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Role of the RhoGEF Net1 in breast cancer cell motility and metastasis

RhoGEF Net1 在乳腺癌细胞运动和转移中的作用

基本信息

批准号：
8697496
负责人：
Jeffrey A. Frost
金额：
$ 31.54万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8697496
关键词：
Acetylation Actomyosin Address Affect Automobile Driving Biological Assay Breast Cancer Cell Breast Cancer Treatment Cell Nucleus Cell Proliferation Cell membrane Cells Cytoskeletal Gene Cytoskeletal Modeling Data Deacetylase Defect Development Disease EGF gene ERBB2 gene Epidermal Growth Factor Receptor Extracellular Matrix Focal Adhesions GTP-Binding Proteins Gene Expression Genes Genetic Growth Factor Receptors Guanine Nucleotide Exchange Factors HDAC6 gene Histone Deacetylase Human In Vitro Integrins Intervention Knockout Mice Ligands MMP14 gene Malignant Neoplasms Mammary Neoplasms Mammary gland Mediator of activation protein Mesenchymal Metastatic to Mitotic Molecular Movement Mus Mutation Neoplasm Metastasis Neuroepithelial Nodal Oncogenes Oncogenic PTK2 gene Phosphorylation Process Protein Family Protein Isoforms Proteins Receptor Activation Role Signal Transduction Site Tubulin United States Woman Work ameboid movement base cancer cell cell motility cell transformation in vivo killings malignant breast neoplasm mammary gland development new therapeutic target novel novel therapeutics overexpression prevent public health relevance rho rho GTP-Binding Proteins tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Molecular mechanisms controlling metastasis in breast cancer are not well understood. During invasion of the extracellular matrix (ECM) cancer cells alternate between fast, amoeboid, and slow mesenchymal types of movement. This plasticity in movement is essential for efficient invasion, but it is not well understood how it is controlled. We have found that the RhoGEF Net1A is an important regulator of invasion plasticity in breast cancer cells, stimulating amoeboid and suppressing mesenchymal movement. Net1A regulates this process by controlling RhoA and deacetylase function to impact cytoskeletal organization and gene expression. Net1A is exceptional among RhoGEFs in that it is sequestered in the nucleus to prevent aberrant RhoA activation, and it is clear that subcellular localization is a key determinant of the oncogenic potential of Net1 isoforms. Recently we have shown that Rac1 activation downstream of integrin or growth factor receptor activation stimulates Net1A relocalization to the plasma membrane. We have also found that Net1A relocalization is maintained by site-specific acetylation, and that the actions of specific deacetylases are critical to suppressing Net1A activity towards RhoA. Moreover, we have observed that Net1A reciprocally controls the activity of specific deacetylases to regulate cytoskeletal organization and expression of key genes associated with cell invasion, such as MT1-MMP. These findings support our hypothesis that that Net1A functions as a nodal point to temporally and spatially regulate RhoA activation and deacetylase activity which underlie breast cancer cell motility, invasion and metastasis. In this proposal we will use a combination of cell-based and in vivo assays to understand how Net1A localization is regulated to drive RhoA activation and reciprocally control deacetylase activity during ECM invasion. We will also determine how Net1 isoforms contribute to mammary gland tumorigenesis and metastasis in vivo. In Aim 1 we will demonstrate how EGFR and HER2 activation stimulates Net1A export from the nucleus to stimulate cell motility and ECM invasion. We will demonstrate how Net1A acetylation affects its function and identify the deacetylases that regulate Net1A. In Aim 2 we will determine how Net1A controls HDAC and Sirtuin function to regulate acetylation of cytoskeletal organizing proteins and gene expression. In Aim 3 we will identify the molecular basis for how genetic deletion of Net1 affects mammary gland development in mice, and determine whether Net1 is required for HER2/Neu driven mammary gland tumorigenesis and metastasis. Completion of these aims will provide a mechanistic understanding of how Net1 isoforms contribute to breast cancer cell motility and invasive potential, and will provide novel targets for intervention in metastatic disease.

描述（申请人提供）：控制乳腺癌转移的分子机制尚不清楚。在侵袭细胞外基质（ECM）期间，癌细胞在快速、变形虫和缓慢的间充质类型运动之间交替进行。这种运动的可塑性对于有效的入侵是必不可少的，但它是如何被很好地理解的