Cytokines are a family of soluble molecules capable of eliciting a diverse array of biologic responses in many different cell types. Work from a number of laboratories over the last several years has revealed that gene activation in response to cytokine stimulation is mediated predominately through the Janus kinase signal transducers and activators of transcription (JAK-STAT) signal transduction pathway. While many of the components of this signaling pathway have now been identified, and a basic paradigm of how the pathway operates has evolved, there are still several key aspects of JAK-STAT signaling that remain to be fully understood. In particular, the molecular mechanisms by which this signaling pathway is regulated have not, at present, been completely characterized. Thus, the overall goal of this application is to identify additional components of the JAK-STAT signaling pathway that serve to regulate STAT function and to elucidate their mechanisms of action. Given the pivotal role of JAK-STAT signaling in mediating cytokine-induced biologic responses, understanding how this pathway is regulated, and ultimately having the ability to manipulate it, will have enormous potential for the treatment of diseases such as autoimmunity and cancer. The experiments outlined in this application seek to test the hypothesis that two genes we have recently identified, a PDZ-LIM containing protein termed SLIM and a protein tyrosine phosphatase (PTPase) named PTP-BL, are key regulatory components of the JAK-STAT signaling pathway.
