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。

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要： KRAS小GTPase激活有丝分裂原激活的蛋白激酶（MAPK），并参与细胞增殖。 KRAS是癌症中最突变的蛋白质之一，其突变发现在98％的胰腺肿瘤中，45％结直肠肿瘤和31％的肺肿瘤。尽管精力集中了数十年，但我们仍然没有任何有效的抑制KRAS肿瘤发生的手段。 KRAS功能主要被划分为细胞等离子体膜（PM），其中Kras与选择的一组脂质相互作用以形成效应器的信号纳米群体募集和信号转导。我们最近表明，KRAS纳米簇特别丰富混合链磷脂酰丝氨酸（PS）物种。结果，KRAS纳米簇和效应子结合在混合链PS的情况下选择性地发生。因此，KRAS功能取决于PS酰基链结构。在这里，我们建议使用溶血磷脂酰胆碱酰基转移酶调节PS酰基链（lpcats）。特别是，我们现在表明，升高的LPCAT1水平降低了主要的混合链PS物种人胰腺肿瘤细胞，并破坏PM上KRAS的纳米簇。这进一步支持癌症患者数据表明，依赖KRAS的胰腺或肺癌患者含有较低的水平 LPCAT1。另一个LPCAT成员LPCAT4升高混合链脂质，并已被证明可以促进 Kras患者的肿瘤发生。我们假设这是通过移动混合链PS的比例 LPCAT1和LPCAT4物种调节KRAS纳米簇和功能。成功测试了我们假设可以为KRAS依赖性患者扰动KRAS病理学提供替代策略肿瘤。我们的假设基于一个完善的前提：KRAS纳米群和功能Selectiveluy 取决于混合链PS物种，其丰度由LPCAT1/4调节。为了检验我们的假设，我们提出了3个具体目标。在AIM 1中，我们将研究LPCAT1/4改变脂质组学之间的相关性全细胞，PM和内膜具有LPCAT1/4对KRAS功能至关重要的PM性质的影响。在 AIM 2，我们将检查一种分子机制，通过该机制LPCAT1/4调节KRAS的空间分布，可能通过重塑PS酰基链。在AIM 3中，我们将检查一种分子机制，以实现LPCAT1/4的方式调节KRAS在哺乳动物和人类肿瘤系的队列中以及体内炎秀丽隐杆线虫（用于研究KRAS肿瘤发生的建立模型系统）。在这里，我们建议严格检查新型机制，通过LPCAT重塑PS酰基链轮廓调节KRAS时空时空组织，信号和功能。我们旨在测试LPCAT作为KRAS肿瘤发生的新调节剂。在生物学上，尽管脂质酰基链有助于各种重要的脂质双层特性，但重要性细胞中通常含有数千种脂质物种的酰基链并未得到充分理解。我们的提出的机制将有助于我们理解脂质酰基链的潜在生物学作用。