Role of Focal Adhesion Kinase in Tumorigenesis

粘着斑激酶在肿瘤发生中的作用

• 批准号: 7476132
• 负责人: David D Schlaepfer
• 金额: $ 19.34万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7476132
• 关键词: 1-Phosphatidylinositol 3-Kinase; Achievement; Adaptor Signaling Protein; Adenocarcinoma Cell; Affect; Angiogenic Factor; Anoikis; Binding; Biological Assay; Breast Carcinoma; C-terminal; Cell Survival; Cells; Complex; Condition; Defect; Development; Dominant-Negative Mutation; Epitopes; Event; Extracellular Matrix Proteins; Extracellular Signal Regulated Kinases; Family; Focal Adhesion Kinase 1; Focal Adhesions; Future; Gene Expression; Gene Expression Alteration; Goals; Growth; Growth Factor; Growth Factor Receptors; Human; In Vitro; Integrins; Invasive; Knowledge; Localized; MAPK8 gene; Maintenance; Malignant Epithelial Cell; Mediating; Messenger RNA; Metalloproteases; Molecular; Mus; Neoplasm Metastasis; Normal Cell; Null Lymphocytes; Numbers; Phosphotransferases; Process; Protein Overexpression; Publishing; Receptor Signaling; Regulation; Role; SH3 Domains; Signal Pathway; Signal Transduction; Site; Solid Neoplasm; Structure; Testing; Therapeutic; Tyrosine; Tyrosine Phosphorylation; Validation; Work; adenoviral-mediated; angiogenesis; cell behavior; cell growth; cell motility; cell transformation; design; human BCAR1 protein; in vivo; innovation; kinase inhibitor; mRNA Expression; mutant; neoplastic cell; neovascularization; receptor; reconstitution; tumor growth; tumor progression; tumorigenesis; v-src Oncogenes

DESCRIPTION (provided by applicant): The overall goal of this proposal is to understand the role of focal adhesion kinase (FAK) signaling with respect to the processes of tumorigenesis. Work from a number of labs has identified FAK as a component of both integrin and growth factor receptor signaling pathways. In many advanced and metastatic tumors, FAK is overexpressed and highly tyrosine phosphorylated. However, our knowledge is very limited with regard to how FAK contributes to the processes of cell transformation and tumor progression in vivo. We will test the overall hypothesis that elevated FAK expression and activity provides a selective advantage promoting solid tumor growth through the enhancement of anchorage-independent cell survival, through the regulation of metalloproteinase expression, and through the release of angiogenic factors in vivo. In particular, we will test the hypothesis that these events are mediated in part through elevated Rac activity, JNK/SAP kinase signaling, and through the alteration of gene expression events. Aim-1 of this proposal will test the functional significance of elevated FAK expression in human adenocarcinoma cells in vitro and in vivo using FAK antisense mRNA. Aim-2 will evaluate the role of elevated FAK tyrosine phosphorylation in the regulation of mammary carcinoma cell growth/survival in vitro and in vivo using dominant-negative FRNK expression. Aim-3 will determine the molecular connections of Src-FAK signaling promoting cell invasion in vitro as well as enhanced tumor growth and angiogenesis in vivo through comparisons of Src-transformed FAK-null and FAK-reconstituted cells. In all of these studies, we will implement an innovative strategy of rescuing the loss or absence of FAK function through the adenoviral-mediated overexpression of epitope-tagged FAK and mutants of FAK. These studies will elucidate the functional differences of FAK as an adaptor protein compared to a role for FAK as signaling kinase. Achievement of these goals will yield new information on the role of FAK signaling and will aid in the development of therapeutic strategies to control the growth and spread of tumor cells.

描述（由申请人提供）：该提案的总体目标是了解局灶性粘附激酶（FAK）信号在肿瘤发生过程中的作用。来自许多实验室的工作已将FAK确定为整合素和生长因子受体信号通路的组成部分。在许多晚期和转移性肿瘤中，FAK过表达且高度酪氨酸磷酸化。但是，关于FAK如何促进体内细胞转化和肿瘤进展的过程，我们的知识非常有限。我们将测试总体假设，即FAK表达和活性升高提供了一个选择性的优势，通过通过调节金属蛋白酶表达的调节以及通过体内释放血管生成因子来促进独立于锚定的细胞存活，从而促进实体瘤的生长。特别是，我们将检验以下假设：这些事件是通过升高的RAC活性，JNK/SAP激酶信号传导以及通过基因表达事件的改变来介导的。该提案的AIM-1将使用FAK反义mRNA在体外和体内测试FAK表达升高的FAK表达的功能意义。 AIM-2将评估FAK酪氨酸磷酸化升高在使用显性阴性FRNK表达的体外和体内乳腺癌细胞生长/存活中的作用。 AIM-3将通过比较SRC变换后的FAK-NULL和FAK-RECONSTTETSTUD的细胞来确定促进体外促进细胞侵袭的SRC-FAK信号传导的分子连接，并确定体内肿瘤的生长和血管生成。在所有这些研究中，我们将通过腺病毒介导的表位标记的FAK和FAK突变体的过表达来挽救FAK功能的损失或缺失的创新策略。与FAK作为信号激酶的作用相比，这些研究将阐明FAK作为衔接蛋白的功能差异。实现这些目标将产生有关FAK信号传导作用的新信息，并将有助于发展治疗策略以控制肿瘤细胞的生长和扩散。