THE EFFECTS OF ENVIRONMENTAL OXIDANTS ON HEPTP STRUCTURE AND MAP KINASE INTERACT

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 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。 T细胞活化的破坏与许多免疫性癌症相关，如白血病。更重要的是，这些癌症的患病率正在增加，尽管其他癌症的患病率正在下降。这种上升的主要原因之一是人们更多地接触环境毒素。基于半胱氨酸的酪氨酸磷酸酶（CBTPs）特别容易被环境毒素灭活。一种CBTP，即造血酪氨酸磷酸酶（HePTP），是一种非受体酪氨酸磷酸酶，其在包括骨髓性白血病的免疫疾病的发展中起关键作用。其最重要的细胞功能之一是结合和调节MAP激酶的活性。重要的是，HePTP对氧化应激高度敏感，因此在响应于暴露于氧化毒素的疾病发展中起作用。本提案的目的是了解HePTP：MAP激酶相互作用调节的分子基础。在具体目标1中，我们将使用X射线晶体学来确定HePTP：Erk 2静息态复合物的结构。在具体目标2中，我们将使用生物物理学研究来了解HePTP如何通过氧化应激失调。这些研究将确立HePTP作为治疗环境毒素所致疾病的药物靶标。

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. Disruptions in T cell activation are correlated with numerous immunological cancers, such as leukemia. More importantly, the prevalence of these cancers is increasing, even though others are on the decline. One of the primary causes of this rise is the increased exposure of people to environmental toxins. Cysteine-based tyrosine phosphatases (CBTPs) are particularly susceptible to inactivation by environmental toxins. One CBTP, Hematopoietic tyrosine phosphatase (HePTP), is a non-receptor tyrosine phosphatase which plays a critical role in the development of immune disorders, including myelogenous leukemia. One of its most important cellular functions is to bind and regulate the activity of MAP kinases. Importantly, HePTP is highly sensitive to oxidative stress and thus plays a role in the development of disease in response to exposure to oxidating toxins. The goal of this proposal is to understand the molecular basis for the regulation of the HePTP:MAP kinase interaction. In Specific Aim 1, we will use X-ray crystallography to determine the structure of the HePTP:Erk2 resting state complex. In Specific Aim 2, we will use biophysical studies to understand how HePTP is dysregulated by oxidative stress. These studies will establish HePTP as a drug target for the treatment of diseases due to environmental toxins.