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

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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.