SIGNAL TRANSDUCTION EVENTS REGULATED BY INTEGRINS

整合素是一个细胞受体家族，它介导着 细胞向细胞外基质或其他细胞转化。的相互作用 整合素及其合适的配体对细胞生存至关重要， 动物细胞的增殖等特殊功能。这个 肿瘤的发生与整合素的改变有关 蛋白质的表达或突变介导了细胞中整合素的功能。 这些变化允许肿瘤细胞在体内存活和增殖 缺乏天然的粘附性相互作用以及迁移和转移 到其他网站。细胞内信号转导途径的阐明 这些整合素调控的细胞事件对于理解 致癌转化的机制。中的研究 这项提议旨在剖析细胞内的成分， 通过定义已知的作用参与整合素信号转导事件 磷脂酶与蛋白酪氨酸和丝氨酸/苏氨酸激酶 整合素介导控细胞的细胞通路的激活 增长、迁徙和生存。提案的一个部分侧重于 磷脂酰肌醇3‘端激酶和蛋白激酶Cs在心肌梗死中的作用 整合素对ERK/MAP激酶家族的调节作用 丝氨酸/苏氨酸激酶Raf。此外，我们还将追求几个 识别整合素信号的新成分的策略 小路。这些涉及提纯磷酸化蛋白质的方法。 在整合素激活后并使用GFP融合文库 识别定位于整合素有核焦点的蛋白质 黏附复合体。此外，我们将使用体外表达 克隆整合素激活的激酶底物的克隆策略 和3‘-磷脂酰肌醇结合蛋白。这些方法应该 识别以前未被认识的蛋白质，因为它们在 整合素信号，并使我们能够扩大我们的知识如何整合素- 激活的蛋白质相互作用，组织信号通路，控制 特定的细胞功能，并可能揭示治疗的新靶点 对癌症的干预。

Integrins are a family of cellular receptors that mediate attachment of cells to extracellular matrix or other cells. The interactions of integrins with their appropriate ligands are critical for cell survival, proliferation, and other specialized functions of animal cells. The development of tumors is associated with alterations in integrin expression or mutations in proteins mediate integrin functions in cells. These alterations allow tumor cells to survive and proliferate in the absence of natural adhesive interactions and to migrate and metastasize to other sites. Elucidation of the intracellular pathways that mediate those integrin regulated cellular events is critical to understanding the mechanisms involved in oncogenic transformation. The studies in this proposal are designed to dissect the intracellular components that are involved in integrin signaling events by defining the role of known phospholipid kinases and protein tyrosine and serine/threonine kinases in integrin mediated activation of cellular pathways that control cell growth, migration and survival. One section of the proposal focuses on the role of phosphatidylinositol 3'kinases and protein kinase Cs in integrin regulation of the Erk/MAP kinase family through the serine/threonine kinase Raf. In addition, we will pursue several strategies designed to identify novel components of integrin signaling pathways. These involve approaches to purify proteins phosphorylated following activation of integrins and to employ libraries of GFP fusion proteins to identify proteins that localize to integrin-nucleated focal adhesion complexes. In addition, we will use in vitro expression cloning strategies to clone substrates of kinases activated by integrins and 3'phosphatidylinositide binding proteins. These approaches should identify proteins that were previously unrecognized for their role in integrin signaling and allow us to expand our knowledge of how integrin- activated proteins interact to organize signaling pathways that control specific cell functions and possibly reveal new targets for therapeutic intervention in cancer.