The laboratory is principally involved in the study of receptor signal transduction for several growth factors and the identification of receptors that share subunits or are members of the same receptor superfamily. These growth factors primarily have effects on cells of lymphoid and hematological origin or as in the case of prolactin, breast tissue normal and transformed. The laboratory has extended its investigations into the role of the JAK/Stat pathway for specific cytokine receptors. Through critical analysis of the IL2, IL4, and prolactin receptor systems we have identified structural and functional requirements responsible for recruitment and activation of JAK and Stat proteins. Additionally, we have identified the structural requirements for the activation of collateral signal pathways associated with PI3 kinase activation and a unique serine kinase which is involved in Stat 5 phosphorylation. The laboratory has continued structure function studies through mutational analysis of JAK2 in order to determine the chemical basis of activation or repression. We have shown that JAK family enzymes are negatively regulated by nitric oxide (NO) a potent physiological mediator produced by monocytes. JAK2 and JAK3 are catalytically inhibited by DE-NO- as well as interleukin induced proliferative responses. These results have suggested a mechanism by which NO participates in immunosuppression. We have identified a trans- inhibitory site within the structure of JAK2 located approximately within the JH4, regian of the enzyme. Mechanistic studies are underway in order to molecularly characterize the phenomenon. AIDS TITLE: N/A LMI
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