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Updated: Jul 1, 2025

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

Philip Weidner1, Daniel Saar2, Michaela Söhn1

  • 1Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

Cancer Letters
|March 10, 2024
PubMed

Insights

Myotubularin-related-protein-7 (MTMR7) inhibits RAS signaling, preventing cancer treatment resistance. MTMR7 mimicry peptides show promise for targeting mutant K-RAS in gastrointestinal cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Cancer treatment resistance often involves reactivation of PI3K and Wnt signaling pathways after inhibiting K-RAS effectors.
  • Myotubularin-related-protein-7 (MTMR7) is known to inhibit PI3K and ERK1/2 signaling downstream of RAS.

Purpose of the Study:

  • To investigate if MTMR7 directly targets RAS to prevent cancer treatment resistance.
  • To explore the therapeutic potential of MTMR7 or its mimics against mutant K-RAS cancers.

Main Methods:

  • Cell and structural biology techniques were employed.
  • In vitro studies involved MTMR7 overexpression in cancer cells.
  • In vivo studies utilized mouse models of gastric and intestinal cancer with MTMR7-CC mimicry peptides.

Main Results:

  • MTMR7 was shown to bind and inhibit RAS at cellular membranes.
  • MTMR7 overexpression reduced RAS activity, ERK1/2 phosphorylation, and cancer cell proliferation.
  • A cell-permeable MTMR7-CC mimicry peptide decreased tumor growth and proliferation markers in mouse cancer models.
  • MTMR7 directly interacts with the K-RASG12V mutant, stabilizing its GDP-bound state.

Conclusions:

  • MTMR7 directly inhibits RAS signaling by binding to it at the cell membrane.
  • MTMR7 mimicry peptides represent a novel therapeutic strategy for targeting mutant K-RAS in cancers, potentially overcoming treatment resistance.
Keywords:
Coiled coilColorectal cancerMTMR7MyotubularinNMRPeptidePhosphataseRAS

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