Pak1 Phosphorylation Enhances Cortactin–N‐WASP Interaction in Clathrin‐Caveolin‐Independent Endocytosis

Growing evidence indicates that kinases are central to the regulation of endocytic pathways. Previously, we identified p21‐activated kinase 1 (Pak1) as the first specific regulator of clathrin‐ and caveolae‐independent endocytosis used by the interleukin 2 receptor subunit (IL‐2R). Here, we address the mechanism by which Pak1 regulates IL‐2Rβ endocytosis. First, we show that Pak1 phosphorylates an activator of actin polymerization, cortactin, on its serine residues 405 and 418. Consistently, we observe a specific inhibition of IL‐2Rβ endocytosis when cells overexpress a cortactin, wherein these serine residues have been mutated. In addition, we show that the actin polymerization enhancer, neuronal Wiskott–Aldrich syndrome protein (N‐WASP), is involved in IL‐2Rβ endocytosis. Strikingly, we find that Pak1 phosphorylation of cortactin on serine residues 405 and 418 increases its association with N‐WASP. Thus, Pak1, by controlling the interaction between cortactin and N‐WASP, could regulate the polymerization of actin during clathrin‐independent endocytosis.