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

Phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P] is implicated in various processes, including hormone-induced signal transduction, endocytosis, and exocytosis in the plasma membrane. However, how HO accumulation regulates the levels of PtdIns(4,5)P in the plasma membrane in cells stimulated with epidermal growth factors (EGFs) is not known. We show that a plasma membrane PtdIns(4,5)P-degrading enzyme, synaptojanin (Synj) phosphatase, is inactivated through oxidation by HO. Intriguingly, HO 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 HO 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.