Role of Focal Adhesion Kinase in Tumorigenesis

描述（由申请人提供）：本提案的总体目标是了解粘着斑激酶（FAK）信号传导在肿瘤发生过程中的作用。许多实验室的工作已经确定FAK是整合素和生长因子受体信号通路的一个组成部分。在许多晚期和转移性肿瘤中，FAK过表达并高度酪氨酸磷酸化。然而，我们的知识是非常有限的关于FAK如何有助于细胞转化和肿瘤进展的过程中在体内。我们将测试的总体假设，即FAK的表达和活性升高提供了一个选择性的优势，促进实体瘤生长，通过增强锚定非依赖性细胞存活，通过调节金属蛋白酶的表达，并通过释放血管生成因子在体内。特别是，我们将测试的假设，这些事件介导的部分通过升高的Rac活性，JNK/SAP激酶信号，并通过改变基因表达事件。本研究的目的一是利用FAK反义mRNA在体外和体内检测FAK在人腺癌细胞中表达升高的功能意义。目的-2将评估FAK酪氨酸磷酸化升高在体外和体内使用显性阴性FRNK表达调节乳腺癌细胞生长/存活中的作用。目的-3将通过比较Src-转化的FAK-无效和FAK-重建的细胞来确定Src-FAK信号传导促进体外细胞侵袭以及增强体内肿瘤生长和血管生成的分子连接。在所有这些研究中，我们将实施一种创新的策略，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功能的丧失或缺失。这些研究将阐明FAK作为衔接蛋白的功能差异相比，FAK作为信号激酶的作用。这些目标的实现将产生关于FAK信号传导作用的新信息，并将有助于控制肿瘤细胞生长和扩散的治疗策略的发展。

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.