Role of iron in the regulation of PTPs: impact on cell signaling and functions

点击翻译按钮获取中文摘要

The goal of this research program is to study the implication of iron in the regulation of a family of enzyme named protein tyrosine phosphatase (PTP). PTPs play a critical role in the regulation of macrophage (MO) functions by influencing and controlling their fine balance with kinases. By dephosphorylating kinase substrates, PTPs can influence the level of kinase activities and consequently the MO functions and innate immune response. Whereas oxidation plays an important role in the regulation of PTPs and this via the action of ROS, we have recently discovered that iron could play a critical in the regulation of PTPs, under the form of a mononuclear dicitrate iron complex precisely fitting itself within PTP's catalytic pocket inhibiting their activity. We believe that such capacity in the context MO function regulations and particuolarly the ones involved in innate immune response could plays a critical role to control homeostatic and abnormal cellular conditions. The actual grant proposal is designed to study the specificity of this iron species toward MO PTPs (Aim 1) and to analyze whether this iron-mediated modulation of PTPs happens in vivo (Aim 2). In Aim 1, we propose to determine whether all MO PTPs (classic, DUS PTPs and RPTPs) are similarly regulated by mononuclear ion-citrate, as well as to follow their sub-cellular mobilization to various compartments in order to interact with specific substrates involved in the signaling events concurring to regulate innate immunity in response to inflammatory agonists. In Aim 2, the findings stemming from in vitro evaluation proposed above, will be further tested in vivo using specific inhibitors for PTPs, inoculation of iron-dextran, as well as to use models with physiologically iron defective mice. Impact of those augmented or reduced availability or iron in vivo will be monitored at cellular, molecular and innate immunity levels.