Control of the signaling role of PtdIns(4)P at the plasma membrane through H₂O₂-dependent inactivation of synaptojanin 2 during endocytosis

Phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P₂] is implicated in various processes, including hormone-induced signal transduction, endocytosis, and exocytosis in the plasma membrane. However, how H₂O₂ accumulation regulates the levels of PtdIns(4,5)P₂ in the plasma membrane in cells stimulated with epidermal growth factors (EGFs) is not known. We show that a plasma membrane PtdIns(4,5)P₂-degrading enzyme, synaptojanin (Synj) phosphatase, is inactivated through oxidation by H₂O₂. Intriguingly, H₂O₂ inhibits the 4-phosphatase activity of Synj but not the 5-phosphatase activity. In EGF-activated cells, the oxidation of Synj dual phosphatase is required for the transient increase in the plasma membrane levels of phosphatidylinositol 4-phosphate [PtdIns(4)P], which can control EGF receptor-mediated endocytosis. These results indicate that intracellular H₂O₂ molecules act as signaling mediators to fine-tune endocytosis by controlling the stability of plasma membrane PtdIns(4)P, an intermediate product of Synj phosphoinositide dual phosphatase.