Targeting plasma membrane phosphatidylserine content to inhibit oncogenic KRAS function

Kattan, Walaa E; Chen, Wei; Ma, Xiaoping; Lan, Tien Hung; Hoeven, Dharini van der; Hoeven, Ransome van der; Hancock, John F.

doi:10.26508/lsa.201900431

Cited by 35 publications

(49 citation statements)

References 54 publications

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“…1 for possible modes of increasing nuclear GAL4/VP16-KRAS4B). Because the asymmetric distribution of phosphatidylserine (PS) in the PM has been shown to produce the negative charge that stabilizes KRAS4B association (26), we expected to find genes involved in PS metabolism or transport (27). The only gene in these pathways that scored consistently positive, albeit without passing our stringent RIGER analysis, was PI4KIIIα, which is responsible for generating the pool of PI4P at the PM that is exchanged with PS generated in the ER (28).…”

Section: Discussionmentioning

confidence: 99%

Scaffold association factor B (SAFB) is required for expression of prenyltransferases and RAS membrane association

Zhou

Kuruvilla

Shi

et al. 2020

Proc Natl Acad Sci USA

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Inhibiting membrane association of RAS has long been considered a rational approach to anticancer therapy, which led to the development of farnesyltransferase inhibitors (FTIs). However, FTIs proved ineffective against KRAS-driven tumors. To reveal alternative therapeutic strategies, we carried out a genome-wide CRISPR-Cas9 screen designed to identify genes required for KRAS4B membrane association. We identified five enzymes in the prenylation pathway and SAFB, a nuclear protein with both DNA and RNA binding domains. Silencing SAFB led to marked mislocalization of all RAS isoforms as well as RAP1A but not RAB7A, a pattern that phenocopied silencing FNTA, the prenyltransferase α subunit shared by farnesyltransferase and geranylgeranyltransferase type I. We found that SAFB promoted RAS membrane association by controlling FNTA expression. SAFB knockdown decreased GTP loading of RAS, abrogated alternative prenylation, and sensitized RAS-mutant cells to growth inhibition by FTI. Our work establishes the prenylation pathway as paramount in KRAS membrane association, reveals a regulator of prenyltransferase expression, and suggests that reduction in FNTA expression may enhance the efficacy of FTIs.

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Section: Discussionmentioning

confidence: 99%

Scaffold association factor B (SAFB) is required for expression of prenyltransferases and RAS membrane association

Zhou

Kuruvilla

Shi

et al. 2020

Proc Natl Acad Sci USA

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“…This supports the idea that any deregulation of ORP5 can distort the signaling capacity of the cell by changing the lipid content of the PM. Corroborating this, a lack of ORP5/8 activity was found to result in lower PS abundance in the PM, reducing the oncogenicity of K-Ras, a signaling protein that is frequently mutated in human cancers (Kattan et al, 2019).…”

Section: Roles Of Ps/pi(4)p Exchange In Other Cellular Regions and Inmentioning

confidence: 85%

Lipid Exchangers: Cellular Functions and Mechanistic Links With Phosphoinositide Metabolism

Lipp

Ikhlef

Milanini

et al. 2020

Front. Cell Dev. Biol.

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Lipids are amphiphilic molecules that self-assemble to form biological membranes. Thousands of lipid species coexist in the cell and, once combined, define organelle identity. Due to recent progress in lipidomic analysis, we now know how lipid composition is finely tuned in different subcellular regions. Along with lipid synthesis, remodeling and flip-flop, lipid transfer is one of the active processes that regulates this intracellular lipid distribution. It is mediated by Lipid Transfer Proteins (LTPs) that precisely move certain lipid species across the cytosol and between the organelles. A particular subset of LTPs from three families (Sec14, PITP, OSBP/ORP/Osh) act as lipid exchangers. A striking feature of these exchangers is that they use phosphatidylinositol or phosphoinositides (PIPs) as a lipid ligand and thereby have specific links with PIP metabolism and are thus able to both control the lipid composition of cellular membranes and their signaling capacity. As a result, they play pivotal roles in cellular processes such as vesicular trafficking and signal transduction at the plasma membrane. Recent data have shown that some PIPs are used as energy by lipid exchangers to generate lipid gradients between organelles. Here we describe the importance of lipid counter-exchange in the cell, its structural basis, and presumed links with pathologies.

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“…Finally, it is also tempting to speculate that the tight regulation of PM PI(4,5)P2 by ORP5/8 could contribute to the ORP8 influence on AKT signaling [ 30 , 45 , 46 ], as this could conceivably also impact the synthesis of PI(3,4,5)P3 by PI3K. Indeed, recently, the depletion of ORP5 or ORP8 reduced PM PS levels resulting in mislocalization of KRas from the PM, an oncogene that requires PM PS for its localization and activity [ 72 ]. Together with effects on Ca 2+ signaling [ 64 ], these are both additional mechanisms based on phospholipid transfer through which ORP5/8 may contribute to the control of proliferation, migration and other functions.…”

Section: Discussionmentioning

confidence: 99%

ORP5 and ORP8: Sterol Sensors and Phospholipid Transfer Proteins at Membrane Contact Sites?

2020

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Oxysterol binding related proteins 5 and 8 (ORP5 and ORP8) are two close homologs of the larger oxysterol binding protein (OSBP) family of sterol sensors and lipid transfer proteins (LTP). Early studies indicated these transmembrane proteins, anchored to the endoplasmic reticulum (ER), bound and sensed cholesterol and oxysterols. They were identified as important for diverse cellular functions including sterol homeostasis, vesicular trafficking, proliferation and migration. In addition, they were implicated in lipid-related diseases such as atherosclerosis and diabetes, but also cancer, although their mechanisms of action remained poorly understood. Then, alongside the increasing recognition that membrane contact sites (MCS) serve as hubs for non-vesicular lipid transfer, added to their structural similarity to other LTPs, came discoveries showing that ORP5 and 8 were in fact phospholipid transfer proteins that rather sense and exchange phosphatidylserine (PS) for phosphoinositides, including phosphatidylinositol-4-phosphate (PI(4)P) and potentially phosphatidylinositol-(4,5)-bisphosphate (PI(4,5)P2). Evidence now points to their action at MCS between the ER and various organelles including the plasma membrane, lysosomes, mitochondria, and lipid droplets. Dissecting exactly how this unexpected phospholipid transfer function connects with sterol regulation in health or disease remains a challenge for future studies.

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Targeting plasma membrane phosphatidylserine content to inhibit oncogenic KRAS function

Cited by 35 publications

References 54 publications

Scaffold association factor B (SAFB) is required for expression of prenyltransferases and RAS membrane association

Scaffold association factor B (SAFB) is required for expression of prenyltransferases and RAS membrane association

Lipid Exchangers: Cellular Functions and Mechanistic Links With Phosphoinositide Metabolism

ORP5 and ORP8: Sterol Sensors and Phospholipid Transfer Proteins at Membrane Contact Sites?

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