SIGNAL TRANSDUCTION EVENTS REGULATED BY INTEGRINS

整合素是介导细胞粘附的细胞受体家族。 细胞到细胞外基质或其它细胞。 的相互作用 整联蛋白及其合适的配体对于细胞存活是关键的， 增殖和动物细胞的其他专门功能。 的 肿瘤的发生与整合素的改变有关 蛋白质中的表达或突变介导细胞中的整联蛋白功能。 这些改变使肿瘤细胞能够在肿瘤细胞中存活和增殖。 缺乏天然粘附相互作用， 到其他网站。 阐明介导细胞凋亡的细胞内途径 这些整合素调节的细胞事件对于理解 致癌转化的机制。 中的研究 该提议旨在剖析细胞内成分， 参与整合素信号传导事件， 磷脂激酶和蛋白酪氨酸和丝氨酸/苏氨酸激酶 在整联蛋白介导细胞通路激活中， 增长、迁移和生存。 该提案的一个部分侧重于 磷脂酰肌醇3 '激酶和蛋白激酶C在 Erk/MAP激酶家族的整合素调控 丝氨酸/苏氨酸激酶Raf。 此外，我们还将继续努力， 旨在鉴定整合素信号传导的新组分的策略 途径。 这些涉及纯化磷酸化蛋白质的方法 在激活整联蛋白后， 蛋白质，以鉴定定位于整联蛋白核灶的蛋白质 粘附复合物 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 鉴定以前未认识到其在以下方面的作用的蛋白质： 整合素信号传导，使我们能够扩大我们的知识整合素如何， 激活的蛋白质相互作用，组织信号通路， 特定的细胞功能，并可能揭示新的治疗目标 干预癌症。

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.