STRUCTURAL BIOLOGY OF SIGNALING AND THE ACTIN CYTOSKELETON

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 我们的子项目集中在两个相互关联的领域  酪氨酸激酶和酪氨酸激酶家族蛋白及其调节剂。 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失调或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家族激酶，以了解它们与细胞因子受体的关联机制，它们如何通过分子内相互作用进行调节，以及这种调节如何在Jak 2或Jak 3突变的血液增殖性疾病（如真性红细胞增多症）中被破坏。 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性的机制，并设计用于治疗EGFR突变引起的肺癌和其他癌症的特异性抑制剂。在我们对Daam 1、mDia和Bni 1等蛋白质的研究中，我们希望了解这些分子是如何被调控的，以及它们在肌动蛋白组装中是如何发挥作用的。

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.