Department of Animal Resource Sciences, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan
Peter Lanzerstorfer
University of Applied Sciences Upper Austria, Wels, Austria
Hideaki Niwa
RIKEN Systems and Structural Biology Center, Yokohama, Japan; RIKEN Center for Life Science Technologies, Yokohama, Japan
Takashi Umehara
RIKEN Systems and Structural Biology Center, Yokohama, Japan; RIKEN Center for Life Science Technologies, Yokohama, Japan; PRESTO, Japan Science and Technology Agency, Kawaguchi, Japan
Takashi Shibano
Department of Animal Resource Sciences, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan
Shigeyuki Yokoyama
RIKEN Systems and Structural Biology Center, Yokohama, Japan; RIKEN Structural Biology Laboratory, Yokohama, Japan
Kazuhiro Chida
Department of Animal Resource Sciences, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan
Julian Weghuber
University of Applied Sciences Upper Austria, Wels, Austria; Austrian Competence Center for Feed and Food Quality, Safety and Innovation, Wels, Austria
Fumihiko Hakuno
Department of Animal Resource Sciences, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan
Insulin-like growth factor-I receptor (IGF-IR) preferentially regulates the long-term IGF activities including growth and metabolism. Kinetics of ligand-dependent IGF-IR endocytosis determines how IGF induces such downstream signaling outputs. Here, we find that the insulin receptor substrate (IRS)−1 modulates how long ligand-activated IGF-IR remains at the cell surface before undergoing endocytosis in mammalian cells. IRS-1 interacts with the clathrin adaptor complex AP2. IRS-1, but not an AP2-binding-deficient mutant, delays AP2-mediated IGF-IR endocytosis after the ligand stimulation. Mechanistically, IRS-1 inhibits the recruitment of IGF-IR into clathrin-coated structures; for this reason, IGF-IR avoids rapid endocytosis and prolongs its activity on the cell surface. Accelerating IGF-IR endocytosis via IRS-1 depletion induces the shift from sustained to transient Akt activation and augments FoxO-mediated transcription. Our study establishes a new role for IRS-1 as an endocytic regulator of IGF-IR that ensures sustained IGF bioactivity, independent of its classic role as an adaptor in IGF-IR signaling.
