecules responsible for transducing the PI3K signal. Studies revealed that many enzymes (eg, protein kinases, phospholipases, and G-proteins) are effector molecules of both PtdIns-3, 4-P2 and PtdIns-3, 4, 5-P3, and whose activities and/or cellular location is affected by the lipid-protein interaction.

In this review, we will focus exclusively on the regulation and function of protein kinases in the PI3K pathway. A wealth of information has come to light recently concerning the role of these enzymes in PI3K signaling, both with respect to their mechanism of regulation as well as their role in cell biology. In a number of cases, multiple downstream substrates for the protein kinases have been described that directly link PI3K, PtdIns-3, 4-P2/PtdIns-3, 4, 5-P3, and the effector to cell function.