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Transforming properties of MET receptor exon 14 skipping can be recapitulated by loss of the CBL ubiquitin ligase binding site.

Author information

Affiliations

  • 1. CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020 - UMR1277 - Canther - Cancer Heterogeneity, Plasticity and Resistance to Therapies, Univ. Lille, France.
      Authors
    • Fernandes M 1
    • Paget S 1
    • Kherrouche Z 1
    • Truong MJ 1
    • Vinchent A 1
    • Cortot AB 1
    • Tulasne D 1
    (7 authors)
  • 2. Plateau de Génomique Fonctionnelle et Structurale, CHU Lille, Univ. Lille, France.
      Authors
    • Meneboo JP 2
    • Sebda S 2
    • Figeac M 2
    (3 authors)
  • 3. CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, US41 - UMS2014 - PLBS, Univ. Lille, France.
      Authors
    • Werkmeister E 3
    (1 author)
  • 4. Department of Molecular Oncology, CHU Lille, Univ. Lille, France.
      Authors
    • Descarpentries C 4
    (1 author)

ORCIDs linked to this article

FEBS Letters, 28 Jul 2023, 597(18):2301-2315
https://doi.org/10.1002/1873-3468.14702 PMID: 37468447 

Abstract 

MET is a receptor tyrosine kinase that is activated in many cancers through various mechanisms. MET exon 14 (Ex14) skipping occurs in 3% of nonsmall cell lung tumors. However, the contribution of the regulatory sites lost upon this skipping, which include a phosphorylated serine (S985) and a binding site for the E3 ubiquitin ligase CBL (Y1003), remains elusive. Sequencing of 2808 lung tumors revealed 71 mutations leading to MET exon 14 skipping and three mutations affecting Y1003 or S985. In addition, MET exon 14 skipping and MET Y1003F induced similar transcriptional programs, increased the activation of downstream signaling pathways, and increased cell mobility. Therefore, the MET Y1003F mutation is able to fully recapitulate responses induced by MET exon 14 skipping, suggesting that loss of the CBL binding site is the main contributor of cell transformation induced by MET Ex14 mutations.

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Read article at publisher's site: https://doi.org/10.1002/1873-3468.14702

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Funding 

Funders who supported this work.

Agence Nationale de la Recherche

    College of Natural Resources and Sciences, Humboldt State University

      Institut National Du Cancer

        Institut National de la Santé et de la Recherche Médicale

          Ligue Contre le Cancer

            Université de Lille