Fig. 2. Model for activation of PI3K during chemotaxis. Chemoattractant binding on a G-protein-coupled-receptor (GPCR) leads to the translocation and activation of Class I PI3Ks at the plasma membrane. This activation mechanism that requires both G protein and Ras GTPase remains poorly understood at the molecular level. Activated PI3K catalyzes the phosphorylation of PtdIns(4,5)P₂ at the 3' position of the inositol ring to produce PtdIns(3,4,5)P₃. In response, PtdIns(3,4,5)P₃ acts as a binding site for a subclass of PH domain proteins. These localize to the plasma membrane and are activated. In neutrophils, Rho family GEFs such as P-Rex are PI3K effectors, which lead to the accumulation of activated Rac (Rac-GTP). The feedback loop required for the amplification of the pathway may involve actin polymerization. In Dictyostelium, the delocalization of PTEN from the plasma membrane at the leading edge may function as an amplification pathway for PI3K signaling by preferentially extending the half-life of PtdIns(3,4,5)P₃ at this site of the membrane.