ICAPL AND BETA 1 INTEGRIN SIGNALING

整合素介导的细胞与细胞外基质的黏附 细胞表面受体家族是一个重要的生理决定因素 对细胞增殖和细胞存活的影响。这是一个长期目标 建议定义黏附依赖细胞的机制 发信号。整合素结合时产生的信息是如何 细胞外基质被处理以启动细胞内信号 是未知的。我们最近发现了一种新的200个氨基酸 Icap1pha，与β1整合素特异相互作用的蛋白质。 我们已经发现，Icap1α与Beta1整合素的结合要求 保守的C-末端ASN-Pro-Lys-Tyr基序和Valine 792 β1整合素胞质结构域。此外，我们还展示了 Icap1α经历一种黏附依赖的蛋白质磷酸化。 在这个方案中，我们将研究整合素的近端事件 信号转导，重点是Icap1α和Beta1之间的相互作用 整合素胞质结构域。首先，对其结构功能进行了分析 将执行Icap1 Alpha。氨基酸序列要求 对于β1整合素和Icap1α之间的相互作用，以及 Icap1α的亚细胞定位将被确定。第二， β1整合素胞质结构域上的氨基酸序列是 启动细胞内信号传递所需的 特色化的。Icap1α参与整合素的假说- 通过研究Valine792的作用将测试介导的信号转导 突变对细胞黏附和细胞增殖的影响。第三，功能 在整合素介导的细胞内的背景下，Icap1α 信号事件，将被调查。野生型Icap1pha 以及Icap1beta，一种不与Beta1绑定的Icap1Alpha变体 整合素，将在细胞中表达，以确定其功能 Icap1阿尔法。与Icap1pha相互作用的蛋白质将被识别。 这项研究的结果将加深我们对粘连的理解-- 依赖于细胞信号，并可提供知识基础 调节细胞黏附和细胞增殖。

Cell adhesion to the extracellular matrix mediated by the integrin family of cell surface receptors is a crucial physiological determinant of cell proliferation and cell survival. A long term goal of this proposal is to define the mechanism of adhesion dependent cell signaling. How the information that originates when integrins bind to the extracellular matrix is processed to initiate intracellular signals is not known. We have recently identified a novel 200 amino acid protein, Icap1alpha, that specifically interacts with beta1 integrins. We have sown that the binding of Icap1alpha to beta1 integrins request the conserved C-terminal Asn-Pro-Lys-Tyr motif and Valine 792 of the beta1 integrin cytoplasmic domain. In addition, we have demonstrated that Icap1alpha undergoes an adhesion dependent protein phosphorylation. In this proposal, we will study the proximal events of integrin signaling, focusing on the interaction between Icap1alpha and the beta1 integrin cytoplasmic domain. First, a structure-function analysis of Icap1alpha will be carried out. The amino acid sequence requirements for the interaction between the beta1 integrin and Icap1alpha, and the subcellular localization of Icap1alpha will be determined. Second, the amino acid sequences on the beta1 integrin cytoplasmic domain that are required for the initiation of intracellular signaling will be characterized. The hypothesis that Icap1alpha is involved in integrin- mediated signaling will be tested by studying the effects of Valine792 mutation on cell adhesion and cell proliferation. Third, the function of Icap1alpha, in the context of integrin-mediated intracellular signaling events, will be investigated. Both the wild type Icap1alpha and Icap1beta, an Icap1alpha variant that does not bind to beta1 integrins, will be expressed in the cell to determine the function of Icap1alpha. Proteins that interact with Icap1alpha will be identified. Results from this study will enhance our understanding of adhesion- dependent cell signaling and may provide a knowledge basis for modulating cell adhesion and cell proliferation.