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

• Published in: EMBO reports Vol. 9; no. 4; pp. 356 - 362
• Main Authors: Grassart, Alexandre, Dujeancourt, Annick, Lazarow, Paul B, Dautry-Varsat, Alice, Sauvonnet, Nathalie
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.04.2008; Blackwell Publishing Ltd; EMBO Press; Nature Publishing Group
• Subjects: Cell Line; Clathrin; Clathrin - metabolism; Cortactin; Cortactin - metabolism; cytokine receptors; Cytokines; cytoskeleton; Endocytosis; Endocytosis - physiology; Humans; kinase; Microscopy, Fluorescence; Molecular biology; p21-Activated Kinases; p21-Activated Kinases - metabolism; rac1 GTP-Binding Protein; rac1 GTP-Binding Protein - metabolism; Receptors, Interleukin-2; Receptors, Interleukin-2 - metabolism; Receptors, Interleukin-2 - physiology; Rho GTPase; RNA Interference; Scientific Report; Substrates; Toxicology
• ISSN: 1469-221X; 1469-3178; 1469-221X
• DOI: 10.1038/embor.2008.28

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 β (IL‐2Rβ). 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‐2Rβ 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‐2Rβ 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‐2Rβ 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‐2Rβ internalization. This study indicates Paks as the first specific regulators of the clathrin‐independent endocytosis pathway.