Abstract
Multiple molecular mechanisms have been identified that are responsible for the deregulation of the quantitative aspects of JAK-STAT signaling. These mechanisms enhance the extent and the duration of, e.g., STAT3 activation and have profound consequences on the phenotypes of the affected cells. The fine tuning of STAT3 signaling is required to maintain its physiological functions and its deregulation is associated with diverse pathological states. Deregulation can be exerted by the gain of function of components mediating the activation of STAT3 or the loss of function of molecules involved in the deactivation steps of STAT3. Gain of function mutations can involve tyrosine kinases that phosphorylate STAT3, mutations in cytokine and growth factor receptors causing their ligand independent activation, mutations in STAT3 that enhance and prolong its tyrosine phosphorylation and the autocrine or paracrine production and secretion of cytokines, most notably IL-6. Diminished deactivation of phosphorylated STAT3 can be due to the reduced expression of tyrosine phosphatases, inactivating mutations in these enzymes, silencing or functional inactivation of SOCS molecules, post-transcriptional inhibition of PIAS3 expression or deletion mutations in the lymphocyte adaptor protein, LNK. STAT3 variants that exhibit autonomous transactivation potential have been detected in 40% of patients with T-cell large granular lymphocytic leukemia in clonally expanded CD8(+) T cells. These patients also were preferentially affected by neutropenia and rheumatoid disorders and the results suggest that activating STAT3 mutations in T lymphocytes could be a cause of autoimmune diseases.