The Janus protein tyrosine kinase family and its role in cytokine signaling.

During the past 2 years, research from quite divergent areas has converged to provide the first insights into the mechanisms by which cytokines that utilize receptors of the cytokine receptor superfamily function. On the one hand, the obscure Jak family of cytoplasmic protein tyrosine kinases was independently implicated in IFN and hematopoietic growth factor signaling. Recent studies have expanded these initial observations to demonstrate that Jaks are critical to the functioning of all the receptors of the cytokine receptor superfamily. A variety of questions remain to be explored regarding the structure and function of Jaks and their interaction with receptors. It will also be important to pursue additional approaches to determine if the Jaks are necessary for various biological responses, particularly for mitogenic responses. The second major area of convergence has been the demonstration that members of the Stat family of transcription factors, initially identified in IFN-regulated gene expression, are generally involved in cytokine signaling. Clearly, a number of Stat-like activities remain to be cloned and it can be anticipated that the family contains additional members. Although a variety of genes are known to be regulated by the Stats association with IFN responses, much less is known concerning the genes regulated by the new Stats in cytokine signaling. Of particular importance is information relating to their potential contribution to mitogenic responses. From a biochemical standpoint, the Stats represent a remarkable family of proteins with regard to the ability of the modification of a single tyrosine residue to so dramatically affect cellular localization and DNA binding activity. Studies to identify the domains involved, and associated proteins that might contribute to either property, will be of considerable interest. More generally, it can hypothesized that Jaks and Stats, if important for proliferation and differentiation, may be the targets for malignant transformation. Although none of the genes map to chromosomal breakpoints that have been implicated in transformation, gain of function mutations is a likely mechanism that needs to be explored. Similarly, the Jak-Stat pathway would appear to be an excellent target for the development of drugs that affect a variety of cytokine functions.