Related Experiment Video

Updated: May 9, 2025

Fully Processed Recombinant KRAS4b: Isolating and Characterizing the Farnesylated and Methylated Protein
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MTMR regulates KRAS function by controlling plasma membrane levels of phospholipids

Taylor E Lange1, Ali Naji2, Ransome van der Hoeven2

  • 1Department of Biochemistry and Molecular Biology, Boonshoft School of Medicine, Wright State University, Dayton, OH, USA.

The Journal of Cell Biology
|May 2, 2025
PubMed

Insights

Myotubularin-related proteins (MTMR) 2, 3, 4, and 7 regulate KRAS protein localization by controlling plasma membrane lipid levels. Their depletion disrupts KRAS binding, impacting cancer cell processes.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • KRAS, a key GTPase in cell signaling, requires plasma membrane (PM) binding for its function.
  • Phosphatidylserine (PtdSer) on the PM is crucial for KRAS membrane association and activity.
  • Activating KRAS mutations are common in human cancers.

Purpose of the Study:

  • To identify genes regulating KRAS PM localization.
  • To elucidate the role of phosphatidylinositol (PI) 3-phosphatases in KRAS membrane targeting.

Main Methods:

  • Genome-wide siRNA screen to identify regulators of KRAS PM localization.
  • Analysis of lipid levels (PI4P, PI3P, PtdSer) at the PM.
  • Assessment of KRAS PM binding and activity upon gene silencing.

Main Results:

  • Silencing myotubularin-related proteins (MTMR) 2, 3, 4, and 7 reduced PM PI 4-phosphate (PI4P) levels.
  • MTMR depletion disrupted the ORP5 lipid transfer protein, impairing PM PtdSer enrichment.
  • MTMR silencing elevated PM PI 3-phosphate (PI3P) and decreased PM and total PtdSer levels, affecting KRAS PM localization.

Conclusions:

  • The PI 3-phosphatase activity of MTMR proteins is essential for maintaining PM PI levels.
  • This activity supports PM PI4P synthesis, crucial for ORP5 function and PtdSer localization.
  • MTMR proteins are critical regulators of PtdSer and KRAS localization at the plasma membrane.

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