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

Publikation: Beitrag in FachzeitschriftArtikelBegutachtung

42 Zitate (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.

OriginalspracheEnglisch
Aufsatznummere32893
FachzeitschrifteLIFE
Jahrgang7
DOIs
PublikationsstatusVeröffentlicht - 11 Apr. 2018

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