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

Elife. 2018 Apr 11:7:e32893. doi: 10.7554/eLife.32893.

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.

Keywords: AP2; IGF; IGF-I receptor; IRS; biochemistry; cell biology; chemical biology; clathrin; human; mouse; rat.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*

Substances

  • FABP4 protein, human
  • Fatty Acid-Binding Proteins
  • IGF1 protein, human
  • IRS1 protein, human
  • Insulin Receptor Substrate Proteins
  • Insulin-Like Growth Factor I
  • Receptor, IGF Type 1

Grants and funding

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.