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Pathogenesis of cancer: Role of EGF receptor endocytosis

癌症发病机制：EGF 受体内吞作用的作用

基本信息

批准号：
8676443
负责人：
ALEXANDER D SORKIN
金额：
$ 32.73万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-12 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8676443
关键词：
Acetylation Advanced Development Binding C-terminal Cancer Cell Growth Cell surface Cells Clathrin Color Complex Cultured Cells Data Databases Degradation Pathway Deubiquitination Development Down-Regulation EGFR Protein Overexpression Endocytosis Endosomes Enzymes Epidermal Growth Factor Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Epithelial Family Growth Factor Head and Neck Cancer Head and Neck Squamous Cell Carcinoma Image In Vitro Intervention Libraries Life Ligands Link Lysine Lysosomes Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of lung Mass Spectrum Analysis Mediating Modeling Modification Molecular Mus Non-Small-Cell Lung Carcinoma Oncogenic Optical Methods Pathogenesis Pathway interactions Pattern Pharmacologic Substance Physiological Play Post-Translational Protein Processing Process Proteins RNA Interference Reagent Receptor Activation Receptor Down-Regulation Receptor Protein-Tyrosine Kinases Receptor Signaling Regulation Relative (related person)Resistance Resolution Role Signal Transduction Sorting - Cell Movement Testing Time Tongue Transgenic Mice Tumor Cell Line Ubiquitin Ubiquitination Xenograft Model cancer cell cancer therapy cell growth cell motility cellular imaging in vivo in vivo Model inhibitor/antagonist intravital imaging member mouse model mutant neoplastic cell new technology novel outcome forecast receptor receptor expression receptor internalization research study screening signal processing small molecule stem subcutaneous therapeutic target tool trafficking tumor tumor growth tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Elucidation of the physiological regulation of epidermal growth factor receptor (EGFR) is the key to understanding of the mechanisms causing its oncogenic activation. Growth factor binding to the EGFR triggers the signal transduction process. Receptor activation also causes rapid internalization and degradation of EGFR in lysosomes, leading to receptor down-regulation. This endocytic trafficking determines the number of active receptors in the cell and, therefore, the intensity and duration of signaling. Endocytosis also orchestrates EGFR signaling network by determining the localization and temporal dynamics of signaling processes. Importantly, EGFR endocytosis is frequently dysregulated in tumor cells. However, the mechanisms of EGFR endocytosis and the role of endocytosis and signaling remain to be poorly understood. During the previous cycle of this project we have defined the molecular mechanisms of EGFR degradation and ubiquitination, the major modification of the receptor that controls EGFR endocytosis. We have also demonstrated the complexity of the internalization step of EGFR endocytosis that is mediated by multiple redundant mechanisms. One of these mechanisms involves a novel post-translational modification of EGFR by acetylation. We have also developed new reagents, such as degradation- and internalization-impaired EGFR mutants, and used these new tools to demonstrate unexpected inhibitory effects of impaired EGFR internalization on tumorigenic signaling. Stemming from the new data and based on the availability of new technologies, such as high-resolution intravital imaging of tumors, ultra-fast confocal imaging of living cultured cells and quantitative mass-spectrometry, we propose to define the molecular mechanisms of EGFR internalization in tumor cell lines and in vivo models and examine the role of EGFR endocytosis in signaling in tumor models in vivo. The specific aims of this proposal are: 1) define the mechanisms of EGFR endocytosis, including the mechanisms and role of EGFR acetylation, under physiological conditions in cancer cells in vitro and in vivo in mouse xenograft models of head-and-neck cancer; 2) examine the effects of inhibited endocytosis and degradation of EGFR on tumor growth in mouse xenograft models and transgenic mouse inducible model of lung cancer; 3) define the regulatory mechanisms of EGFR ubiquitination and deubiquitination, and examine the potential of EGFR-specific deubiquitination enzymes as therapeutic targets in EGFR-dependent tumors.

描述（由申请人提供）：阐明表皮生长因子受体（EGFR）的生理调节是理解导致其致癌激活的机制的关键。生长因子与 EGFR 结合会触发信号转导过程。受体激活还会导致 EGFR 在溶酶体中快速内化和降解，从而导致受体下调。这种内吞运输决定了细胞中活性受体的数量，从而决定了信号传导的强度和持续时间。内吞作用还通过确定信号传导过程的定位和时间动态来协调 EGFR 信号传导网络。重要的是，EGFR 内吞作用在肿瘤细胞中经常失调。然而，EGFR 内吞作用的机制以及内吞作用和信号传导的作用仍然知之甚少。在该项目的上一个周期中，我们定义了 EGFR 降解和泛素化的分子机制，这是控制 EGFR 内吞作用的受体的主要修饰。我们还证明了 EGFR 内吞作用的内化步骤的复杂性，该步骤是由多种冗余机制介导的。这些机制之一涉及通过乙酰化对 EGFR 进行新型翻译后修饰。我们还开发了新的试剂，例如降解和内化受损的 EGFR 突变体，并使用这些新工具来证明受损的 EGFR 内化对致瘤信号传导的意外抑制作用。基于新数据和新技术的可用性，例如肿瘤的高分辨率活体成像、活体培养细胞的超快共焦成像和定量质谱分析，我们建议定义肿瘤细胞系和体内模型中EGFR内化的分子机制，并研究EGFR内吞作用在体内肿瘤模型信号传导中的作用。该提案的具体目标是： 1) 明确头颈癌小鼠异种移植模型中体外和体内癌细胞生理条件下 EGFR 内吞作用的机制，包括 EGFR 乙酰化的机制和作用； 2）在小鼠异种移植模型和转基因小鼠肺癌诱导模型中检测抑制EGFR内吞作用和降解对肿瘤生长的影响； 3）定义EGFR泛素化和去泛素化的调节机制，并研究EGFR特异性去泛素化酶作为EGFR依赖性肿瘤治疗靶点的潜力。