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有效性。溶血磷脂酸（LPA）具有类似生长因子的作用。LPA信号主要通过g蛋白偶联受体家族LPA^ LPA2和LPA3介导。尽管对LPA信号传导的研究已经进行了十多年，但受体亚型特异性信号传导及其功能尚未完全阐明。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LPA2在包括结肠癌在内的几种类型的癌症中表达增加。这一观察结果表明，LPA2可能在促进癌症发展中发挥重要的病理生理作用，更好地了解LPA2引发的信号通路和机制是必要的。我们的研究表明，LPA激活了KLF5转录因子，KLF5是肠道细胞增殖的促进因子，提示KLF5可能是LPA生物学效应的中间转导。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，我们已经鉴定出MAGI-3是另一个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，MAGI-3对lpa2介导的信号传导有负作用。我们的数据表明，LPA信号在不同条件下出现差异的一个原因可能是存在或不存在相互作用的伙伴。基于这些数据，我们假设LPA2通过介导多种促进癌细胞增殖和存活的生物学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)明确LPA2介导的生物学效应及其促进结直肠癌形成的潜在机制。(2)我们将确定MAGI-3在结肠癌细胞中调控lpa2介导的信号通路中的作用。(3)我们将通过转基因小鼠来描述LPA和LPA2在体内的作用。我们的研究将加深我们对LPA和LPA2受体在结直肠癌发生中的重要性和机制的认识。我们的发现将有助于治疗结直肠癌的发展。

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.