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

<div class='caption-title'>IRS-1 interacts with the clathrin adaptor AP2 complex through its YxxΦ motifs.</div>
<div class='caption-title'>Three YxxΦ motifs in IRS-1 mediate the interaction with μ2 of AP2 complex.</div>
<div class='caption-title'>IRS-1 promotes cell surface retention of activated IGF-IR via its YxxΦ motifs.</div>
Yoneyama Y, Lanzerstorfer P, Niwa H, Umehara T, Shibano T, Yokoyama S, Chida K, Weghuber J, Hakuno F, Takahashi SI
OpenAccess logo Elife 7 (2018)
Related entries: 5wrk, 5wrl

Cited: 25 times
EuropePMC logo PMID: 29661273

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.

Articles - 5wrm mentioned but not cited (1)

  1. IRS-1 acts as an endocytic regulator of IGF-I receptor to facilitate sustained IGF signaling. Yoneyama Y, Lanzerstorfer P, Niwa H, Umehara T, Shibano T, Yokoyama S, Chida K, Weghuber J, Hakuno F, Takahashi SI. Elife 7 e32893 (2018)


Reviews citing this publication (8)

  1. New Insights from IGF-IR Stimulating Activity Analyses: Pathological Considerations. Janssen JAMJL. Cells 9 E862 (2020)
  2. Controlled Signaling-Insulin-Like Growth Factor Receptor Endocytosis and Presence at Intracellular Compartments. Rieger L, O'Connor R. Front Endocrinol (Lausanne) 11 620013 (2020)
  3. Emerging concepts of receptor endocytosis and concurrent intracellular signaling: Mechanisms of guanylyl cyclase/natriuretic peptide receptor-A activation and trafficking. Mani I, Pandey KN. Cell Signal 60 17-30 (2019)
  4. Ubiquilin Networking in Cancers. Jantrapirom S, Piccolo LL, Pruksakorn D, Potikanond S, Nimlamool W. Cancers (Basel) 12 E1586 (2020)
  5. Regulation of insulin resistance and glucose metabolism by interaction of PIM kinases and insulin receptor substrates. Aziz AUR, Farid S, Qin K, Wang H, Liu B. Arch Physiol Biochem 126 129-138 (2020)
  6. IGF-1R targeting in cancer - does sub-cellular localization matter? Soni UK, Jenny L, Hegde RS. J Exp Clin Cancer Res 42 273 (2023)
  7. PI3K signaling through a biochemical systems lens. Madsen RR, Toker A. J Biol Chem 299 105224 (2023)
  8. The Role of Insulin Receptor Substrate Proteins in Bronchopulmonary Dysplasia and Asthma: New Potential Perspectives. Gorgisen G, Aydin M, Mboma O, Gökyildirim MY, Chao CM. Int J Mol Sci 23 10113 (2022)

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