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

Yosuke Yoneyama, Peter Lanzerstorfer, Hideaki Niwa, Takashi Umehara, Takashi Shibano, Shigeyuki Yokoyama, Kazuhiro Chida, Julian Weghuber, Fumihiko Hakuno, Shin-Ichiro Takahashi

Research output: Contribution to journalArticlepeer-review

39 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article numbere32893
JournaleLIFE
Volume7
DOIs
Publication statusPublished - 11 Apr 2018

Keywords

  • Cell Line
  • Endocytosis
  • Fatty Acid-Binding Proteins/metabolism
  • Humans
  • Insulin Receptor Substrate Proteins/metabolism
  • Insulin-Like Growth Factor I/metabolism
  • Protein Binding
  • Protein Interaction Maps
  • Receptor, IGF Type 1/metabolism
  • Signal Transduction

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