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Molecular Analysis of Signal Transduction in Cell Migration

细胞迁移信号转导的分子分析

基本信息

批准号：
7578940
负责人：
JUN-LIN GUAN
金额：
$ 27.92万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
1992
资助国家：
美国
起止时间：
1992-08-01 至 2010-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7578940
关键词：
1-Phosphatidylinositol 3-Kinase Affect Binding Biological Models Biological Process Cell Adhesion Cell physiology Cells Complex Cytoplasmic Tail Dynamin Embryonic Development Epithelial Fibronectins Focal Adhesion Kinase 1 Focal Adhesions Funding Goals Grant Injection of therapeutic agent Integrins Knockout Mice Malignant Neoplasms Mammary gland Mediating Microfluidic Microchips Modeling Molecular Molecular Analysis Mus N-terminal Neoplasm Metastasis Nude Mice PH Domain Phosphatidylinositols Phosphorylation Phosphorylation Site Phosphotransferases Process Property Recruitment Activity Regulation Role Signal Pathway Signal Transduction Signaling Molecule Tail Veins Work Wound Healing cell motility cell transformation directional cell in vivo kinase inhibitor malignant breast neoplasm migration novel novel strategies response scaffold

项目摘要

The long term goal of the proposed studies is to understand the signal transduction mechanisms in the regulation of cell migration. Previous funding period focused on the role of focal adhesion kinase (FAK) and its downstream target Grb7 and a putative novel FAK inhibitor FIP200 in the regulation of cell migration. We identified and characterized Grb7 interaction with phosphoinositides through its PH domain and a role for Grb7 in mediating EphB1 stimulation of cell migration, showed the critical importance of focal contacts localization of the FAK signaling complexes, and characterized FIP200 inhibition of FAK activity and cell migration. We also found an interaction between FAK and N-WASP and showed that FAK phosphorylation of N-WASP regulates N-WASP subcellular localization and promotion of cell migration. In addition, we found an interaction between integrin p1 and 14-3-3p and studied the role of 14-3-3p in the regulation of cell spreading and migration, and an intra-molecular interaction between the N-terminal FERM-like domain and the kinase domain of FAK that regulate FAK activation in an auto-inhibitory mechanism. In preliminary studies, we identified an interaction between FAK and endophilin A2 and showed that endophilin A2 association with FAK and phosphorylation by FAK/Src complex regulated its interaction with dynamin and affected invasion of Src transformed cells. We are also in the process of creating mammary epithelial-specific FAK conditional knockout mice to study the role of FAK and its interaction with endophilin A2 in breast cancer metastasis in vivo. Lastly, to facilitate studies of directional cell migration on ECMgradients which better mimic in vivo conditions, we fabricated microfluidics devices to generate defined and quantitative FN gradients and showed directional cell migration on the gradients with novel properties. In this proposal, we will 1) determine the mechanism and role of FAK interaction with endophilin A2 in the regulation of cell migration and invasion, 2) investigate the potential role of FAK and its interaction with endophilin A2 in cancer metastasis in vivo, and 3) analyze the responses and roles of FAK and other signaling molecules in directional cell migration on defined FN gradients. These studies will enhance our understanding of the molecular mechanisms of signal transduction in cell migration and invasion which are critical factors in biological processes such as embryonic development, wound healing and cancer.

这些研究的长期目标是了解细胞内的信号转导机制。调节细胞迁移。上一个资助期的重点是粘着斑激酶（FAK）的作用，其下游靶点Grb 7和一种新的FAK抑制剂FIP 200在细胞迁移调控中的作用。我们鉴定并表征了Grb 7通过其PH结构域与磷酸肌醇的相互作用， Grb 7介导EphB 1刺激细胞迁移，显示了焦点接触的关键重要性定位FAK信号复合物，并表征FIP 200对FAK活性和细胞增殖的抑制作用。迁移我们还发现了FAK和N-WASP之间的相互作用，并表明FAK磷酸化调节N-WASP的亚细胞定位和促进细胞迁移。此外，我们还发现，整合素p1与14-3- 3 p的相互作用，研究了14-3- 3 p在细胞凋亡调控中的作用。扩散和迁移，以及N-末端FERM样结构域和蛋白质之间的分子内相互作用。在自身抑制机制中调节FAK活化FAK激酶结构域。在初步研究中，我们鉴定了FAK和内亲和素A2之间的相互作用， FAK/Src复合物的磷酸化调节了其与发动蛋白的相互作用， Src转化细胞的侵袭。我们也在创造乳腺上皮特异性FAK的过程中，用条件性基因敲除小鼠研究FAK及其与endophilin A2的相互作用在乳腺癌中的作用体内转移。最后，为了便于研究ECM梯度上的定向细胞迁移，模拟体内条件，我们制造了微流体装置，以产生确定和定量的FN 梯度，并显示出具有新特性的梯度上的定向细胞迁移。在本提案中，我们将1）确定FAK与内啡肽A2相互作用的机制和在细胞调节中的作用， 2）研究FAK及其与内亲和素A2的相互作用， 3）分析FAK和其他信号分子在肿瘤转移中的反应和作用，在确定的FN梯度上定向细胞迁移。这些研究将增进我们对细胞迁移和侵袭中的信号转导的分子机制是细胞增殖的关键因素。生物过程，如胚胎发育、伤口愈合和癌症。