STATs: Signal Transducers and Activators of Transcription

further duplicated. In recent evolution, the Stat5 gene Signal transducers and activators of transcription further duplicated. Since the Drosophila gene appears (STATs) were first identified as a unique family of DNAto be most related to Stat5, the Stat3–Stat5a/Stat5b site binding proteins approximately four years ago. Since may represent the ancestral gene site. that time, the number of mammalian family members STAT: Structure and Functional Domains has grown, and in this issue of Cell, two reports now The STATs share several conserved structural and funcextend the STAT family to Drosophila (Hou et al., 1996; tional domains (Figure 1). The most interesting and conYan et al., 1996). The STATs have drawn considerable served domain is a potential phosphotyrosine-binding, attention because of their unique mode of activation SRC homology 2 domain (SH2). Several observations and the diversity of biological effects they are thought support this prediction, including the finding that mutato mediate from antiviral responses to cell transformation of the predicted phosphotyrosine-binding Arg tion. As in any emerging field, there has been a rapid residue eliminates activity. However, the isolated SH2 explosion of information and speculation. Now the dust domains have yet to be shown to bind phosphotyrosineis settling, and a more enduring picture is beginning to containing peptides selectively. Nevertheless, the SH2 emerge as exemplified by two articles that deal with domain plays three important roles. It is critical for the STAT1 function in this issue of Cell (Durbin et al., 1996; recruitment of STATs to activated receptor complexes Meraz et al., 1996). This review provides a brief overview (detailed below). It is required for the interaction with of STAT structure, function, and possible evolution. Sevthe Janus protein-tyrosine kinases (JAKs), which phoseral reviews (Darnell et al., 1994; Schindler and Darnell, phorylate the STATs. Finally, the SH2 domain is required 1995; Ihle, 1995; Ihle and Kerr, 1995; Ihle et al., 1995) for STAT dimerization and the associated ability to bind provide more detail and, more importantly, references DNA. The STATs were also reported to contain SH3 to primary information. domains. This region is much less conserved, including STAT Family Members the critical residues involved in proline binding, and no The first STAT family members were identified as DNAevidence has emerged to suggest an SH3 function. binding proteins in interferon (IFN)-regulated gene exDNA binding by purified STAT1 is totally dependent pression. From these studies, two STATs and two disupon tyrosine phosphorylation at a single site (Tyr-701), tinct models of STAT involvement emerged. In response carboxyl to the SH2 domain. Similarly, the DNA-binding to IFNa/IFNb, a DNA-binding complex is rapidly formed activity of all STATs is dependent upon tyrosine phosconsisting of STAT1, STAT2, and a DNA-binding protein phorylation and, where examined, involves a comparatermed p48, which binds an IFN-stimulated response bly located tyrosine. Considerable evidence supports element (ISRE). In contrast, in response to IFNg, a DNAthe hypothesis that tyrosine phosphorylation results in binding complex is formed of STAT1 homodimers that dimerization of STATs through the intermolecular interbinds a unique element termed the IFNg-activated seaction of the SH2 domains and the carboxyl sites of quence (GAS). Formation of either complex is dependent tyrosine phosphorylation and that this dimerization is upon tyrosine phosphorylation of STAT2 and STAT1, or essential for DNA binding. just STAT1, respectively. The DNA-binding domain of STATs is located in the Following the cloning of Stat1 and Stat2, it became middle in a highly conserved domain that is not found obvious that STAT-like activities were activated by variin other DNA-binding proteins. Consistent with both doous cytokines. This prompted efforts that resulted in the main conservation and the requirement for dimerization, identification of five additional mammalian Stat genes all but one of the STATs bind very similar symmetrical, (Figure 1). Stat3 was cloned as an interleukin-6 (IL-6)dyad sequences (Figure 1). Indeed, the consensus seactivated transcription factor or by homology to Stat1. quences, defined by using STAT homodimers in binding Stat4 was cloned by homology approaches. Stat5 was and amplification reactions with random oligonucleocloned as a prolactin-activated transcription factor from tides, only differ in the center core nucleotide or, in sheep. Subsequently, it was found that in mice there the case of STAT6, the preference for two central core are two highly related Stat5 genes, Stat5a and Stat5b. nucleotides. Curiously, phosphorylated STAT2 does Most recently, Stat6 was cloned as an IL-4-activated not, or weakly, binds DNA, suggesting that it may only DNA binding as well as by homology. Although well function as a heterodimer with STAT1, in complex with characterized in mammals, the existence of nonmamthe p48 DNA-binding component. malian STATs has only recently been shown as reported STATs may also form heterodimers. In addition to