The Continuing Fascination with Jaks and Stats: An Introduction
The origins of the discovery of Jak-Stat signal transduction date back to the late 1980s when research groups headed by Jim Darnell, Ian Kerr and George Stark were fascinated by the fact that gene transcription could be induced within minutes after treating cells with type I interferons (IFN-I). The speed with which a signal generated by the plasma membrane–associated IFN-I receptor travelled to nuclear target genes suggested few intermediate steps. The Darnell, Kerr and Stark labs identified bifunctional signal transducers and activators of transcription (Stats) as responsible for IFN-induced transcription by using complementary biochemical and genetic approaches (reviewed in Darnell et al. 1994). Shortly after this seminal discovery, the labs of Sandra Pellegrini, Jim Ihle and Christine Carter-Su independently identified non-receptor protein tyrosine kinases (pTK) in the signaling pathways stimulated by, respectively, the IFN, erythropoietin and growth hormone receptors (Argetsinger et al. 1993; Velazquez et al. 1992; Witthuhn et al. 1993). The same kinases had previously emerged from screens for novel pTKs, conducted in the labs of John Krolewski and Andrew Wilks and named Janus kinases by the latter (Firmbach-Kraft et al. 1990; Wilks et al. 1991). With recombinant Jaks and Stats at hand it was possible to reconstitute IFN signaling between receptor and nuclear targets with just two components: receptor associated Jaks that activate Stats by tyrosine phosphorylation. Tyrosine phosphorylated Stats localize to the cell nucleus and bind to promoter DNA of specific target genes (Fig. 1).