FIGURE 8.

Schematic diagram summarizing the role of phosphoinositides on regulation of NHE1-dependent cell survival. In response to apoptotic stress, NHE1 is initially stimulated by PI(4,5)P₂ binding to mediate cytoprotection. NHE1 then indirectly activates PI 3-kinase to phosphorylate PI(4,5)P₂. The resulting PI(3,4,5)P₃ dually stimulates sustained downstream Akt survival signaling, and negatively feeds back to dampen NHE1 activity through competitive inhibition, as well as depletion of PI(4,5)P₂ pools.