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USP15 attenuates IGF-I signaling by antagonizing Nedd4-induced IRS-2 ubiquitination

Toshiaki Fukushima1, Hidehito Yoshihara2, Haruka Furuta3

  • 1Department of Medical Science, Graduate School of Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima City, Hiroshima, 734-8553, Japan; Cell Biology Unit, Institute of Innovative Research, Tokyo Institute of Technology, 4259 Nagatsuta, Midori-ku, Yokohama, 226-8501, Japan.

Biochemical and Biophysical Research Communications
|January 28, 2017
PubMed

Insights

Ubiquitin-specific protease 15 (USP15) reduces insulin receptor substrate-2 (IRS-2) ubiquitination, thereby attenuating insulin-like growth factor-I (IGF-I) signaling and cell proliferation.

Area of Science:

  • Cellular signaling pathways
  • Protein ubiquitination and deubiquitination
  • Receptor tyrosine kinase signaling

Background:

  • Insulin receptor substrates (IRSs) are key mediators of insulin-like growth factor-I (IGF-I) receptor signaling, regulating crucial cellular processes like proliferation.
  • Nedd4, an E3 ubiquitin ligase, enhances IGF-I signaling by promoting IRS-2 mono-ubiquitination and subsequent tyrosine phosphorylation.
  • The precise regulation of IRS-2 ubiquitination and its impact on IGF-I signaling requires further elucidation.

Purpose of the Study:

  • To investigate the role of ubiquitin-specific protease 15 (USP15) in modulating Nedd4-mediated IRS-2 ubiquitination and IGF-I signaling.
  • To determine whether USP15 antagonizes the effects of Nedd4 on IRS-2 phosphorylation and downstream signaling.
  • To explore the functional consequences of USP15-IRS-2 interaction in cellular models.

Main Methods:

  • Co-immunoprecipitation assays to identify USP15 binding to ubiquitinated IRS-2.
  • Western blotting to assess IRS-2 ubiquitination and tyrosine phosphorylation levels in response to Nedd4 and USP15 manipulation.
  • Overexpression and knockdown studies in HEK293 and PC-3 cells to evaluate signaling pathway activity.

Main Results:

  • USP15 was identified as a binding partner for ubiquitinated IRS-2.
  • USP15 co-expression decreased Nedd4-induced IRS-2 ubiquitination and IGF-I-dependent tyrosine phosphorylation in HEK293 cells.
  • USP15 knockdown enhanced IRS-2 tyrosine phosphorylation and downstream signaling in PC-3 prostate cancer cells.

Conclusions:

  • USP15 acts as a negative regulator of IGF-I signaling by counteracting Nedd4-mediated IRS-2 ubiquitination.
  • This interaction between USP15 and Nedd4 provides a novel regulatory mechanism for IGF-I pathway activity.
  • Targeting the USP15-Nedd4-IRS-2 axis may offer therapeutic strategies for cancers driven by aberrant IGF-I signaling.
Keywords:
Insulin receptor substrate (IRS)-2Insulin-like growth factor (IGF)Nedd4Ubiquitin-specific protease 15 (USP15)Ubiquitination

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