Phosphatidylserine acyl chain remodeling regulates KRAS spatial distribution and function on the plasma membrane.

磷脂酰丝氨酸酰基链重塑调节 KRAS 在质膜上的空间分布和功能。

• 批准号: 10400166
• 负责人: Yong Zhou
• 金额: $ 32.76万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10400166
• 关键词: Acute; Acyl Coenzyme A; Acyltransferase; Binding; Biological; Biological Models; Caenorhabditis elegans; Caliber; Cancer Biology; Cancer Patient; Cell Proliferation; Cell Proliferation Regulation; Cell membrane; Cell physiology; Cells; Colorectal Neoplasms; Data; Human; Impairment; Lecithin; Light; Lipid Bilayers; Lipids; Lung Neoplasms; Lysophosphatidylcholines; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Membrane; Membrane Microdomains; Mitogen-Activated Protein Kinases; Modeling; Molecular; Molecular Conformation; Monomeric GTP-Binding Proteins; Mutate; Mutation; Normal Cell; Pancreas; Pathology; Patients; Pharmaceutical Preparations; Phase; Phosphatidylserines; Plasma Cells; Probability; Property; Protein Isoforms; Proteins; RAS genes; Role; Sampling; Signal Transduction; Site; Solid; Spatial Distribution; Specificity; Structure; Testing; Transmembrane Transport; Xenograft procedure; base; cohort; improved; in vivo; lipidome; lipidomics; member; nanocluster; neoplastic cell; novel; overexpression; pancreatic cancer cells; pancreatic neoplasm; recruit; spatiotemporal; tumor; tumorigenesis

Project Summary: KRAS small GTPase activates mitogen-activated protein kinases (MAPKs) and participates in cell proliferation. KRAS is one of the most mutated proteins in cancer, with its mutations found in 98% of pancreatic tumors, 45% of colorectal tumors and 31% of lung tumors. Despite decades of intense focus, we still do not have any effective means of inhibiting KRAS oncogenesis. KRAS function is mostly compartmentalized to the cell plasma membrane (PM), where KRAS interacts with a select set of lipids to form signaling nanoclusters for effector recruitment and signal transduction. We recently showed that KRAS nanoclusters are specifically enriched with the mixed-chain phosphatidylserine (PS) species. In consequence, KRAS nanoclustering and effector binding occur selectively in the presence of the mixed-chain PS. Thus, KRAS function depends on PS acyl chain structures. We, here, propose to modulate PS acyl chains using lysophosphatidylcholine acyltransferases (LPCATs). In particular, we now show that increasing LPCAT1 levels reduces major mixed-chain PS species in human pancreatic tumor cells, and disrupts the nanoclustering of KRAS on the PM. This is further supported by cancer patient data showing that patients with KRAS-dependent pancreatic or lung cancer contain lower levels of LPCAT1. Another LPCAT member, LPCAT4, elevates the mixed-chain lipids and has been shown to promote KRAS oncogenesis in patients. We hypothesize that, by shifting the proportions of the mixed-chain PS species, LPCAT1 and LPCAT4 modulate KRAS nanoclustering and function. A successful testing of our hypothesis may provide an alternative strategy for perturbing KRAS pathology for patients with KRAS-dependent tumors. Our hypothesis is based on a well-established premise: KRAS nanoclustering and function selectiveluy depend on the mixed-chain PS species, whose abundance is modulated by LPCAT1/4. To test our hypothesis, we propose 3 Specific Aims. In Aim 1, we will examine a correlation between LPCAT1/4-altered lipidomics in whole-cell, the PM and endomembrane with effects of LPCAT1/4 on PM properties critical to KRAS function. In Aim 2, we will examine a molecular mechanism, by which LPCAT1/4 regulate spatial distribution of KRAS, potentially via remodeling PS acyl chains. In Aim 3, we will examine a molecular mechanism for how LPCAT1/4 modulate KRAS function in a cohort of mammalian and human tumor lines, as well as in vivo Caenorhabditis elegans (established model system for studying KRAS oncogenesis). Here, we propose to rigorously examine a novel mechanism, whereby remodeling PS acyl chain profiles by LPCATs modulates KRAS spatiotemporal organization, signaling and function. We aim to test LPCATs as novel regulators of KRAS oncogenesis. Biologically, although lipid acyl chains contribute to various important lipid bilayer properties, the importance of acyl chains in cells, which typically contain thousands of lipid species, has not been well-understood. Our proposed mechanism will contribute to our understanding of the potential biological roles of lipid acyl chain.

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