Clathrin-independent endocytosis used by the IL-2 receptor is regulated by Rac1, Pak1 and Pak2

There are several endocytic pathways, which are either dependent on or independent of clathrin. This study focuses on a poorly characterized mechanism - clathrin- and caveolae-independent endocytosis - used by the interleukin-2 receptor beta (IL-2R beta). We address the question of its regulation in comparison with the clathrin- dependent pathway. First, we show that Ras-related C3 botulinum toxin substrate 1 ( Rac1) is specifically required for IL-2R beta entry, and we identify p21-activated kinases (Paks) as downstream targets. By RNA interference, we show that Pak1 and Pak2 are both necessary for IL-2R beta uptake, in contrast to the clathrin- dependent route. We observe that cortactin, a partner of actin and dynamin - two essential endocytic factors - is required for IL-2R beta uptake. Furthermore, we find that cortactin acts downstream from Paks, suggesting control of its function by these kinases. Thus, we describe a cascade composed of Rac1, Paks and cortactin specifically regulating IL-2R beta internalization. This study indicates Paks as the first specific regulators of the clathrin- independent endocytosis pathway.