ALTERNATE PATHWAYS FOR INTERFERON AND CYTOKINE SIGNALING

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The long term objective of this project is to understand the regulation of signal transduction pathways elicited by interferons (IFNs) and their interplay with pathways activated by other cytokines and growth factors. Central to this is the Jak-Stat pathway which operates via a cascade of specific protein-protein interactions followed by DNA-protein interactions in which protein phosphorylation plays a key role. Cross-talk between the Jak-Stat pathway and other signaling systems includes the involvement of cytosolic phospholipase A2 (cPLA2) in IFN-alpha (but not IFN-gamma) signaling, the involvement of the dsRNA-dependent protein kinase PKR in IFN signaling of NFkappaB and IRF-1 and a PDGF-dependent physical and functional interaction between PKR and Stat3. Different proteins tyrosine phosphatases (PTPs) also regulate the Jak-Stat pathway. To better understand the relative contributions of these components to cell signaling by IFNs and other cytokines we propose the following specific aims: 1. To test the hypothesis that cPLA2 is an essential component of the IFN- alpha signaling pathway we will a) investigate the role of cPLA2 in ISGF3 activation; b) characterize the interaction between Jak1 and cPLA2 by mapping the physical domains required for this interaction, and c) determine the role of phosphorylation of cPLA2 in IFN-alpha signaling. 2. To test the hypothesis that PKR plays a distinctive role in IFNalpha and PDGF signaling pathways, we will a) dissect the pathway that leads to IFNgamma activation of PKR and regulation of transcription factors NFkappaB and IRF-1, b) investigate the physical and functional interactions of Stat3 with PKR and establish the role of PKR in Stat3- mediated PDGF-dependent activation of immediate early genes. 3. To test the hypothesis that different PTPs are involved in the negative regulation of Jak-Stat signaling we will: a) characterize the regulation of IL-4/IL-13 signaling in Shp-1-deficient cells, b) investigate physical and functional interactions between components of the IL-4/IL-13 signaling pathway, and c) identify additional PTP-activities that negatively control IL-4/IL-13 signaling. Understanding the complexities of cell signaling by cytokines and growth factors will provide new insights into the control of cell growth and identify areas for future therapeutic intervention in malignancies.