IRS-1 acts as an endocytic regulator of IGF-I receptor to facilitate sustained IGF signaling

• Published in: eLife Vol. 7
• Main Authors: Yoneyama, Yosuke, Lanzerstorfer, Peter, Niwa, Hideaki, Umehara, Takashi, Shibano, Takashi, Yokoyama, Shigeyuki, Chida, Kazuhiro, Weghuber, Julian, Hakuno, Fumihiko, Takahashi, Shin-Ichiro
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 11.04.2018; eLife Sciences Publications, Ltd
• Subjects: AKT protein; AP2; Biochemistry and Chemical Biology; Biological activity; Cell Biology; Cell surface; Clathrin; Deficient mutant; Endocytosis; Forkhead protein; Glycerol; IGF; IGF-I receptor; Insulin; Insulin receptor substrate 1; Insulin-like growth factor I; Insulin-like growth factors; IRS; Kinases; Ligands; Mammalian cells; Medicin och hälsovetenskap; Peptides; Proteins; Transcription activation; Variance analysis; Yokohama Japan; Austria; Japan; mouse; IGF-I receptor; AP2; cell biology; chemical biology; clathrin; rat; biochemistry; IGF; IRS; human
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/elife.32893

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.