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 have 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.
Gautreau
A
A
Laboratoire de Morphogenèse et Signalisation Cellulaires, Unité Mixte de Recherche, 144 Centre National de la Recherche Scientifique/Institut Curie, 26 rue d'Ulm, 75248 Paris Cedex 05, France.
Poullet
P
P
Louvard
D
D
Arpin
M
M
D008841:Actin Cytoskeleton / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002460:Cell Line; D002462:Cell Membrane / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D003598:Cytoskeletal Proteins; D004847:Epithelial Cells / Q000166:cytology* / Q000502:physiology*; D006801:Humans; D007668:Kidney / Q000166:cytology; D051379:Mice; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D010750:Phosphoproteins / Q000502:physiology*; D011817:Rabbits; D015398:Signal Transduction / Q000502:physiology*; D000099149:Ezrin
D003598:Cytoskeletal Proteins; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D000099149:Ezrin