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

While 3% of lung cancers harbor mutations in exon 14 (Ex14) of the MET receptor, its oncogenic capabilities remain elusive, in particular the involvement of several regulatory sites in the juxtamembrane domain. The MET Y1003F mutation fully recapitulates the responses induced by MET exon 14 skipping, suggesting that loss of the CBL ubiquitin ligase binding site is the main factor in the cellular transformation induced by MET Ex14 mutations. MET is a receptor tyrosine kinase that is activated in many cancers through various mechanisms. MET exon 14 (Ex14) skipping occurs in 3% of non-small 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), remain elusive. Sequencing of 2808 lung tumors revealed 71 mutations leading to MET exon 14 skipping and 3 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.

Source: FEBS Letters - July 23, 2023 Category: Biochemistry Authors: Marie Fernandes, Sonia Paget, Zoulika Kherrouche, Marie ‐José Truong, Audrey Vinchent, Jean‐Pascal Meneboo, Shéhérazade Sebda, Elisabeth Werkmeister, Clotilde Descarpentries, Martin Figeac, Alexis B Cortot, David Tulasne Tags: Research Article Source Type: research