Interferons (IFN), cytokines and growth factors play important roles as a first defense against viral infections, in the treatment of different types of cancers and in the regulation of the immune and hematopoietic system. Cytokines, growth factors and IFNs have similar signaling mechanisms that involve the activation of tyrosine kinases of the Jak family, and activation of transcription factors of the Stat family (Signal Transducers and Activators of Transcription), having as a final result the transcriptional activation of the genes responsible for the different cytokine responses. In the last three years, significant progress has been achieved in terms of knowing how the Stat factors activate gene transcription. However, little is known about the mechanisms by which cytokine receptors activate the Jak kinases and Stat factors. It has been proposed that the Stat factors are recruited to the IL-6 and IFN-gamma receptor complexes through the interaction of the Stat-SH2 domains with phosphotyrosine residues on the receptor subunits. However, this model is not compatible with those cytokine receptors such as the erythropoietin and growth hormone receptors in which tyrosine phosphorylation of receptor subunits is not required for signaling. Based on data obtained with the long form of the beta subunit of the IFN-alpha receptor (IFNaR), the applicant proposes an alternative model in which Stat factors constitutively interact with receptor subunits resulting in a constitutive Receptor-Jak-Stat complex. This proposal will test this model and will attempt to fill the gap of knowledge concerning how cytokine receptors activate the Jak kinases and the Stat transcription factor. Using the IFNaR as a working system, he will test the constitutive association of the Stat factors with IFNaR receptor subunits, and then determine if a similar model applies to other cytokine receptors. The results obtained with this proposal will be important for our long term objectives that involve the elucidation of the crosstalk between cytokine systems such the IFN system that have a negative regulatory effect on cell proliferation, and growth factors/cytokines that mediate cell proliferation.
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