RADIATION SIGNALING THROUGH THE ALPHA6 BETA 4 INTEGRIN

描述(申请人提供)：整合素是细胞黏附和信号传递 对细胞外环境变化作出反应的受体。在 在之前的三年资助中，我们的目标是确定电离 辐射激活A6整合素，导致磷酸酪氨酸信号和 以确定这是否会受到自然或合成的影响 配基。我们的结果表明，A6整合素被激活以响应 辐射和电离辐射将激活包含A6整合素 粘连部位。整合素连接的激酶(ILK)被认为是一种下游信号。 自检测到相应的Akt/PKB磷酸化以来的信号事件。这个 细胞外基质配体影响反应。此外，a 位于巴西林上的粘附点内的磷酸酪氨酸信号是 检测到。我们建议扩大这些研究的范围，以期达到以下目的： 1.确定IR信号机制是否涉及整合素连接激酶 (Ilk)激活。 2.确定粘着斑蛋白是否是产生IR所必需的 信号。 3.确定A6整合素的胞外区(包含 β桶结构域)或B1整合素的特定剪接变异体 对于磷酸化信号来说是必不可少的。 4.确定抗粘附肽或天然配体是否会改变IR 信号。 拟议的工作将增加我们目前对细胞信号转导的了解 辐射损伤反应，基本整合素生物学并提出增加的方法 放射治疗表达A6整合素的上皮细胞的疗效 癌症。

DESCRIPTION (Provided by applicant): Integrins are cell adhesion and signaling receptors responsive to alterations in the extracellular environment. In the previous three year grant, our objective was to determine whether ionizing radiation activates the A6 integrin resulting in a phosphotyrosine signal and to determine whether this can be influenced by the natural or synthetic ligands. Our results show that the A6 integrin is activated in response to irradiation and that ionizing radiation will activate A6 integrin containing adhesion sites. The integrin linked kinase (ILK) is implicated as a downstream signaling event since a corresponding Akt/PKB phosphorylation is detected. The extracellular matrix ligands influence the response. In addition, a phosphotyrosine signal within the adhesion site located on paxillin is detected. We propose to extend these studies with the following aims: 1. Determine if the mechanism of IR signaling involves integrin linked kinase (ILK) activation. 2. Determine if focal adhesion site proteins are essential to the IR generated signal. 3. Determine if the extracellular domain of the A6 integrin (containing the beta barrel domain) or a specific splice variant of the B1 integrin is essential to the phosphorylation signals. 4. Determine if anti-adhesion peptides or natural ligands will alter the IR signal. The proposed work will add to our current knowledge of cellular signaling of a radiation damage response, basic integrin biology and suggest ways to increase the efficacy of the radiation treatment of A6 integrin expressing epithelial cancers.