What does Stat3 do?

The Stat protein family was discovered in the course of studies of signaling specificity from IFN receptors (1). The initial finding of a family of related proteins, each activated by a different cytokine receptor, suggested that these proteins would fulfill the requirements predicted for carriers of intracellular signaling information capable of retaining the specificity inherent in cytokine-receptor interactions (2). While studies in cell culture systems belied some of this early promise, the initial findings with genetically manipulated mice, especially using gene-targeting approaches, generally suggested a high degree of specificity for the various Stat proteins in individual signaling pathways. As reviewed elsewhere in this Perspective series, the analysis of mice lacking one or more Stat genes has shown relatively discrete phenotypes, assigning each Stat protein to a relatively specific pathway. Not so with Stat3. Unlike all other members of the Stat gene family, ablation of Stat3 leads to embryonic lethality (3). This finding, along with evidence of its activation by a wide variety of cytokines, growth factors, and other stimuli (4, 5), implied that Stat3 might be more generally deployed than its relatives and has led to the suggestion that it might represent a primordial Stat protein. Recent data, especially from the analysis of conditional loss of Stat3 protein in adult tissues, confirm that Stat3 participates in a wide variety of physiological processes and even directs seemingly contradictory responses.