Role of Cortactin in Tyrosine Kinase Signaling

描述：（由申请人提供）这个K22教师过渡奖是 旨在为独立研究计划提供初步支持， 候选人斯科特·A·大麻韦德博士被任命为终身教职 在科罗拉多大学健康科学中心， 他的博士后训练他正在继续研究细胞骨架， 信号蛋白，coronin。Weed博士在基础科学系的任命 牙科学院的科学和口腔研究使他能够接触到所有 主要的现代仪器的形式，他的研究，并提供了一个 智力刺激的环境。Weed博士和他的实验室 参加了各种研究小组会议，涉及所有部门 实验室，他可以接触到医学院的所有成员的研究 通过联合任命在UCHSC社区。他的长期目标包括 进一步阐明了皮质激素和相关蛋白在 板状伪足的功能与正常细胞信号转导有关， 运动，以及这种蛋白质在口腔癌中是如何失调的。这项建议 特别是在酪氨酸激酶为基础的细胞中， 信号事件。Corneum是Src的底物，在30个细胞中过表达。 头颈部鳞状细胞癌（HNSCC）的百分比。基于他 根据初步数据，推测皮质激素的酪氨酸磷酸化 涉及多种信号传导途径，包括部分激活Rho 42.第四十二章 这里描述的研究将使用生物化学和细胞生物学分析， 成纤维细胞系，探讨酪氨酸磷酸化的假设， 皮质醇是重要的信号复合物的组装中心， 皮质肌动蛋白组装和运动。在AIM 1中，他将解决如果Coreun 与Src结合激活Src激酶活性，如果Rac诱导Src易位， 是在板状伪足中与皮质素区室化所必需的， 鉴定与磷酸酪氨酸残基相互作用的蛋白质。AIM 2将检查 cornea蛋白在ACK磷酸化事件中的作用， 如果ACK-介导的Corpine磷酸化，Corpine是ACK底物， 影响肌动蛋白细胞骨架，如果ACK引起的coronin磷酸化作用， 参与Cdc 42介导的细胞运动。第三章EGF的作用 通过测定激酶的酪氨酸磷酸化受体 参与EGFR介导的corneumen磷酸化，corneumen发挥的作用 在EGF磷酸化事件中，以及125 kDa的 EGFR激活后与coronin复合的磷蛋白。

DESCRIPTION: (provided by applicant) This K22 Faculty Transition Award is intended to provide the initial support for the independent research program of the candidate, Scott A. Weed. Dr. Weed was appointed to a tenure track position at the University of Colorado Health Sciences Center following completion of his postdoctoral training. He is continuing his studies on the cytoskeletal and signaling protein, cortactin. Dr. Weed's appointment in the Department of Basic Sciences and Oral Research in the School of Dentistry allows him access to all forms of major modern instrumentation for his studies and provides an intellectually stimulating environment. Dr. Weed and his laboratory are involved in a variety of research group meetings involving all Departmental laboratories, he has access to all members of the School of Medicine research community at UCHSC through a joint appointment. His long-term goals involve further elucidation of the role of cortactin and associated proteins in lamellipodia function as it pertains to normal cell signal transduction and motility, and how this protein is malregulated in oral cancer. This proposal specifically addresses the function of cortactin in tyrosine kinase-based cell signaling events. Cortactin is a substrate for Src and is overexpressed in 30 percent of head and neck squamous cell carcinomas (HNSCCs). Based on his preliminary data, it is hypothesized that tyrosine phosphorylation of cortactin involves multiple signaling pathways including in part activation of the Rho GTPases, Rac and Cdc 42. The studies described here will use biochemical and cell biological analysis of fibroblast cell lines to explore the hypothesis that tyrosine phosphorylation of cortactin is central to the assembly of signaling complexes important for cortical actin assembly and motility. In AIM 1 he will address if cortactin binding to Src activates Src kinase activity, if Rac-induced Src translocation is required for compartmentalization with cortactin in lamellipodia, and to identify proteins interacting with phosphotyrosine residues. AIM2 will examine the role cortactin plays in ACK phosphorylation events by determining if cortactin is an ACK substrate, if ACK-mediated cortactin phosphorylation effects the actin cytoskeleton, and if phosphorylation of cortactin by ACK is involved in Cdc42-mediated cell motility. AIM3 will examine the role of the EGF receptor in cortactin tyrosine phosphorylation by determining the kinases involved in EGFR-mediated cortactin phosphorylation, the role cortactin plays in EGF phosphorylation events, and the identity and function of a l25kDa phosphoprotein complexed with cortactin following EGFR activation.