What does Stat3 do? (original) (raw)

Stat3 was first described as a DNA-binding activity from IL-6–stimulated hepatocytes, capable of selectively interacting with an enhancer element in the promoter of acute-phase genes, known as the acute-phase response element (6–9). Molecular definition of this factor demonstrated that the same protein, a close relative of Stat1, is activated by the entire family of IL-6–type cytokines, which signal through gp130 and related receptors (5, 10, 11). Moreover, at least in cell culture systems, Stat3 is also activated by such diverse agents as growth factors, oncogenes, and IFNs.

Structurally, Stat3 is similar to other Stat proteins, having a conserved amino-terminus involved in tetramerization, a DNA-binding domain with a sequence specificity for a palindromic IFN-γ–activated sequence (GAS) element very similar to that of Stat1, an SH2 domain involved in receptor recruitment as well as Stat dimerization, and a carboxy-terminal transactivation domain. As with other Stat proteins, Stat3 is activated by tyrosine phosphorylation at a single site close to the carboxy-terminus (Y705), as well as by serine phosphorylation at a site within the transactivation domain (S727). Tyrosine phosphorylation in response to cytokine stimulation is mediated by a Janus kinase, most often JAK1 (12), and is required for Stat3 dimerization, nuclear translocation, and DNA binding. Targeted phosphorylation of Stat3 appears to follow the general paradigm of receptor recruitment first worked out for Stat1 activation in response to IFN-γ (13), involving a specific interaction between the Stat3 SH2 domain and a phosphotyrosine on the gp130 cytoplasmic domain within the consensus sequence YxxQ. Serine phosphorylation occurs within a mitogen-activated protein kinase consensus site.

The identity of the serine kinase for Stat3 is somewhat controversial, most likely because different activation signals lead to serine phosphorylation by any of several kinases, including ERK1, ERK2, p38, JNK, and an H-7–sensitive kinase (14). Most evidence suggests a positive role for S727 phosphorylation in Stat3 transcriptional activation, presumably through enhanced recruitment of necessary transcriptional cofactors, as is the case for serine phosphorylation of Stat1 (15). However, there is also evidence for a negative role for serine phosphorylation, although its underlying mechanism is unclear.

The function of Stat3 has been extensively studied in cell culture systems. IL-6–type cytokines evoke a number of distinct responses in different cells, including induction of an acute-phase response in hepatoma cells, stimulation of proliferation in B lymphocytes, activation of terminal differentiation and growth arrest in monocytes (11), and maintenance of the pluripotency of embryonic stem cells (16–19). The finding that Stat3 is involved in all these distinct functions has suggested that Stat3 is the major signal transducer downstream of gp130-like receptors. Moreover, this conclusion raises the interesting issue of how a single transcription factor can be involved in seemingly contradictory cell responses. The answer to this riddle may be found at least in part in the induction of distinct sets of target genes by Stat3 in different cells (5). For instance, part of the mechanism by which Stat3 stimulates B cell proliferation is through inhibition of apoptosis, a function mediated by induction of the antiapoptotic gene Bcl-2. In contrast, activation of Stat3 in monocytic cells leads to downregulation of c-myc and c-myb and induction of junB and IRF-1, a pattern of gene regulation consistent with differentiation and growth arrest. Likewise, a different set of Stat3-dependent genes are upregulated in IL-6–stimulated hepatocytes, genes for the secreted proteins of the acute-phase response (20).

Additional signaling systems also appear to rely heavily on Stat3, at least in cell culture systems. For instance, G-CSF receptor signaling during granulopoiesis leads to a striking activation of Stat3. Moreover, the Stat3 requirement site on the receptor is required for G-CSF–driven proliferation, and expression of dominant negative Stat3 impairs proliferation (21). HGF activates Stat3 during the process of tubule outgrowth in epithelial cells (22). IL-10 requires Stat3 activation for its anti-inflammatory properties on macrophages (23). How a common transcription factor activates a distinct gene program dependent on cell type is an area of active investigation.

Stat3, like other Stat proteins (24), has also been implicated in cancer (see Bromberg, this Perspective series, ref. 25; and references therein). Following the seminal discovery that Stat3 is constitutively phosphorylated in v-Src–transformed cells (26), considerable evidence has accumulated suggesting a critical role for activated Stat3 during malignant transformation. Activated Stat3 has been observed in a variety of experimental malignancies, and its abrogation by use of dominant negative inhibitors or antisense oligonucleotides has led to reversal of the malignant phenotype. Expression of a constitutively active version of Stat3 on its own can lead to fibroblast transformation, suggesting that Stat3 is an oncogene. Moreover, numerous mouse and human malignancies have shown activated Stat3, including many head and neck cancers, mammary carcinomas, multiple myelomas, and other hematological malignancies. In these situations, Stat3 has been described as mediating largely a survival function, and induction of such antiapoptotic genes as Bcl-2 and Bcl-X has been suggested as a target of Stat3 action.