STAT3: A multifaceted oncogene

Abstract

Signal transducers and activators of transcription (STAT) proteins are a family of transcription factors first characterized for their role in cytokine signaling. These versatile proteins contain a site for specific tyrosine phosphorylation, a modification that results in a conformational rearrangement and dimerization through phosphotyrosine–SH2 domain interactions (1). Once activated in this manner, phosphorylated STAT protein dimers accumulate in the cell nucleus, bound to enhancer elements of target genes. STAT proteins were first characterized as intermediaries in IFN signaling, a growth inhibitory cytokine pathway involved in antiviral and innate immune responses. However, as additional members of this protein family were discovered, they caught the eyes of cancer biologists as potential mediators of growth control and possibly oncogenic events. In particular, it became recognized that STAT3 and, to a lesser extent, STAT5 were stimulated by classic growth-promoting signals, such as activated growth factor receptors. Even more compelling were the seminal observations that STAT3 was a substrate for the catalytic activity of the tyrosine kinase oncoprotein v-Src (2) and that phosphorylated STAT3 accumulated in many human cancers, leading to the hypothesis that activated STAT3 is an oncogene (3). A considerable amount of experimental and clinical observations have now confirmed such a role for STAT3, and a remarkable degree of diversity has been uncovered for the molecular mechanisms at the basis of STAT3 action. Much early work has focused on direct growth-control and cell survival …