LPA receptor signaling in colonic epithelia

结肠上皮细胞中的 LPA 受体信号传导

• 批准号: 7921162
• 负责人: Changhyon Chris Yun
• 金额: $ 9.9万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-20 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7921162
• 关键词: Affect; Anchorage-Independent Growth; Apoptosis; Azoxymethane; Binding Proteins; Biological; Cell Proliferation; Cell Survival; Colon; Colon Carcinoma; Colorectal Cancer; Data; Development; Edg4 Protein; Epidermal Growth Factor Receptor; Epithelium; Family; G-Protein-Coupled Receptors; Genus Cola; Goals; Growth Factor; Induction of Apoptosis; Intestines; Knockout Mice; Knowledge; Left; Literature; Lysophosphatidic Acid Receptors; Lysophospholipids; Malignant Neoplasms; Malignant neoplasm of testis; Mediating; Molecular; Mus; Ovarian; Pathway interactions; Physiological; Play; Property; Proteins; Receptor Signaling; Regulation; Research; Research Personnel; Role; Scaffolding Protein; Signal Pathway; Signal Transduction; Specificity; Therapeutic Intervention; Transactivation; Transgenic Mice; Xenograft Model; activating transcription factor; base; cancer cell; cancer type; chemokine; computerized data processing; design; genetic regulatory protein; in vivo; interest; intestinal epithelium; lipid mediator; lysophosphatidic acid; membrane-associated guanylate kinase; novel; promoter; protein protein interaction; receptor; response; therapeutic development; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Our long-term goal is to understand the cellular signaling mechanisms in the intestinal epithelia with an emphasis on how protein-protein interaction affects the specificity and efficacy of signaling processes. Lysophosphatidic acid (LPA) has been shown to exert growth factor-like effects. Signaling by LPA is primarily mediated through a family of G-protein-coupled receptors, LPA^ LPA2 and LPA3. Despite more than a decade of study on LPA signaling, receptor subtype specific signaling and functions are not fully elucidated. However, this knowledge is a key to the rational design of therapeutic interventions targeting the novel intermediates and the pivotal pathways. We have recently found that there is an increase in LPA2 expression in several types of cancer, including colon cancer. This observation suggests that LPA2 is likely to play an essential pathophysiologic role that enhances cancer development and a better understanding of the signaling pathways and mechanism elicited by LPA2 is necessary. Our studies show that LPA activates the transcription factor KLF5, which is a promoter of cellular proliferation in the intestine, suggesting that KLF5 may be an intermediate transducing the biological effects of LPA. Recently, we and others have also shown that LPA2 interacts with a scaffold protein NHERF2. In addition, we have identified MAGI-3 as another LPA2 binding protein. Our preliminary studies show that the effects of MAGI-3 on LPA2-mediated signaling are unique and MAGI-3 negatively impacts the LPA-mediated signaling. Our data suggest that one reason for the divergence in LPA signaling under different conditions may be the presence or absence of interacting partners. Based on these data, we hypothesize that LPA2 facilitates tumor development in the colon by mediating multiple biological effects that promote proliferation and survival of cancer cells. We further hypothesize that the activity of LPA2 is regulated via the interaction with MAGI-3 and NHERF2. We propose the following studies. (1) We will define the biological effects mediated by LPA2 and the underlying mechanisms that enhance the formation of colorectal cancer. (2) We will determine the role of MAGI-3 in regulation of LPA2-mediated signaling in colon cancer cells. (3) We will delineate the effect of LPA and the LPA2 in vivo by using transgenic mice. Our studies will enhance our understanding of the importance and mechanism of tumorigenesis of colorectal cancer by LPA and LPA2 receptor. Our findings should help the therapeutic development against colorectal cancer.

描述（由申请人提供）：我们的长期目标是了解肠上皮细胞中的细胞信号传导机制，重点是蛋白质-蛋白质相互作用如何影响信号传导过程的特异性和功效。溶血磷脂酸 (LPA) 已被证明具有类似生长因子的作用。 LPA 信号传导主要通过 G 蛋白偶联受体家族 LPA、LPA2 和 LPA3 介导。尽管对 LPA 信号传导进行了十多年的研究，但受体亚型特异性信号传导和功能尚未完全阐明。然而，这一知识是合理设计针对新型中间体和关键途径的治疗干预措施的关键。我们最近发现，包括结肠癌在内的多种癌症中 LPA2 表达增加。这一观察结果表明，LPA2 可能在促进癌症发展方面发挥重要的病理生理作用，因此有必要更好地了解 LPA2 引发的信号传导途径和机制。我们的研究表明，LPA 激活转录因子 KLF5，而 KLF5 是肠道细胞增殖的促进剂，表明 KLF5 可能是转导 LPA 生物学效应的中间体。最近，我们和其他人还证明 LPA2 与支架蛋白 NHERF2 相互作用。此外，我们还鉴定出 MAGI-3 是另一种 LPA2 结合蛋白。我们的初步研究表明，MAGI-3 对 LPA2 介导的信号传导的影响是独特的，并且 MAGI-3 对 LPA 介导的信号传导产生负面影响。我们的数据表明，不同条件下 LPA 信号传导出现差异的原因之一可能是相互作用伙伴的存在或不存在。基于这些数据，我们假设 LPA2 通过介导促进癌细胞增殖和存活的多种生物效应来促进结肠肿瘤的发展。我们进一步假设 LPA2 的活性是通过与 MAGI-3 和 NHERF2 的相互作用来调节的。我们建议进行以下研究。 (1)我们将定义LPA2介导的生物学效应以及促进结直肠癌形成的潜在机制。 (2)我们将确定MAGI-3在调节结肠癌细胞中LPA2介导的信号传导中的作用。 (3)我们将通过使用转基因小鼠来描述LPA和LPA2在体内的作用。我们的研究将加深我们对LPA和LPA2受体在结直肠癌肿瘤发生中的重要性和机制的理解。我们的研究结果应该有助于结直肠癌治疗的发展。