Urokinase Receptor-initiated Cell-signaling

尿激酶受体启动的细胞信号传导

基本信息

批准号：
7909207
负责人：
STEVEN L. GONIAS
金额：
$ 27.35万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7909207
关键词：
1-Phosphatidylinositol 3-Kinase Adopted Affinity Agonist Animal Model Animals Basement membrane Binding Biological Biological Models Breast Cancer Cell Breast Carcinoma Cell Adhesion Cell Survival Cell membrane Cell physiology Cell surface Cells Complex Data Defect Development E-Cadherin Enzyme Precursors Enzymes Epidermal Growth Factor Epithelial Epithelial Cells Event Extracellular Matrix Proteins Extracellular Signal Regulated Kinases Feedback Fibroblasts Foundations G-Protein-Coupled Receptors Genes Genetic Transcription Goals Grant Growth Factor Infection Inflammatory Integrins Knockout Mice Learning Ligands Ligation Link Location Malignant Epithelial Cell Malignant Neoplasms Membrane Membrane Proteins Mesenchymal Metalcaptase Metalloproteases Mitogens Modeling Morphology Multiprotein Complexes Mus Nature Neoplasm Metastasis Neoplasms Non-Malignant Pathway interactions Peptide Hydrolases Plasmin Plasminogen Plasminogen Activator Platelet-Derived Growth Factor Process Property Protein Tyrosine Kinase Proteins Receptor Protein-Tyrosine Kinases Receptor Signaling Recruitment Activity Regulation Reporting Research Personnel Research Project Grants Rho-associated kinase Role SRC gene Serine Protease Signal Pathway Signal Transduction Signaling Protein System Testing Therapeutic Tissues Upper arm Urokinase Urokinase Plasminogen Activator Receptor Vimentin Vitronectin Work Xenograft procedure autocrine base cancer cell cell growth cell motility cell type design extracellular in vivo malignant breast neoplasm member migration mouse model novel programs receptor research study response tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): This research project focuses on the urokinase receptor (uPAR), a multifunctional GPI-anchored membrane protein that has been implicated in breast cancer progression. Our long-term goal is to understand mechanisms by which uPAR regulates cancer cell physiology. uPAR binds at least two ligands: the plasminogen activator, urokinase-type plasminogen activator (uPA), and the provisional extracellular matrix protein, vitronectin. Within the plasma membrane, uPAR laterally associates with integrins, G-protein coupled receptors, and receptor-tyrosine kinases (RTKs). These "co-receptor" interactions result in the formation of a dynamic, multiprotein signaling receptor complex (MSRC). uPA and vitronectin activate uPAR-dependent cell signaling; however, the pathways are distinct. uPA-binding activates ERK/MAP kinase whereas vitronectin activates Rad. Other signaling proteins, such as STAT-5b, may be recruited downstream of uPAR depending on the co-receptors that associate with uPAR in the MSRC. Co-receptors also determine the nature of the cellular response, such as whether uPA is mitogenic. In this application, four specific aims are proposed. In Aim 1, we propose to elucidate the pathway that leads from uPAR to Rac1 and determine the mechanism by which ligation of a single receptor (uPAR) with two distinct ligands (uPA or vitronectin) causes completely distinct cell signaling responses. Aim 2 builds on preliminary data in which we have demonstrated that uPAR over-expression induces epithelial-mesenchymal transformation (EMT), a well known process associated with cancer progression in which epithelial cells adopt a fibroblast-like morphology, lose cell-cell contacts, demonstrate increased vimentin expression and decreased E-cadherin expression. Experiments planned in Aim 2 will determine the mechanism by which uPAR induces EMT. In Aim 3, we will test the hypothesis that uPAR-dependent cell signaling regulates the response of cancer cells not only to uPA but also to growth factors such as EGF and PDGF. Understanding crosstalk between uPAR and RTKs is a critical objective. Finally, in Aim 4, we propose studies to determine whether uPAR-dependent cell signaling is involved in cancer development and progression in vivo. Xenograft and spontaneous neoplasia mouse-model systems will be applied. These studies will elucidate the role of uPAR in cancer and provide critical information regarding how uPAR may be targeted for novel cancer therapeutics design.

描述（由申请人提供）：该研究项目着重于尿激酶受体（UPAR），这是一种多功能的GPI锚定膜蛋白，与乳腺癌的进展有关。我们的长期目标是了解UPAR调节癌细胞生理的机制。 UPAR至少结合了两个配体：纤溶酶原激活剂，尿激酶型纤溶酶原激活剂（UPA）和临时细胞外基质蛋白玻璃体蛋白。在质膜内，UPAR侧向与整联蛋白，G蛋白偶联受体和受体 - 酪氨酸激酶（RTKS）相关。这些“共受体”相互作用导致形成动态的多蛋白信号受体复合物（MSRC）。 UPA和玻璃体素激活UPAR依赖性细胞信号传导；但是，路径是不同的。 UPA结合激活ERK/MAP激酶，而玻璃体蛋白激活RAD。其他信号蛋白（例如Stat-5b）可以根据MSRC中与UPAR相关的共受体下游募集。共受体还确定了细胞反应的性质，例如UPA是否具有有丝分裂。在此应用程序中，提出了四个具体目标。在AIM 1中，我们建议阐明从UPAR到RAC1导致的途径，并确定具有两个不同的配体（UPA或玻璃体）的单个受体（UPAR）的连接机制，从而导致完全不同的细胞信号反应。 AIM 2基于初步数据，在这些数据中，我们已经证明UPAR过表达诱导上皮 - 间质转化（EMT），这是一个与癌症进展相关的已知过程，在癌症的进展中，上皮细胞产生成纤维细胞样的形态，失去细胞细胞的接触，表现出增长的乙蛋白表达和降低的e-Cadherherin表达。在AIM 2中计划的实验将确定UPAR诱导EMT的机制。在AIM 3中，我们将检验以下假设：UPAR依赖性细胞信号传导不仅调节了癌细胞对UPA的反应，还调节了EGF和PDGF等生长因子的反应。了解UPAR和RTK之间的串扰是一个关键目标。最后，在AIM 4中，我们提出的研究以确定UPAR依赖性细胞信号传导是否参与体内癌症的发展和进展。异种移植物和自发的肿瘤小鼠模型系统将被应用。这些研究将阐明UPAR在癌症中的作用，并提供有关如何针对新型癌症治疗设计的关键信息。