EH-DOMAIN FROM EHD-1

来自 EHD-1 的 EH 域

• 批准号: 7954660
• 负责人: PAUL L SORGEN
• 金额: $ 0.35万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7954660
• 关键词: Address; Affect; Binding; C-terminal; CD29 Antigen; Cell Proliferation; Cell membrane; Cell physiology; Computer Retrieval of Information on Scientific Projects Database; Disseminated Malignant Neoplasm; Endocytosis; Event; Funding; Goals; Grant; Growth Factor Receptors; Immigration; Institution; Integrins; Laboratories; Lead; Malignant Neoplasms; Manuscripts; Molecular; Normal Cell; Phosphatidylinositols; Proteins; Receptor Signaling; Recycling; Regulation; Research; Research Personnel; Resources; Signal Transduction; Solutions; Source; Structure; United States National Institutes of Health; attenuation; base; cell motility; genetic regulatory protein; insight; novel; receptor; trafficking

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The main objective is to solve the structure of the EH-domain of the C-terminal Eps15 homology domain(EHD) protein, EHD1. We shall thus determine how it regulates endocytic transport and recycling of integrinand signaling receptors at the plasma membrane, and assess the impact of EHD1 on mitogenesis.A key cause of aberrant cell proliferation is the unchecked transduction of mitogenic signals by receptorslocalized to the plasma membrane. The internalization of growth factor receptors leads to attenuation ofstimulatory signals and receptors defective in endocytosis induce prolonged mitogenic effects. Subversion ofthe endocytic trafficking machinery is predicted to affect cell proliferation and lead to cancer. Recent studieshave also begun to address the endocytic itineraries of beta1 integrins, key receptors that interact with theextracellular matrix and coordinately transduce growth factor receptor signals that culminate in geneexpression, proliferation, and motility, thereby directly influencing cancer and metastatic potential.EHD1 is a central player in endocytic transport and recycling and we have recently demonstrated impairedb1 integrin recycling and localization to the plasma membrane as well as downstream events including cellspreading and migration in the absence of EHD1 (Jovic et al, manuscript submitted, Appendix I).Accordingly, the loss of EHD1 and/or its interactions with the network of proteins that regulate the endocyticmachinery disrupts normal cell function, and understanding the molecular basis by which the EH-domain ofEHD1 interacts with these regulatory proteins is a key goal of this proposal. Research in our laboratory hasidentified a novel function for EH-domains: direct binding to inositol phospholipids. However, the mode bywhich EH-domains interaction partners has yet to be determined. The proposed collaborative study will allowus to elucidate the molecular mechanisms of EHD1 function by NMR-based solution of the EHD1 EH-domainstructure, and provide novel insights into the functioning of this key protein and its regulation of integrins.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 主要目的是解决C末端Eps15同源结构域(EHD)蛋白EHD1的EH结构。因此，我们将确定它是如何调节细胞内质膜上整合素和信号受体的运输和循环的，并评估EHD1对有丝分裂的影响。细胞异常增殖的一个关键原因是定位在质膜上的受体对有丝分裂信号的无节制转导。生长因子受体的内化导致刺激信号的减弱，而内吞作用缺陷的受体则会导致长时间的有丝分裂效应。内吞运输机制的颠覆预计会影响细胞增殖并导致癌症。最近的研究也开始讨论β1整合素的胞内行程，它是与细胞外基质相互作用的关键受体，并协调地转导生长因子受体信号，最终导致基因表达、增殖和运动，从而直接影响癌症和转移潜能。EHD1是胞内运输和再循环的核心角色，我们最近证明，在没有EHD1的情况下，β1整合素的回收和定位受损，以及下游事件，包括细胞扩散和迁移(Jovic等，提交的手稿，附录I)。因此，EHD1的丢失和/或它与调节内细胞器的蛋白质网络的相互作用破坏了正常的细胞功能了解EHD1的EH结构域与这些调节蛋白相互作用的分子基础是这项提议的一个关键目标。我们实验室的研究已经确定了EH结构域的一个新功能：直接与肌醇磷脂结合。然而，EH域交互伙伴的模式尚未确定。这项合作研究将使我们能够通过基于核磁共振的EHD1 EH结构域结构的解决方案来阐明EHD1功能的分子机制，并为这一关键蛋白的功能及其对整合素的调节提供新的见解。