Myotubularin-related-protein-7 inhibits mutant (G12V) K-RAS by direct interaction

Philip Weidner, Daniel Saar, Michaela Söhn, Torsten Schroeder, Yanxiong Yu, Frank G. Zöllner, Norbert Ponelies, Xiaobo Zhou, André Zwicky, Florian N. Rohrbacher, Vijaya R. Pattabiraman, Matthias Tanriver, Alexander Bauer, Hazem Ahmed, Simon M. Ametamey, Philipp Riffel, Rony Seger, Jeffrey W. Bode, Rebecca C. Wade, Matthias P.A. EbertBirthe B. Kragelund, Elke Burgermeister*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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Abstract

Inhibition of K-RAS effectors like B-RAF or MEK1/2 is accompanied by treatment resistance in cancer patients via re-activation of PI3K and Wnt signaling. We hypothesized that myotubularin-related-protein-7 (MTMR7), which inhibits PI3K and ERK1/2 signaling downstream of RAS, directly targets RAS and thereby prevents resistance. Using cell and structural biology combined with animal studies, we show that MTMR7 binds and inhibits RAS at cellular membranes. Overexpression of MTMR7 reduced RAS GTPase activities and protein levels, ERK1/2 phosphorylation, c-FOS transcription and cancer cell proliferation in vitro. We located the RAS-inhibitory activity of MTMR7 to its charged coiled coil (CC) region and demonstrate direct interaction with the gastrointestinal cancer-relevant K-RASG12V mutant, favouring its GDP-bound state. In mouse models of gastric and intestinal cancer, a cell-permeable MTMR7-CC mimicry peptide decreased tumour growth, Ki67 proliferation index and ERK1/2 nuclear positivity. Thus, MTMR7 mimicry peptide(s) could provide a novel strategy for targeting mutant K-RAS in cancers.

Original languageEnglish
Article number216783
JournalCancer Letters
Volume588
Number of pages19
ISSN0304-3835
DOIs
Publication statusPublished - 2024

Bibliographical note

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© 2024 The Authors

Keywords

  • Coiled coil
  • Colorectal cancer
  • MTMR7
  • Myotubularin
  • NMR
  • Peptide
  • Phosphatase
  • RAS

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