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Nedd4-induced monoubiquitination of IRS-2 enhances IGF signalling and mitogenic activity

Toshiaki Fukushima1, Hidehito Yoshihara2, Haruka Furuta3

  • 11] Department of Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan [2] Department of Medical Science, Graduate School of Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima City, Hiroshima 734-8553, Japan.

Nature Communications
|April 17, 2015
PubMed

Insights

Nedd4 acts as an IRS-2 ubiquitin ligase, promoting cell proliferation and growth. This monoubiquitination enhances insulin-like growth factor (IGF) signaling, impacting both normal development and cancer progression.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Insulin-like growth factors (IGFs) are crucial for cell proliferation, somatic growth, and cancer development.
  • Insulin receptor substrate (IRS)-1/2 phosphorylation by the IGF-I receptor tyrosine kinase is vital for IGF signaling pathways.

Purpose of the Study:

  • To identify novel regulators of IGF signaling.
  • To elucidate the role of Nedd4 in IRS-2 function and IGF-mediated cellular responses.

Main Methods:

  • Identification of Nedd4 as an IRS-2 ubiquitin ligase.
  • Analysis of Nedd4-mediated IRS-2 monoubiquitination and its effects on Epsin1 association.
  • Investigation of Nedd4-IRS-2 interactions in thyroid (FRTL-5) and prostate cancer (PC-3) cells.
  • In vivo studies using zebrafish to assess Nedd4's role in embryonic growth.

Main Results:

  • Nedd4 directly monoubiquitinates IRS-2, enhancing its binding to Epsin1 and promoting membrane recruitment.
  • Nedd4 enhances IGF-I receptor-induced tyrosine phosphorylation of IRS-2.
  • Nedd4-IRS-2 association is critical for IGF-I-induced proliferation in FRTL-5 and PC-3 cells.
  • Nedd4 overexpression accelerates zebrafish embryonic growth via IRS-2.

Conclusions:

  • Nedd4 functions as an IRS-2 ubiquitin ligase, mediating monoubiquitination that enhances IGF signaling.
  • This Nedd4-dependent mechanism amplifies IGF-induced mitogenic activity and cellular proliferation.
  • Nedd4 plays a significant role in regulating IGF signaling pathways in both normal growth and cancer contexts.

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