Negative regulation of Janus kinases

The precise regulation of both the magnitude and the duration of Janus kinase (JAK) catalytic activity is essential for the cytokine orchestration of many biological processes, and the dysregulation of JAK activity has pathological implications. Immunosuppressive disease states, such as X-linked severe combined immunodeficiency, arise from inappropriate JAK inhibition. In contrast, a limited number of cancers, primarily leukemias, result from constitutive or enhanced activation of JAK activity. JAKs are no longer implicated only in classic cytokine receptor-mediated signaling pathways, but are now also known to integrate indirectly into other receptor-mediated signal transduction processes. Therefore, an increasing number of therapeutic applications exist for biological-response modifiers that can restore aberrant JAK activity to normal levels. Exciting breakthroughs in both physiological and pharmacological methods of selective inhibition of cytokine-JAK-signal transducers and activators of transcription pathways have recently emerged in the form of suppressors of cytokine signaling (also known as cytokine-inducible SH2 protein, JAK-binding protein, or STAT-induced STAT inhibitor) proteins and novel dimethoxyquinazoline derivatives, respectively. The basis of these and other mechanisms of negative regulation of JAK activity, including the suppression of jak expression levels caused by tumor- or pathogen-derived agents, the complex interactions of JAKs with phosphatases, and the redox regulation of JAK catalytic activity, is the focus of this review.