MTMR regulates KRAS function by controlling plasma membrane levels of phospholipids

Taylor E Lange; Ali Naji; Ransome van der Hoeven; Hong Liang; Yong Zhou; Gerald R V Hammond; John F Hancock; Kwang-Jin Cho

doi:10.1083/jcb.202403126

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MTMR regulates KRAS function by controlling plasma membrane levels of phospholipids

Journal article

Peer reviewed

MTMR regulates KRAS function by controlling plasma membrane levels of phospholipids

Taylor E Lange, Ali Naji, Ransome van der Hoeven, Hong Liang, Yong Zhou, Gerald R V Hammond, John F Hancock and Kwang-Jin Cho

The Journal of cell biology, Vol.224(7), e202403126

07/07/2025

DOI: 10.1083/jcb.202403126

PMCID: PMC12047185

PMID: 40314454

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Abstract

KRAS, a small GTPase involved in cell proliferation and differentiation, frequently gains activating mutations in human cancers. For KRAS to function, it must bind the plasma membrane (PM) via interactions between its membrane anchor and phosphatidylserine (PtdSer). Therefore, depleting PM PtdSer abrogates KRAS PM binding and activity. From a genome-wide siRNA screen to identify genes regulating KRAS PM localization, we identified a set of phosphatidylinositol (PI) 3-phosphatases: myotubularin-related proteins (MTMR) 2, 3, 4, and 7. Here, we show that silencing MTMR 2/3/4/7 disrupts KRAS PM interactions by reducing PM PI 4-phosphate (PI4P) levels, thereby disrupting the localization and operation of ORP5, a lipid transfer protein maintaining PM PtdSer enrichment. Concomitantly, silencing MTMR 2/3/4/7 elevates PM PI3P levels while reducing PM and total PtdSer levels. We also observed MTMR 2/3/4/7 expression is interdependent. We propose that the PI 3-phosphatase activity of MTMR is required for generating PM PI, necessary for PM PI4P synthesis, promoting the PM localization of PtdSer and KRAS.

Cell Line, Tumor

Cell Membrane - metabolism

Humans

Phosphatidylinositol Phosphates - metabolism

Phosphatidylserines - metabolism

Phospholipids - metabolism

Phosphoric Monoester Hydrolases - genetics

Phosphoric Monoester Hydrolases - metabolism

Proto-Oncogene Proteins p21(ras) - genetics

Proto-Oncogene Proteins p21(ras) - metabolism

Receptors, Steroid - genetics

Receptors, Steroid - metabolism

Details

Title: Subtitle: MTMR regulates KRAS function by controlling plasma membrane levels of phospholipids
Creators: Taylor E Lange - Wright State University
Ali Naji - The University of Texas Health Science Center at Houston
Ransome van der Hoeven - The University of Texas Health Science Center at Houston
Hong Liang - The University of Texas Health Science Center at Houston
Yong Zhou - The University of Texas Health Science Center at Houston
Gerald R V Hammond - University of Pittsburgh School of Medicine
John F Hancock - The University of Texas Health Science Center at Houston
Kwang-Jin Cho - Wright State University
Resource Type: Journal article
Publication Details: The Journal of cell biology, Vol.224(7), e202403126
DOI: 10.1083/jcb.202403126
PMID: 40314454
PMCID: PMC12047185
NLM abbreviation: J Cell Biol
ISSN: 1540-8140
eISSN: 1540-8140
Publisher: ROCKEFELLER UNIV PRESS
Grant note: 2R35GM119412 / NIGMS NIH HHS R00-CA188593 / NCI NIH HHS CPRIT RP200047 / Cancer Prevention and Research Institute of Texas Wright State University
Language: English
Date published: 07/07/2025
Academic Unit: Dental Research; Periodontics
Record Identifier: 9984816012802771

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