Urokinase Receptor-initiated Cell-signaling

尿激酶受体启动的细胞信号传导

• 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
• 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

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）：该研究项目重点关注尿激酶受体（uPAR），这是一种多功能 GPI 锚定膜蛋白，与乳腺癌进展有关。我们的长期目标是了解 uPAR 调节癌细胞生理学的机制。 uPAR 至少结合两个配体：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连蛋白。在质膜内，uPAR 与整合素、G 蛋白偶联受体和受体酪氨酸激酶 (RTK) 横向结合。这些“共受体”相互作用导致动态多蛋白信号受体复合物（MSRC）的形成。 uPA 和玻连蛋白激活 uPAR 依赖性细胞信号传导；然而，途径是不同的。 uPA 结合激活 ERK/MAP 激酶，而玻连蛋白则激活 Rad。其他信号蛋白，例如 STAT-5b，可能会被招募到 uPAR 下游，具体取决于 MSRC 中与 uPAR 相关的共受体。共受体还决定细胞反应的性质，例如 uPA 是否具有促有丝分裂作用。在此应用中，提出了四个具体目标。在目标 1 中，我们建议阐明从 uPAR 到 Rac1 的途径，并确定单个受体 (uPAR) 与两个不同配体（uPA 或玻连蛋白）的连接引起完全不同的细胞信号传导反应的机制。目标 2 建立在初步数据的基础上，我们已经证明 uPAR 过表达会诱导上皮间质转化 (EMT)，这是一种与癌症进展相关的众所周知的过程，其中上皮细胞采用成纤维细胞样形态，失去细胞-细胞接触，表现出波形蛋白表达增加和 E-钙粘蛋白表达减少。目标 2 中计划的实验将确定 uPAR 诱导 EMT 的机制。在目标 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癌细胞对 uPA 的反应，还调节癌细胞对 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，在目标 4 中，我们提出研究以确定 uPAR 依赖性细胞信号传导是否参与体内癌症的发生和进展。将应用异种移植和自发性肿瘤小鼠模型系统。这些研究将阐明 uPAR 在癌症中的作用，并提供有关如何将 uPAR 应用于新型癌症治疗设计的关键信息。