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USP25 Regulates EGFR Fate by Modulating EGF-Induced Ubiquitylation Dynamics

Carlos A Niño1, Nadine Wollscheid1, Giovanni Giangreco2

  • 1IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, 20139 Milan, Italy.

Biomolecules
|November 18, 2020
PubMed

Insights

Ubiquitin Specific Peptidase 25 (USP25) restrains epidermal growth factor receptor (EGFR) degradation by regulating its internalization. USP25 acts as a negative regulator, suggesting it

Area of Science:

  • Molecular Biology
  • Oncology
  • Cell Signaling

Background:

  • Deregulated epidermal growth factor receptor (EGFR) signaling drives oncogenesis.
  • Cancer cells evade EGFR down-modulation to sustain uncontrolled signaling.
  • Ubiquitylation of EGFR is crucial for its internalization, trafficking, and degradation.

Purpose of the Study:

  • To investigate the role of Ubiquitin Specific Peptidase 25 (USP25) in EGFR regulation.
  • To determine USP25's impact on EGFR internalization and degradation.
  • To assess USP25 as a potential therapeutic target for EGFR-dependent tumors.

Main Methods:

  • Qualitative and quantitative assays were employed.
  • EGFR internalization and degradation were measured following USP25 depletion.
  • The association between USP25, c-Cbl, and EGFR was analyzed.

Main Results:

  • USP25 depletion significantly altered EGFR internalization and degradation.
  • USP25 restrains EGFR degradation by facilitating c-Cbl E3 ligase association with EGFR.
  • USP25 modulates the amplitude of EGFR ubiquitylation at early internalization steps.

Conclusions:

  • USP25 acts as a negative regulator of EGFR down-modulation.
  • USP25's mechanism involves modulating EGFR ubiquitylation and c-Cbl association.
  • USP25 represents a promising therapeutic target to inhibit oncogenic EGFR signaling.
Keywords:
EGFRcancerdeubiquitylating enzymesubiquitinubiquitylation

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