JAK-STAT Signaling: From Interferons to Cytokines

50 years ago Isaacs and Lindenmann (1) first described inter-ferons (IFNs)2 as founding members of the cytokine family. Over the next 25 years, these and several other four-helix bun-dle cytokines were characterized. The subsequent 25 years wit-nessed an exponential growth in number of four-helix bundle cytokines and their corresponding receptors. The early availability of recombinant IFNs afforded an opportunity to investigate how cytokines induce gene expres-sion, culminating in the identification of the JAK-STAT signal-ing paradigm (see Fig. 1). Subsequent studies identified 7 STATs and 4 JAKs, providing important insight into how the 50 members of the four-helix bundle cytokine family trans-duce their potent biological responses. This review will briefly summarize this signaling paradigm (reviewed in Refs. 2–5) and then focus on STAT-dependent transcription.