Stimulation of phosphatidylinositol kinase type 1-mediated phosphatidylinositol (4,5)-bisphosphate synthesis by AP-2μ-cargo complexes

Phosphatidylinositol (4,5)-bisphosphate [PI(4,5)P-2] is an important factor for a variety of cellular functions ranging from cell signaling to actin cytoskeletal dynamics and endocytic membrane traffic. Here, we have identified the clathrin adaptor complex AP-2 as a regulator of phosphatidylinositol 4-phosphate 5-kinase (PIPK)-mediated PI(4,5)P2 synthesis. AP-2 directly interacts with the kinase core domain of type I PIPK isozymes via its mu 2-subunit in vitro and in native protein extracts. Endocytic cargo protein binding to mu 2 leads to a potent stimulation of PIPK activity. These data thus identify a positive feedback loop consisting of endocytic cargo proteins, AP-2 mu, and PIPK type I which may provide a specific pool of PI(4,5)P2 dedicated to clathrin/AP-2-dependent receptor internalization.