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Nectin-4 cis-interacts with ErbB2 and its trastuzumab-resistant splice variants, enhancing their activation and DNA

Shin Kedashiro1, Ayumu Sugiura1, Kiyohito Mizutani2

  • 1From the Division of Pathogenetic Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, 1-5-6 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan.

Scientific Reports
|December 14, 2019
PubMed

Insights

Nectin-4 interacts with ErbB2 and its resistant variants, activating cancer cell growth pathways. This discovery offers new insights into breast cancer mechanisms and potential therapeutic targets.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Biology

Background:

  • Nectin-4 and ErbB2 are upregulated in cancers, promoting proliferation and metastasis.
  • Understanding their interaction is crucial for developing targeted therapies.

Purpose of the Study:

  • To investigate the cis-interaction between nectin-4 and ErbB2 in breast cancer cells.
  • To elucidate the downstream signaling pathways activated by this interaction.
  • To explore the role of nectin-4 in resistance to ErbB2-targeted therapies.

Main Methods:

  • Utilized human breast cancer cell lines (T47D, SUM190-PT) with upregulated nectin-4 and ErbB2.
  • Analyzed nectin-4 and ErbB2 dimerization and activation.
  • Investigated the involvement of phosphoinositide 3-kinase-AKT and JAK-STAT3 signaling pathways.

Main Results:

  • Nectin-4 cis-interacts with ErbB2, enhancing its dimerization and activating the PI3K-AKT pathway for DNA synthesis.
  • Nectin-4 binds to the third immunoglobulin-like domain of nectin-4 and domain IV of ErbB2.
  • Nectin-4 interacts with trastuzumab-resistant ErbB2 variants (p95-ErbB2, ErbB2ΔEx16), activating PI3K-AKT and JAK-STAT3 pathways.

Conclusions:

  • Nectin-4 cis-interaction with ErbB2 and its resistant variants represents a novel mechanism for receptor activation.
  • This interaction enhances downstream signaling, contributing to cancer progression.
  • Nectin-4 may play a significant role in therapeutic resistance, suggesting it as a potential therapeutic target.

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