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Identification of EGFR and RAS Inhibitors using Caenorhabditis elegans
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CNKSR1 serves as a scaffold to activate an EGFR phosphatase via exclusive interaction with RhoB-GTP

Kanako Nishiyama1,2, Masashi Maekawa3,4, Tomoya Nakagita5

  • 1Department of Hepato-Biliary-Pancreatic Surgery and Breast Surgery, Ehime University Graduate School of Medicine, Toon, Japan.

Life Science Alliance
|June 30, 2021
PubMed

Insights

Degradation of RhoB by CUL3/KCTD10 is crucial for HER2-positive breast cancer cell growth by regulating EGFR and HER2 phosphorylation. This finding offers a potential therapeutic target for HER2-positive breast cancers.

Area of Science:

  • Oncology
  • Cell Biology
  • Biochemistry

Background:

  • HER2-positive breast cancer proliferation is driven by epidermal growth factor receptor (EGFR) and human EGFR 2 (HER2) phosphorylation.
  • Targeting phosphatases for these receptors presents a potential therapeutic strategy.

Purpose of the Study:

  • To investigate the role of RhoB degradation by the CUL3/KCTD10 complex in regulating EGFR and HER2 phosphorylation.
  • To elucidate the mechanism by which RhoB influences phosphatase activity in HER2-positive breast cancer cells.

Main Methods:

  • Utilized human protein arrays synthesized via a wheat cell-free system to identify protein interactions.
  • Investigated the effects of CUL3 and KCTD10 depletion on RhoB and PTPRH localization and activity.
  • Examined the interaction between RhoB-GTP, CNKSR1, and PTPRH.

Main Results:

  • RhoB degradation by CUL3/KCTD10 is essential for EGFR and HER2 phosphorylation.
  • CNKSR1 interaction with PTPRH, leading to EGFR phosphatase inactivation, is enabled by RhoB degradation.
  • Depletion of CUL3 or KCTD10 causes RhoB-GTP accumulation, leading to PTPRH activation.

Conclusions:

  • A novel mechanism for PTPRH activation via RhoB-GTP binding to CNKSR1 is proposed.
  • The CUL3/KCTD10-RhoB pathway is critical for maintaining EGFR and HER2 phosphorylation in HER2-positive breast cancer.
  • This pathway represents a potential therapeutic target for HER2-positive breast cancers.

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