ZFIN ID: ZDB-PUB-150417-4
Nedd4-induced monoubiquitination of IRS-2 enhances IGF signalling and mitogenic activity
Fukushima, T., Yoshihara, H., Furuta, H., Kamei, H., Hakuno, F., Luan, J., Duan, C., Saeki, Y., Tanaka, K., Iemura, S.I., Natsume, T., Chida, K., Nakatsu, Y., Kamata, H., Asano, T., Takahashi, S.I.
Date: 2015
Source: Nature communications   6: 6780 (Journal)
Registered Authors: Duan, Cunming
Keywords: none
MeSH Terms:
  • Adaptor Proteins, Vesicular Transport/metabolism
  • Animals
  • Cell Line
  • Cell Line, Tumor
  • Cell Proliferation/genetics*
  • Cyclic AMP/metabolism
  • Endosomal Sorting Complexes Required for Transport/genetics*
  • HEK293 Cells
  • Humans
  • Insulin Receptor Substrate Proteins/metabolism*
  • Insulin-Like Growth Factor I/metabolism*
  • Male
  • Mitosis/genetics*
  • Phosphorylation
  • Prostatic Neoplasms/genetics
  • Rats
  • Receptor, IGF Type 1/metabolism
  • Somatomedins
  • Ubiquitin-Protein Ligases/genetics*
  • Ubiquitination*
  • Zebrafish
  • Zebrafish Proteins/genetics
PubMed: 25879670 Full text @ Nat. Commun.
Insulin-like growth factors (IGFs) induce proliferation of various cell types and play important roles in somatic growth and cancer development. Phosphorylation of insulin receptor substrate (IRS)-1/2 by IGF-I receptor tyrosine kinase is essential for IGF action. Here we identify Nedd4 as an IRS-2 ubiquitin ligase. Nedd4 monoubiquitinates IRS-2, which promotes its association with Epsin1, a ubiquitin-binding protein. Nedd4 recruits IRS-2 to the membrane, probably through promoting Epsin1 binding, and enhances IGF-I receptor-induced IRS-2 tyrosine phosphorylation. In thyroid FRTL-5 cells, activation of the cyclic AMP pathway increases the association of Nedd4 with IRS-2, thereby enhancing IRS-2-mediated signalling and cell proliferation induced by IGF-I. The Nedd4 and IRS-2 association is also required for maximal activation of IGF-I signalling and cell proliferation in prostate cancer PC-3 cells. Nedd4 overexpression accelerates zebrafish embryonic growth through IRS-2 in vivo. We conclude that Nedd4-induced monoubiquitination of IRS-2 enhances IGF signalling and mitogenic activity.