Receptor PTPs, Cell Contact & Signal Transduction

描述（由申请人提供）：该项目的长期目标是研究蛋白酪氨酸磷酸酶（PTP）家族的结构、调控和功能。现在很明显，蛋白酪氨酸激酶（PTKs）和蛋白酪氨酸激酶（PTPs）在体内的协调和竞争作用是相互结合的，控制着生长和增殖、分化、生存、运动和代谢等基本过程。此外，PTPs和PTKs作用之间微妙平衡的破坏与人类疾病的病因有关，包括癌症、糖尿病和炎症。因此，表征ptp是全面了解酪氨酸磷酸化的生理后果以及这种信号事件如何在疾病中被取消的先决条件。本研究的重点是通过可逆氧化和失活来调节PTP功能，作为酪氨酸磷酸化依赖信号传导的新调控层。在之前的资助期内，开发了一种新的测定方法，并得到了广泛的验证，该方法可以测量PTP家族所有主要类别细胞中的可逆氧化。在这个竞争性的更新中，实验室开发的各种工具将被应用于检查PTP氧化在癌症模型中的作用。此外，可逆氧化过程中还原步骤的机制，再生PTP的活性形式，但迄今为止一直被忽视，将被表征。预计这些研究将对酪氨酸磷酸化依赖性信号转导的调控产生新的见解，并对个体ptp在癌症中的功能产生新的见解。为此，本研究计划的具体目标为：1 .研究受体磷酸酶PTP1在乳腺癌细胞和动物模型中的调节和功能；2 .研究PTP氧化在癌基因诱导的衰老的发生和旁路中的作用；3 .研究氧化PTP1B的还原和再激活的调节机制；4 .研究硫氧还蛋白在PTP可逆氧化中的作用。

DESCRIPTION (provided by applicant): The broad, long-term objectives of the project are to characterize the structure, regulation and function of the protein tyrosine phosphatase (PTP) family of enzymes. It is now apparent that the coordinated and competing actions of both protein tyrosine kinases (PTKs) and PTPs are integrated in vivo to control such fundamental processes as growth and proliferation, differentiation, survival, motility and metabolism. Furthermore, disruption of the delicate balance between the action of PTPs and PTKs has been implicated in the etiology of human diseases, including cancer, diabetes and inflammation. Therefore, characterization of the PTPs is a prerequisite to gaining a complete understanding of the physiological consequences of tyrosine phosphorylation and how such signaling events are abrogated in disease. The focus of this proposal is the regulation of PTP function by reversible oxidation and inactivation, as a new tier of control of tyrosine phosphorylation-dependent signaling. In the previous funding period, a novel assay was developed, and extensively validated, that measures the reversible oxidation in cells of all the major categories of the PTP family. In this competitive renewal various tools that have been developed in the lab will be applied to examine the role of PTP oxidation in cancer models. In addition, the mechanisms underlying the reduction step in the process of reversible oxidation, which regenerates the active form of the PTP, but which has been neglected to date, will be characterized. It is anticipated that these studies will generate new insights into the regulation of tyrosine phosphorylation-dependent signal transduction, as well as new insights into the function of individual PTPs in cancer. To achieve this, the Specific Aims of the research program are: 1: To investigate the regulation and function of the receptor phosphatase PTP1 in cell and animal models of breast cancer, 2: To investigate the role of PTP oxidation in onset and bypass of oncogene-induced senescence, 3: To investigate mechanisms regulating the reduction and reactivation of oxidized PTP1B, and 4: To investigate the role of thioredoxin in reversible PTP oxidation.