G Proteins and Their Receptors in Tumor Cell Metastasis

描述（由申请人提供）：转移涉及参与细胞运动的不同蛋白质沿着归巢受体、其配体和细胞外基质降解蛋白酶的表达。 近年来的研究发现，溶血磷脂酸（LPA）调控的信号通路在卵巢癌细胞的生长和转移中起着重要作用。 根据我们的初步调查结果，G？13（这可以激活LPA）和Hax-1相互作用所需的细胞运动，我们假设在这里，G？13-HAX-1-coronin相互作用在LPA反应性卵巢癌细胞的转移中起关键作用。 这一假设将在以下具体目标进行测试：目标1：G？13-Hax-1相互作用。 Hax-1与G？13和coronin的定点突变方法进行定义;目的2：分析G？13-Hax-1-corn复合物。 Hax-1、G？13，Cordyn和Rac在形成四元复合物和Hax-1和G？目的3：分析其他Hax-1相互作用的信号传导成分。 G？13-Hax-1复合物将通过分析特异性GEF和uPA和/或MMP 2的调节来鉴定;目的4：Hax-1对G？13：我们将调查是否G？13-Hax-1协会参与卵巢癌细胞的肿瘤生长;和目的5：G？13-Hax在肿瘤细胞迁移和转移中的作用。 Hax-1或G的作用？13关于卵巢癌细胞的迁移和侵袭潜力的研究将使用由马萨诸塞州总医院的Sandra Orsulic博士（Co-P.I）开发的新型小鼠模型系统进行分析。 我们希望，识别参与肿瘤细胞运动的信号位点，如这里所提出的，将定义新的治疗干预目标。

DESCRIPTION (provided by applicant): Metastasis involves the expression of different proteins involved in cell motility along with homing receptors, their ligands, and extracellular matrix degrading proteases. Recent studies have identified that the signaling pathways regulated by lysophosphatidic acid (LPA) play a critical role in ovarian cell growth and metastasis. Based on our preliminary findings that G?13 (which can be activated by LPA) and Hax-1 interaction is required for cell motility, we hypothesize here that G?13-HAX-1-cortactin interaction is critically involved in the metastasis of LPA-responsive ovarian cancer cells. This hypothesis will be tested under the following specific aims: Aim 1: Characterization of G?13-Hax-1 interaction. Hax-1 interaction sites with G?13 and cortactin will be defined by site-directed mutagenesis approach; Aim 2: Analysis of G?13-Hax-1-cortactin complex. The interrelationship of Hax-1, G?13, Cortactin, and Rac in forming the quadnary complex and the role of Hax-1 and G?13 in cortactin-phosphorylation will be defined; Aim 3: Analysis of other Hax-1 interacting signaling components. The target pathways regulated by G?13-Hax-1 complex will be identified by the analysis for specific GEFs and regulation of uPA and/or MMP2; Aim 4: Effect of Hax-1 on the oncogenic activity of G?13: We will investigate whether G?13-Hax-1 association is involved in neoplastic growth of ovarian cancer cells; and Aim 5: Role of G?13-Hax in tumor cell migration and metastasis. The role of Hax-1 or G?13 on the migration and invasive potentials of ovarian cancer cells will be analyzed using the novel mouse model system developed by Dr. Sandra Orsulic (Co-P.I) at Massachusetts General Hospital, Boston. We hope that the identification of a signaling locus involved in tumor cell motility, as proposed here, will define newer targets for therapeutic intervention.