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

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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 majority of mammalian cells by influencing and controlling another important family of enzyme named kinases. By dephosphorylating substrates of kinases, the PTPs can therefore influence the level of activity of those kinases and consequently the cellular functions that are themselves regulating. Whereas oxidation plays an important role in the regulation of PTPs and this via the action of reactive oxygen species, we have recently discovered that iron could play a critical in the regulation of PTPs, we even found that a mononuclear iron can very precisely fit itself within the catalytic pocket of PTPs and consequently inhibit their activity. We believe that such capacity in the context of regulation of cell functions and in particular the ones involved in the innate immune response, are in addition to ROS, plays a critical role to control homeostatic and abnormal cellular conditions. In the first portion of our research program, we are proposing experiments that should permit to determine whether iron is effectively strongly implicated in PTPs activtation, as well as to control their cellular mobilization to various sub-cellular compartment in order to interact with specific substrates involved in the signaling events concurring to induce immune cell functions in response to various agonists. In the second portion of our program, the findings stemming from our 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 using physiologically defective mice for iron. Impact of those augmented or reduced availability or iron in vivo will be monitored at cellular, molecular and functional levels. Findings from these studies will shed light on the importance of iron in the regulation of mammalian PTPs and its impact on global signaling and functional cellular homeostasis, in particular as its critical role to keep the fine balance between kinases and phosphatases of eukaryotic cells throughout evolution of the immune system.