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.
Grassart
Alexandre
A
Institut Pasteur, Unité de Biologie des Interactions Cellulaires, CNRS URA 2582, 25 rue du Docteur Roux, 75724 Paris Cedex 15, France.
Dujeancourt
Annick
A
Lazarow
Paul B
PB
Dautry-Varsat
Alice
A
Sauvonnet
Nathalie
N
D002460:Cell Line; D002966:Clathrin / Q000378:metabolism; D051356:Cortactin / Q000378:metabolism; D004705:Endocytosis / Q000502:physiology*; D006801:Humans; D008856:Microscopy, Fluorescence; D034622:RNA Interference; D015375:Receptors, Interleukin-2 / Q000378:metabolism / Q000502:physiology*; D054462:p21-Activated Kinases / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
D002966:Clathrin; D051356:Cortactin; C107953:RAC1 protein, human; D015375:Receptors, Interleukin-2; C515903:PAK1 protein, human; C515907:PAK2 protein, human; D054462:p21-Activated Kinases; D020830:rac1 GTP-Binding Protein