ICAPL AND BETA 1 INTEGRIN SIGNALING

整合素介导的细胞与细胞外基质的粘附 细胞表面受体家族是一个重要的生理决定因素 细胞增殖和细胞存活的关键。 这一长期目标 建议是明确粘附依赖细胞的机制， 发信号。 当整合素结合时， 细胞外基质被处理以启动细胞内信号 不知道。 我们最近发现了一种新的200个氨基酸 一种与β 1整合素特异性相互作用的蛋白质Icap 1 α。 我们已经证明，Icap 1 α与β 1整合素的结合需要 保守的C-末端Asn-Pro-Lys-Tyr基序和缬氨酸792 β 1整联蛋白胞质结构域。此外，我们还证明了 Icap 1 α经历了一个依赖于粘附的蛋白磷酸化。 在这个建议中，我们将研究整合素的近端事件 信号传导，重点是Icap 1 α和β 1之间的相互作用 整合素胞质结构域。 第一，结构功能分析， Icap 1alpha将被执行。 氨基酸序列要求 β 1整合素和Icap 1 α之间的相互作用，以及 将确定Icap 1 α的亚细胞定位。 二是 β 1整联蛋白胞质结构域上的氨基酸序列， 启动细胞内信号传导所需的 表征了 Icap 1 α参与整合素- 将通过研究缬氨酸792的作用来测试介导的信号传导 突变对细胞粘附和细胞增殖的影响。 三、功能 在整合素介导的细胞内 信号事件，将被调查。 野生型Icap 1alpha 和Icap 1 β，一种不与β 1结合的Icap 1 α变体 整合素，将在细胞中表达，以决定 Icap1alpha。 与Icap 1alpha相互作用的蛋白质将被鉴定。 这项研究的结果将增强我们对粘附的理解- 依赖细胞信号传导，并可以提供知识基础， 调节细胞粘附和细胞增殖。

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.