Endosomal ErbB Receptor and Src Signaling in Cancer

癌症中的内体 ErbB 受体和 Src 信号转导

• 批准号: 6916571
• 负责人: Hamid Band
• 金额: $ 31.16万
• 依托单位: NORTHSHORE UNIVERSITY HEALTHSYSTEM
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6916571
• 关键词: athymic mouse; biological signal transduction; epidermal growth factor; growth factor receptors; ligands; mammary epithelium; neoplasm /cancer genetics; pathologic process; protein localization; protein protein interaction; protein structure function; protein tyrosine kinase; protooncogene; receptor binding; regulatory gene; tissue /cell culture; transfection; vesicle /vacuole

DESCRIPTION (provided by applicant): ErbB receptor tyrosine kinases play essential physiological roles in mediating cell proliferation, differentiation, survival, migration and differentiation during development and tissue homeostasis, and their overexpression and/or hyperactivity are directly linked to oncogenesis in a number of human cancers. ErbB receptor activation also initiates cytoprotective signaling that limits the extent of tumor killing by radiation and/or chemotherapy, and their inhibition represents an important strategy for radio- and chemo-sensitization of tumors. Elucidating novel aspects of ErbB receptor signaling is therefore a major goal in cancer biology. Ligand binding to ErbB receptors induces rapid intemalization into endosomes followed by a sorting process to target them to lysosomal degradation or for recycling. Rather unexpectedly, recent studies have shown that activated ErbB receptors continue to signal after their internalization. The nature of the signaling endosomal compartment(s), the specific signaling events that take place in endosomes, and the cellular mechanisms that regulate the delivery of activated ErbB receptors into these signaling compartments remain unknown. A number of experimental findings lead us to postulate a novel role for Src tyrosine kinase as a positive regulator and/or mediator of ErbB signaling within the endosomal compartment. To test our hypotheses, we will compare immortalized, non-tumorigenic human mammary epithelial cells (MECs) with their isogenic derivatives overexpressing EGFR or ErbB2 with or without Src, which models the co-overexpression of these tyrosine kinases in breast and other cancers. We will first establish that Src is a positive regulator of ErbB receptor signals and biological responses in MECs. We will then use two-color imaging and biochemical analyses to determine the colocalization of Src and ErbB2 within the endocytic pathway, and identify the specific compartment in which they reside. We will carry out analyses to assess if endosomal ErbB receptor-Src complexes signal and determine the nature of such signals and their biological consequences, using Src kinase inhibition and perturbations of transport within the endocytic compartments. Validation of our hypotheses will represent a major shift in the current paradigm of ErbB receptor signaling, and will provide novel biochemical insights into the role of Src overexpression together with ErbB receptors in breast and other epithelial cancers. Our studies may identify novel targets for therapeutic intervention relevant to ErbBand Src-overexpressing human cancers.

描述（由申请人提供）：ErbB 受体酪氨酸激酶在发育和组织稳态过程中介导细胞增殖、分化、存活、迁移和分化中发挥重要的生理作用，并且它们的过度表达和/或过度活跃与许多人类的肿瘤发生直接相关。癌症。 ErbB 受体激活还启动细胞保护信号传导，限制放射和/或化学疗法杀死肿瘤的程度，并且它们的抑制代表了肿瘤放射和化学敏化的重要策略。因此，阐明 ErbB 受体信号传导的新方面是癌症生物学的一个主要目标。与 ErbB 受体结合的配体会诱导快速内化到内涵体中，然后进行分选过程，将其靶向溶酶体降解或回收。出乎意料的是，最近的研究表明，激活的 ErbB 受体在内化后继续发出信号。信号传导室的性质、发生在内涵体中的特定信号传导事件以及调节激活的 ErbB 受体递送至这些信号传导室的细胞机制仍然未知。许多实验结果使我们推测 Src 酪氨酸激酶作为内体区室内 ErbB 信号传导的正调节剂和/或介体的新作用。 为了检验我们的假设，我们将比较永生化、非致瘤性人乳腺上皮细胞 (MEC) 及其在有或没有 Src 的情况下过表达 EGFR 或 ErbB2 的同基因衍生物，这模拟了这些酪氨酸激酶在乳腺癌和其他癌症中的共过表达。我们将首先确定 Src 是 MEC 中 ErbB 受体信号和生物反应的正调节因子。然后，我们将使用双色成像和生化分析来确定 Src 和 ErbB2 在内吞途径中的共定位，并识别它们所在的特定区室。我们将利用 Src 激酶抑制和内吞室内运输的扰动进行分析，以评估内体 ErbB 受体-Src 复合物是否发出信号，并确定此类信号的性质及其生物学后果。我们假设的验证将代表当前 ErbB 受体信号传导模式的重大转变，并将为 Src 过度表达与 ErbB 受体在乳腺癌和其他上皮癌中的作用提供新的生化见解。我们的研究可能会确定与 ErbBand Src 过度表达的人类癌症相关的治疗干预的新靶点。