Crossroads of PI3K and Rac pathways

Abstract

Rac and PI3Ks are intracellular signal transducers able to regulate multiple signaling pathways fundamental for cell behavior. PI3Ks are lipid kinases that produce phosphorylated lipids which, in turn, transduce extracellular cues within the cell, while Rac is a small G protein that impacts on actin organization. Compelling evidence indicates that in multiple circumstances the 2 signaling pathways appear intermingled. For instance, phosphorylated lipids produced by PI3Ks recruit and activate GEF and GAP proteins, key modulators of Rac function. Conversely, PI3Ks interact with activated Rac, leading to Rac signaling amplification. This review summarizes the molecular mechanisms underlying the cross-talk between Rac and PI3K signaling in 2 different processes, cell migration and ROS production.

Keywords: PI3K; ROS production; actin polymerization; inflammation; migration; rho GTPase.

Figure 1.

Schematic representation of signaling events activated by PI3K leading to cell polarization. GPCR activation stimulates the lipid kinase activity of PI3K to activate Rac through the GEF protein P-Rex (A) A positive feedback loop mediated by the interaction between PI3K and activated Rac sustains cell polarization (B) ArhGAP15 binds to PtdIns(3,4,5)P₃ produced by PI3K to terminate Rac signaling at the leading edge (C).

Figure 2.

Schematic representation of signaling events activated by PI3K leading to ROS production. GPCR activation stimulates the production of PtdIns(3,4,5)P₃ at the plasma membrane to activate Rac through the GEF protein P-Rex. The phosphorylated lipids produced by PI3K activate p40^phox and p47^phox through Akt and PKC phosphorylation. The assembly of the NADPH oxidase complex on the phagosomal membrane is favored by the PtdIns(3)P produced by Vps34.