STRUCTURAL BIOLOGY OF SIGNALING AND THE ACTIN CYTOSKELETON

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 我们的子项目专注于两个相互关联的领域：酪氨酸激酶和福尔明家族蛋白及其调节因子。我们正在努力了解酪氨酸激酶的结构和调节，特别是那些在癌症中调节失调或成为抗癌药物靶点的酪氨酸激酶。我们正在研究粘着斑激酶(FAK)，以了解它是如何调节的，并促进FAK特异性抑制剂的开发。我们正在研究JAK家族的激酶，以了解它们与细胞因子受体的结合机制，它们是如何被分子内相互作用调节的，以及这种调节在JAK2或JAK3突变的血液增殖性疾病(如真性红细胞增多症)中是如何被破坏的。通过我们对EGFR激酶突变体结构的研究，我们希望阐明致癌激活和耐药的机制，并设计出突变体特异性的抑制剂，用于治疗由EGFR突变引起的肺癌和其他癌症。在我们对Daam1、MDIA和Bni1等Forin蛋白的研究中，我们希望了解这些分子是如何调控的，以及它们在肌动蛋白组装中的作用。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Our subproject focuses in two inter-related areas  tyrosine kinases and formin family proteins and their regulators. We are working to understand the structure and regulation of tyrosine kinases, especially those that are dysregulated in cancer or are targets for anti-cancer drugs. We are studying focal adhesion kinase (FAK) in order to understand how it is regulated and to facilitate development of FAK-specific inhibitors. We are studying Jak-family kinases in order to understand their mechanism of association with cytokine receptors, how they are regulated by intramolecular interactions and how this regulation is disrupted in hematoproliferative disorders (such as polycythemia vera) in which Jak2 or Jak3 is mutated. Through our studies of the structure of EGFR kinase mutants, we hope elucidate mechanisms of oncogenic activation and drug resistance, and also to design inhibitors that are mutant-specific for use in the treatment of lung and other cancers that arise from EGFR mutations. In our investigations of formin proteins such as Daam1, mDia, and Bni1 we hope to learn how these molecules are regulated and how they function in actin assembly.