LPA receptor signaling in colonic epithelia

描述(由申请人提供)：我们的长期目标是了解肠上皮细胞的信号机制，重点是蛋白质-蛋白质相互作用如何影响信号过程的特异性和有效性。溶血磷脂酸(LPA)具有生长因子样效应。LPA的信号转导主要通过一系列G蛋白偶联受体LPA、LPA2和LPA3来实现。尽管对LPA信号的研究已有十多年的历史，但受体亚型特异的信号转导和功能仍不完全清楚。然而，这些知识是合理设计针对新中间体和关键途径的治疗干预措施的关键。我们最近发现，LPA2在几种类型的癌症中表达增加，包括结肠癌。这一观察结果表明，LPA2可能在促进肿瘤发展的过程中发挥重要的病理生理作用，因此有必要更好地了解LPA2所引发的信号通路和机制。我们的研究表明，LPA激活了转录因子KLF5，KLF5是肠道细胞增殖的促进剂，提示KLF5可能是LPA生物学效应的中间转导因子。最近，我们和其他人也证明了LPA2与支架蛋白NHERF2相互作用。此外，我们还发现MAGI-3是另一种LPA2结合蛋白。我们的初步研究表明，MAGI-3在LPA2介导的信号转导中的作用是独特的，MAGI-3对LPA介导的信号转导具有负面影响。我们的数据表明，不同条件下LPA信号差异的一个原因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学效应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)我们将确定LPA2介导的生物学效应和促进结直肠癌形成的潜在机制。(2)我们将确定MAGI-3在LPA2介导的结肠癌细胞信号转导中的作用。(3)利用转基因小鼠研究LPA和LPA2在体内的作用。我们的研究将加深我们对LPA和LPA2受体在结直肠癌发生中的重要性和作用机制的认识。我们的发现将有助于结直肠癌治疗的发展。

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.