Role of Iron in the Regulation of PTPs: Impact on Cell Signaling and Functions

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* * 0* 0* 1* 338* 1860* McGill University* 15* 4* 2194* 14.0* * * 96* 800x600* *** * Normal* 0* * * 21* * * false* false* false* * FR-CA* JA* X-NONE* * * * * * * * * * * * * * * * * * * * * * * * ** * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * *** **** /* Style Definitions */*table.MsoNormalTable* {mso-style-name:"Tableau Normal";* mso-tstyle-rowband-size:0;* mso-tstyle-colband-size:0;* mso-style-noshow:yes;* mso-style-priority:99;* mso-style-parent:"";* mso-padding-alt:0cm 5.4pt 0cm 5.4pt;* mso-para-margin:0cm;* mso-para-margin-bottom:.0001pt;* mso-pagination:widow-orphan;* font-size:10.0pt;* font-family:Calibri;}****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. ***Findings stemming from these studies could permit in a near future to*develop new ways to render more resistant animals from industry toward*infectious agents by reinforcing their innate immune system, and this by adding*newly identified mononuclear dicitrate iron to their diet.***