Targeting Endocytic Recycling of EGF Receptor in Cancer

靶向癌症中 EGF 受体的内吞再循环

基本信息

批准号：
8788739
负责人：
Hamid Band
金额：
$ 4.62万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-07-01 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8788739
关键词：
ATP phosphohydrolase Accounting Address Animal Model Animals Antibodies Antineoplastic Agents Apoptosis Architecture Attenuated Autoimmunity Back Behavior Binding Biochemical Biological Breast Breast Cancer Cell C-terminal Cancerous Cell Culture Techniques Cell Proliferation Cell surface Cells Cellular biology Complex Development Diabetes Mellitus Dimerization Disease Effectiveness Endocytosis Endosomes Epidermal Growth Factor Receptor Epithelial Equilibrium ErbB Receptor Family Protein Event Experimental Models Family Fc Receptor Funding Future Genes Genetic Health Homeostasis Homo Human Hyperactive behavior In Vitro Knockout Mice Laboratories Laboratory Study Lead Learning Ligand Binding Ligands Link Lung Lysosomes Maintenance Malignant Neoplasms Mediating Modality Molecular Mus Mutation Normal Cell Nucleotides Oncogenic Output Pathway interactions Patients Pharmaceutical Preparations Physiological Play Preventive Process Protein Family Protein Tyrosine Kinase Proteins Radiation Reagent Receptor Activation Receptor Protein-Tyrosine Kinases Recycling Regulation Research Design Resistance development Role Route Signal Transduction Sorting - Cell Movement Structure Surface System Testing Therapeutic Tissues Ubiquitination Work Xenograft procedure anti-cancer therapeutic base cancer therapy chemotherapeutic agent chemotherapy design drug development in vivo insight kinase inhibitor malignant breast neoplasm member migration mouse model new therapeutic target novel novel strategies overexpression receptor receptor function response small molecule therapeutic target trafficking tumor progression tumorigenesis ubiquitin ligase

项目摘要

DESCRIPTION (provided by applicant): EGF receptor and other members of the ErbB family of receptor tyrosine kinases (RTKs) play essential physiological roles in development and maintenance of epithelial tissues by generating cell proliferation, survival, differentiation, and migration signals in response to specific ligands. Activation of ErbB receptors is also linked to the initiation and progression of human cancers. These RTKs have emerged as important therapeutic targets of anti-receptor antibodies and kinase inhibitors, although both therapeutic modalities suffer from rapid resistance development, necessitating alternate approaches to ErbB-targeted therapy. An essential pre-requisite for cellular response to EGFR and other RTK ligands is that an activation-competent pool of RTKs must be displayed on the cell surface. ErbB receptor overexpression increases this activation-ready pool. Sufficiently high levels of ErbB receptor overexpression induce ligand-independent activation, which can also be achieved by cancer-associated activating mutations. A fundamental feature of RTK function is that the newly synthesized as well as ligand-internalized receptors undergo a sorting process that determines whether they will recycle back to the cell surface for ligand binding and signaling or will be targeted for lysosomal degradation. We, and others, have shown that Cbl family of ubiquitin ligases are essential regulators of the lysosomal fate. Studies carried out by others and by us during the current funding period have led to a novel hypothesis that members of the C-terminal Eps15-homology (EH) domain-containing (EHD) protein family function as key regulators of the recycling fate of receptors. In this competing renewal application, we will employ unique EHD knockout mouse models and cellular reagents derived from these animals together with a vast array of immunological, biochemical and cellular reagents that have been generated to test the hypotheses: EHD protein-dependent endocytic recycling is a key controller of the cell surface display and recycling fate of EGFR; loss of EHD function will attenuate the ability of EGFR to propagate oncogenic signals in vitro and will abrogate EGFR-driven oncogenesis in vivo; and abrogation of endocytic recycling will enhance the efficacy of EGFR targeted therapy with an inhibitory antibody. Thus, this proposal will evaluate the endocytic recycling of EGFR as a novel therapeutic target in EGFR-driven cancer. Insights gained from these studies should further our understanding of the molecular and cell biological regulators of oncogenic signaling by RTKs, and help validate the endocytic recycling of RTKs as a new approach to rationally design anti-cancer agents to potentiate existing RTK-targeted therapies.

描述（由申请人提供）：EGF受体和ERBB受体酪氨酸激酶（RTKS）家族的其他成员通过产生细胞增殖，生存，分化和迁移信号来响应于特定的配体，从而在上皮组织的发展和维持中起着重要的生理作用。 ERBB受体的激活也与人类癌症的起始和进展有关。尽管两种治疗方法都均具有快速耐药性的发展，但这些RTK已成为抗受体抗体和激酶抑制剂的重要治疗靶标，但必须采取其他方法进行ERBB靶向疗法。细胞对EGFR和其他RTK配体的细胞反应的基本先决条件是，必须在细胞表面上显示功能能力的RTK库。 ERBB受体过表达增加了这种激活就绪的池。足够高的ERBB受体过表达诱导非配体非依赖性激活，这也可以通过癌症相关的激活突变来实现。 RTK函数的一个基本特征是，新合成的以及配体内部化受体经历了一个分类过程，该分类过程确定它们是否会回收到细胞表面，以进行配体结合和信号传导，还是将其靶向溶酶体降解。我们和其他人表明，泛素连接酶的CBL家族是溶酶体命运的重要调节剂。在当前的资助期间，他人和我们进行的研究导致了一个新的假设，即C末端EPS15-词素学（EH）结构域（EHD）蛋白质家族的成员是受体回收命运的关键调节剂。在这种竞争性更新应用中，我们将采用独特的EHD敲除鼠标模型和细胞试剂，并从这些动物中衍生出，以及已经生成的一系列免疫学，生化和细胞试剂来测试假设：EHD蛋白质依赖性的内核循环系统是细胞表面表面显示和侦探效果的钥匙控制者； EHD功能的丧失将减弱EGFR在体外传播致癌信号的能力，并消除EGFR驱动的体内造成的造成。内吞回收的废除将增强EGFR靶向治疗的抑制抗体的功效。因此，该提案将评估EGFR作为EGFR驱动癌症的新型治疗靶标的内吞回收。从这些研究中获得的见解应进一步理解RTK的分子和细胞生物学调节剂，并有助于验证RTK的内吞回收，这是一种合理设计抗癌药物的新方法，以增强现有的RTK靶向疗法。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

EHD4 is a novel regulator of urinary water homeostasis.

EHD4 是一种新型的尿水稳态调节剂。

DOI：
10.1096/fj.201601182rr
发表时间：
2017
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
0
作者：
Rahman,ShammaS;Moffitt,AlexandraEJ;Trease,AndrewJ;Foster,KirkW;Storck,MatthewD;Band,Hamid;Boesen,ErikaI
通讯作者：
Boesen,ErikaI