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

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...

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Main Authors: Weidner, Philip (Author) , Saar, Daniel (Author) , Söhn, Michaela (Author) , Schroeder, Torsten (Author) , Yu, Yanxiong (Author) , Zöllner, Frank G. (Author) , Ponelies, Norbert (Author) , Zhou, Xiao-Bo (Author) , Zwicky, André (Author) , Rohrbacher, Florian N. (Author) , Pattabiraman, Vijaya R. (Author) , Tanriver, Matthias (Author) , Bauer, Alexander (Author) , Ahmed, Hazem (Author) , Ametamey, Simon M. (Author) , Riffel, Philipp (Author) , Seger, Rony (Author) , Bode, Jeffrey W. (Author) , Wade, Rebecca C. (Author) , Ebert, Matthias (Author) , Kragelund, Birthe B. (Author) , Burgermeister, Elke (Author)
Format: Article (Journal)
Language:English
Published: 28 April 2024
In: Cancer letters
Year: 2024, Volume: 588, Pages: 1-19
ISSN:1872-7980
DOI:10.1016/j.canlet.2024.216783
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1016/j.canlet.2024.216783
Verlag, kostenfrei, Volltext: https://www.sciencedirect.com/science/article/pii/S0304383524001769
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Author Notes: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. Ebert, Birthe B. Kragelund, Elke Burgermeister
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Summary: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.
Item Description:Online verfügbar: 9. März 2024, Artikelversion: 18. März 2024
Gesehen am 04.02.2025
Physical Description:Online Resource
ISSN:1872-7980
DOI:10.1016/j.canlet.2024.216783

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