Regulation of Ras and Rho Family GTPases in Lung Cancer

描述(由申请人提供)：RAS和RHO家族中多个小GTP酶的激活促进了非小细胞肺癌(NSCLC)细胞的增殖和迁移，从而促进了NSCLC肿瘤的发生和转移。令人惊讶的是，关于小GTP酶是如何在NSCLC细胞中被激活以促进肿瘤发生和转移的，人们知之甚少。我们的研究表明，独特的鸟嘌呤核苷酸交换因子SmgGDS是NSCLC中小GTP酶活性的主要调节因子。SmgGDS唯一地激活RAS和RHO家族中的多个小GTP酶。我们先前报道SmgGDS在NSCLC肿瘤中高水平表达，并刺激NSCLC细胞的增殖和迁移。我们最近发现，非小细胞肺癌细胞表达多种形式的SmgGDS。我们的结果支持不同形式的SmgGDS促进小GTP酶K-RAS、rac1、RhoA、Rap1A和Rap1B的翻译后加工的模型。该模型将在以下目标中进行测试。目的：明确不同形式的SmgGDS在非小细胞肺癌患者肿瘤及细胞系中的表达。目的2：确定SmgGDS的哪种形式以及与SmgGDS相互作用的哪些小GTP酶对NSCLC细胞的增殖、迁移、肿瘤形成和实验性转移有最大贡献。目的3：研究不同形式的SmgGDS如何调控非小细胞肺癌中不同小GTP酶的活性、翻译后加工和亚细胞定位。这项研究将确定SmgGDS在非小细胞肺癌中调节K-RAS、rac1、RhoA、Rap1A和Rap1A活性的独特能力，并将有助于确定这些蛋白在肺癌中的治疗潜力。 与公共健康相关：肺癌细胞会产生一组名为“小GTP酶”的蛋白质。当这些小的GTP酶在肺癌细胞中被激活时，它们诱导肺癌细胞增殖和迁移，从而促进肿瘤的发生和转移。我们的实验室正在研究这些小GTP酶是如何在肺癌中被激活的，因为这些信息将帮助我们设计新的方法来阻止小GTP酶的激活，从而阻止肺癌的发生和转移。我们发现，一种名为SmgGDS的蛋白质能激活肺癌细胞中的小GTP酶，并在患者的肺癌中大量合成。我们提出的研究将定义SmgGDS如何在肺癌中激活不同的小GTP酶。这项研究可能会发现小的GTP酶在肺癌中是如何被激活的，从而可能找到新的方法来阻止这些蛋白促进肺癌的发生和转移。

DESCRIPTION (provided by applicant): Activation of multiple small GTPases in the Ras and Rho families promotes the proliferation and migration of non-small cell lung carcinoma (NSCLC) cells, which contributes to NSCLC tumorigenesis and metastasis. Surprisingly little is known about how small GTPases are activated in NSCLC cells to promote tumorigenesis and metastasis. Our research indicates that the unique guanine nucleotide exchange factor known as SmgGDS is a major regulator of small GTPase activity in NSCLC. SmgGDS uniquely activates multiple small GTPases in the Ras and Rho families. We previously reported that SmgGDS is expressed at high levels in NSCLC tumors and stimulates the proliferation and migration of NSCLC cells. We recently discovered that NSCLC cells express several forms of SmgGDS. Our results support the model that different forms of SmgGDS promote post-translational processing of the small GTPases K-Ras, Rac1, RhoA, Rap1A, and Rap1B. This model will be tested in the following aims. Aim1: Define the expression of different forms of SmgGDS in NSCLC tumors from patients and in NSCLC cell lines. Aim 2: Determine which form of SmgGDS and which of the small GTPases that interact with SmgGDS contribute the most to NSCLC cell proliferation, migration, tumorigenesis, and experimental metastasis. Aim 3: Characterize how different forms of SmgGDS regulate the activity, post-translational processing, and subcellular localization of different small GTPases in NSCLC. This research will define the unique ability of SmgGDS to regulate the activities of K-Ras, Rac1, RhoA, Rap1A, and Rap1A in NSCLC, and will help determine the therapeutic potential of these proteins in lung cancer. PUBLIC HEALTH RELEVANCE: Lung cancer cells make a group of proteins called "small GTPases". When these small GTPases are activated in lung cancer cells, they induce the lung cancer cells to proliferate and migrate, which promotes tumorigenesis and metastasis. Our laboratory is investigating how these small GTPases are activated in lung cancer, because this information will help us design new ways to stop the activation of small GTPases, and thereby stop lung cancer tumorigenesis and metastasis. We found that a protein called SmgGDS activates small GTPases in lung cancer cells and is made in high amounts in lung tumors from patients. Our proposed research will define how SmgGDS activates different small GTPases in lung cancer. This research may discover how small GTPases are activated in lung cancer and thus may identify new approaches to stop these proteins from promoting lung cancer tumorigenesis and metastasis.