Ezrin, a plasma membrane-microfilament linker, signals cell survival through the phosphatidylinositol 3-kinase/Akt pathway

ERM (Ezrin-Radixin-Moesin) proteins function as plasma membrane-actin cytoskeleton linkers and participate in the formation of specialized domains of the plasma membrane, We hare investigated ezrin function in tubulogenesis of a kidney-derived epithelial cell line, LLC-PK1, Here we show that cells overproducing a mutant form of ezrin in which Tyr-353 was changed to a phenylalanine (Y353F) undergo apoptosis when assayed for tubulogenesis. while investigating the mechanism responsible for this apoptosis we found that ezrin interacts with p85, the regulatory subunit of phosphatidylinositol 3-kinase (PI 3 kinase), Two distinct sites of ezrin are involved in this interaction, the amino-terminal domain containing the first 309 aa and the phosphorylated Tyr-353 residue which binds to the carboxyl terminal SH2; domain of p85. Cells producing Y353F: ezrin are defective in activation of the protein kinase Akt! a downstream target of PI 3-kinase that protects cells against apoptosis, Furthermore, the apoptotic phenotype of these cells is rescued by production of a constitutively activated form of PI 3-kinase, Taken together, these results establish a novel function for ezrin in determining survival of epithelial cells by activating the PI 3-kinase/Akt pathway.