RADIATION SIGNALING THROUGH THE ALPHA6 BETA 4 INTEGRIN

描述（由申请人提供）：整合素是细胞粘附和信号传导 对细胞外环境的改变有反应的受体。在 前三年的赠款，我们的目标是确定是否电离 辐射激活A6整联蛋白，导致磷酸酪氨酸信号， 以确定这是否会受到天然或合成的 配体。我们的研究结果表明，A6整合素被激活， 辐射和电离辐射将激活含有A6整联蛋白 粘连部位。整合素连接激酶（ILK）被认为是下游的 这是因为检测到相应的Akt/PKB磷酸化。的 细胞外基质配体影响应答。另外还有按 位于桩蛋白上的粘附位点内的磷酸酪氨酸信号是 检测到我们建议扩展这些研究，目的如下： 1.确定IR信号传导机制是否涉及整合素连接激酶 (ILK)activation. 2.确定粘着斑部位蛋白质是否是产生IR所必需的 信号了 3.确定A6整联蛋白的细胞外结构域（含有 β桶结构域）或B1整联蛋白的特异性剪接变体， 对磷酸化信号至关重要。 4.确定抗粘附肽或天然配体是否会改变IR 信号了 拟议的工作将增加我们目前对细胞信号传导的知识， 辐射损伤反应，基本整合素生物学，并建议如何增加 放射治疗表达A6整合素的上皮细胞的功效 癌的

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.