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Research Interests:
Research Synopsis:The focus of our research is to study protein kinase-mediated signal transduction with a specific emphasis on identifying key targets for protein kinases as well as investigating the pharmacological application of kinase inhibitors as therapeutic agents. Regulation of Nucleoside Transport by Protein Kinases and Protein Kinase InhibitorsNucleoside transporters are crucial for the cellular transport of a wide variety of both natural and chemotherapeutic nucleoside analogs. We found that a number of commonly used protein kinase inhibitors block the cellular uptake of nucleosides and nucleoside analogs into tumor cells. These studies show that nucleoside transporters are targets for direct inhibition by these compounds. In addition we observed that other kinase inhibitors influenced nucleoside uptake through effects consistent with inhibition of kinase-dependent expression of these proteins. Thus our objectives are to determine the kinase-dependent signals that regulate nucleoside transport expression as well as to investigate the pharmacological effects of inhibiting nucleoside uptake in both normal or tumor cells. Regulation of CAD and CTP Synthetase by PhosphorylationCAD and CTP Synthetase (CTPS) are 2 key enzymes in the synthesis of pyrimidine nucleotides (uridine and cytidine); essential molecules for cell proliferation and development. Both enzymes are phosphoproteins and using mass spectrometry we have identified a number of novel phosphorylation sites in these proteins. In addition, CAD and CTPS are likely regulated by interacting proteins. Thus our objectives are to determine the effects of phosphorylation on the regulation of these enzymes during growth and development and to identify interacting protein partners by mass spectrometry and protein arrays. Activation of MAP Kinases by PPAR ligandsThe EGF receptor (EGFR) kinase is "transactivated" by a number of stimuli (G-protein receptor activation, UV, H202 and other cell signals). Our studies show that an important class of compounds used for the treatment of type II diabetes (peroxisome proliferators (PPAR) agonists- TZDs), induced EGFR transactivation and activation of the ERK and p38 MAPK's by both EGFR-dependent and independent mechanisms. These studies suggested that PPAR agonists elicited "non-genomic" events that could influence cellular responses to these compounds. Thus our objectives are to investigate the mechanisms by which TZDs activate EGFR and the effects of MAP kinase activation on regulating responses to insulin signaling. Recent Publications:
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