Role of Cortactin in Tyrosine Kinase Signaling

描述：(申请者提供)本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·韦德。威德博士被任命为终身教职。 在科罗拉多大学健康科学中心完成 他的博士后培训。他正在继续他对细胞骨架和 信号蛋白，皮质素。威德博士在基础部的任命 牙科学院的科学和口腔研究使他能够接触到所有 为他的研究提供了主要的现代仪器形式，并提供了 智力刺激的环境。威德博士和他的实验室 参加各种研究小组会议，涉及所有部门 实验室，他可以接触到医学院的所有成员研究 通过联合任命在UCHSC的社区。他的长期目标包括 进一步阐明皮质蛋白及其相关蛋白在细胞周期中的作用 片脂蛋白的功能与正常的细胞信号转导和 运动性，以及这种蛋白质在口腔癌中是如何失调的。这项建议 特指皮质蛋白在基于酪氨酸激酶的细胞中的功能 信号事件。Cortactin是Src的底物，在30%的细胞中过表达 头颈部鳞状细胞癌(HNSCC)的百分比。基于他的 初步数据推测，皮质酮的酪氨酸磷酸化 涉及多个信号通路，包括部分激活Rho GTP酶、RAC和CDC 42。 这里描述的研究将使用生化和细胞生物学分析 成纤维细胞系探讨酪氨酸磷酸化的假说 Cortactin是组装信号复合体的中心，对 皮质肌动蛋白的组装和运动。在目标1中，他将阐述如果Cortactin 如果RAC诱导了Src易位，与Src的结合激活了Src激酶的活性 在片状脂血症中需要与Cortactin隔间，并 鉴定与磷酸酪氨酸残基相互作用的蛋白质。AIM2将检查 皮质肌动蛋白在ACK磷酸化事件中的作用 如果ACK介导的皮质肌动蛋白磷酸化，则皮质肌动蛋白是ACK底物 对肌动蛋白细胞骨架的影响，如果ACK使皮质肌动蛋白磷酸化 参与了Cdc42介导的细胞运动。AIM3将研究EGF的作用 肌动蛋白酪氨酸磷酸化过程中的受体 参与EGFR介导的皮质肌动蛋白磷酸化，皮质肌动蛋白所起的作用 在EGF磷酸化事件中，以及I25 kDa的身份和功能 EGFR活化后，磷酸化蛋白与皮质蛋白形成复合体。

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.