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期间介导细胞增殖，分化，生存，迁移和分化以及它们的过表达和/或过度活性在许多人类癌中的发病直接相关。 ERBB受体激活还启动了细胞保护信号传导，该信号限制了通过放射线和/或化学疗法杀死肿瘤的程度，它们的抑制作用代表了肿瘤的放射和化学敏化的重要策略。因此，阐明ERBB受体信号传导的新颖方面是癌症生物学的主要目标。配体与ERBB受体的结合诱导内体的快速识别，然后是分类过程，将其靶向溶酶体降解或回收利用。相当出乎意料的是，最近的研究表明，活化的ERBB受体在内部化后继续发出信号。信号传导内体室的性质，内体中发生的特定信号事件以及调节活化ERBB受体传递到这些信号室中的细胞机制仍然未知。许多实验发现导致我们假设SRC酪氨酸激酶是内体室内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，我们将与或不具有SRC的过表达EGFR或ERBB2过表达EGFR或ERBB2的永生，非肿瘤性人类乳腺上皮细胞（MEC），与或不具有SRC，这对乳房和其他癌症中这些酪氨酸激酶的共骨表达进行了模拟。我们将首先确定SRC是MEC中ERBB受体信号和生物反应的积极调节剂。然后，我们将使用两色成像和生化分析来确定内吞途径内SRC和ERBB2的共定位，并确定其居住的特定隔室。我们将进行分析，以评估内体ERBB受体-SRC复合物是否信号并确定此类信号及其生物学后果的性质，并使用内吞区室内的SRC激酶抑制和转运扰动。对我们的假设的验证将代表ERBB受体信号传导的当前范式的重大转变，并将为SRC过表达的作用以及ERBB受体在乳腺癌和其他上皮癌中提供新颖的生化见解。我们的研究可能会确定与ERBBAND SRC过表达的人类癌症有关的治疗干预措施的新靶标。