Urokinase Receptor-initiated Cell-Signaling

描述(申请人提供)：尿激酶型纤溶酶原结合 其受体uPAR的激活物(UPA)激活多种细胞信号 途径，包括Ras-ERKJMAP激酶途径，从而调节细胞 迁移、生长和细胞凋亡。UPAR启动的细胞信号转导对 低浓度的uPA，只需要3x103拷贝的细胞表面 UPAR。此外，在侵袭性癌细胞中，自分泌途径可能是 建立了内源性产生的uPA与uPAR的结合 负责维持较高的基础激活ERK水平。我们假设 UPAR启动的细胞信号转导是癌细胞的主要决定因素 体内的攻击性。本研究项目的主要目的是阐明 UPA-uPAR细胞信号系统。具体目标1重点放在基本 UPAR启动的细胞信号的生物化学。建议进行研究以 描述与细胞信号有关的上调连接的动力学， 确定细胞如何整合uPAR和整合素启动的细胞信号 反应，决定互补通路的功能，如RAS-ERK 和RhoRho-Kinase通路，并识别关闭的反馈环路 UPAR结扎后的细胞信号传导。我们还将解决这样一种可能性 UPAR可能部分通过uPA非依赖性机制调节细胞信号。在……里面 具体目标2，我们将检验我们的假设，即uPA启动的细胞信号 反映了包括纤溶酶原在内的生化系统的活性， 纤溶酶原激活物抑制物-1(PAI-1)、其他蛇酶和低密度脂蛋白受体 同系物，如VLDLr受体。具体目标的主要目标2 是在体外重建由uPAR启动的细胞信号转导系统 可能调节体内的细胞信号。在具体目标3中，翻译研究 建议将uPA-uPAR细胞信号系统表征为 新的抗癌治疗药物的开发。我们将研究…的活动 阻断uPA与uPAR结合的抗体及其与uPAR的结合 赫赛汀、顺铂或依托泊苷。我们还将开发新型嵌合体 可以快速分解uPA的受体，减少uPA的数量 可用于结扎上肢。拟议的研究提供了澄清 UPA和PAL-1的性质目前还不清楚，进一步我们的 了解这一关键的细胞调控系统，并制定新的策略 用来治疗癌症。

DESCRIPTION (provided by applicant): Binding of urokinase-type plasminogen activator (uPA) to its receptor, uPAR, activates diverse cell-signaling pathways, including the Ras-ERKJMAP kinase pathway, and thereby regulates cell migration, growth, and apoptosis. uPAR-initiated cell-signaling is sensitive to low concentrations of uPA and requires as few as 3x103 copies of cell-surface uPAR. Furthermore, in aggressive cancer cells, an autocrine pathway may be established in which binding of endogeneously-produced uPA to uPAR is responsible for maintaining a high basal level of activated ERK. We hypothesize that uPAR-initiated cell-signaling is a major determinant of cancer cell aggressiveness in vivo. The major goal of this research project is to elucidate the uPA-uPAR cell-signaling system. Specific Aim 1 focuses on the basic biochemistry of uPAR-initiated cell-signaling. Studies are proposed to characterize the kinetics of uPAR-ligation in relation to cell-signaling, determine how the cell integrates uPAR- and integrin-initiated cell-signaling responses, determine the function of complementary pathways such as the Ras-ERK and RhoRho-kinase pathways, and identify feedback-loops that shut-down cell-signaling after uPAR ligation. We will also address the possibility that uPAR may regulate cell-signaling, in part by uPA-independent mechanisms. In Specific Aim 2, we will test our hypothesis that uPA-initiated cell-signaling reflects the activity of a biochemical system that includes plasminogen, plasminogen activator inhibitor-1(PAI-1), other Serpins, and LDL receptor homologues, such as the VLDL receptor (VLDLr). A major goal of Specific Aim 2 is to reconstitute uPAR-initiated cell-signaling in vitro with components that may regulate cell-signaling in vivo. In Specific Aim 3, translational studies are proposed to characterize the uPA-uPAR cell-signaling system as a target for the development of novel anticancer therapeutics. We will study the activity of antibodies that block uPA-binding to uPAR alone and in combination with herceptin, cisplatin or etoposide. We will also develop novel chimeric receptors that may rapidly catabolize uPA, decreasing the amount of uPA available to ligate uPAR. The proposed studies offer the potential to elucidate properties of uPA and PAL-1 that are not currently understood, further our understanding of this key cell-regulatory system, and generate novel strategies for treating cancer.