STAT proteins: a kaleidoscope of canonical and non-canonical functions in immunity and cancer (original) (raw)
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STAT proteins: from normal control of cellular events to tumorigenesis
Journal of cellular physiology, 2003
Signal transducers and activators of transcription (STAT) proteins comprise a family of transcription factors latent in the cytoplasm that participate in normal cellular events, such as differentiation, proliferation, cell survival, apoptosis, and angiogenesis following cytokine, growth factor, and hormone signaling. STATs are activated by tyrosine phosphorylation, which is normally a transient and tightly regulates process. Nevertheless, several constitutively activated STATs have been observed in a wide number of human cancer cell lines and primary tumors, including blood malignancies and solid neoplasias. STATs can be divided into two groups according to their specific functions. One is made up of STAT2, STAT4, and STAT6, which are activated by a small number of cytokines and play a distinct role in the development of T-cells and in IFNgamma signaling. The other group includes STAT1, STAT3, and STAT5, activated in different tissues by means of a series of ligands and involved in ...
Activation of STAT transcription factors in oncogenic tyrosine kinase signaling
Journal of Biomedical Science, 1998
Signal transducers and activators of transcription (STATs) are cytoplasmic transcription factors that translocate to the nucleus and regulate gene expression in response to cytokine and growth factor stimulation. Emerging evidence indicates that STAT signaling is also frequently activated by oncogenes and in tumor cells. Constitutive activation of STAT proteins has been reported in cell lines stably transformed by diverse oncoproteins that directly or indirectly activate specific tyrosine kinase signaling pathways. In addition, STAT activation has been detected in a variety of human tumors and tumor cell lines, many of which are known to harbor activated tyrosine kinases. Recent findings support a model in which activation of STAT signaling in the context of oncogenesis induces gene expression that participates in malignant transformation. *o~olooo~oileoooeeleee Signal transducer and activator of transcription (STAT) proteins were originally discovered as normal effectors of interferon-induced signaling from the cell surface to the nucleus [15]. Current models suggest that the following events are critical to interferon-induced biological responses [14, 39]. Upon ligand engagement of cell surface receptors, interferon induces receptor dimerization that leads to activation of receptor-associated tyrosine kinases of the Janus kinase (JAK) family. JAK kinases are activated by autophosphorylation and in turn phosphorylate the cytoplasmic tails of the interferon receptor subunits. These phosphotyrosines on the activated receptor serve as docking sites for the recruitment of STATs, which normally exist as inactive forms in the cytoplasm. Recruitment of STAT proteins to the receptors occurs through interaction between a src-homology 2 (SH2) domain on the STAT protein and specific JAKinduced phosphotyrosine residues on the receptors. Receptor-associated STATs become phosphorylated on tyrosine by the JAK kinases, after which the activated STATs dissociate from the receptor and dimerize through reciprocal SH2-phosphotyrosine interactions. The STAT dimers then translocate to the nucleus, bind DNA-response elements in promoters and regulate interferon-specific gene expression [14, 39]. Activation of STATs by Diverse Cytokines and Growth Factors While STATs were originally discovered in the context of interferon signaling, it was subsequently found that numerous other cytokines and growth factors could also activate STATs [29, 39]. In the case of these other cytokines, such as interleukin 6 (IL-6) [1], activation of STATs proceeds through events similar to those outlined above for interferon-induced signaling [39]. Among the growth factors, platelet-derived growth factor (PDGF) and epidermal growth factor (EGF) induce activation of STATs [17, 30, 37, 49, 58]. Some STAT family members had been
Oncogene, 1997
JAK is believed to be an essential tyrosine kinase that mediates signals from the cytokine receptor to its downstream events. JAK associates with the cytoplasmic domain of the type I cytokine receptor superfamily and upon the ligand stimulation it can be activated, resulting in the receptor phosphorylation. In signaling from gp130, a common signal transducer for the IL-6 family cytokines, STAT3, a transcription factor that contains an SH2 domain, is recruited by phosphotyrosines on gp130 and is subsequently phosphorylated by gp130associated JAKs. In this study, we attempted to ®nd a new target for JAK that is directly activated by JAK, independent of gp130 tyrosine phosphorylation, by using a yeast two-hybrid system. In the process we found that the JH2 domain of JAK1, JAK2 or JAK3 could speci®cally associate with the carboxy-terminal portion of STAT5, but not with STAT3 or STAT1. The interaction was con®rmed using both a transient expression system in a cell line and a GST-fusion protein binding assay. Furthermore, we showed that the activation of STAT5 via gp130 did not need any phosphotyrosines on gp130 while that of STAT3 strictly depended on phosphotyrosines on gp130. Mutations of STAT5 that eliminated the interaction with JAK1 reduced the activation of STAT5 upon the gp130 stimulation, although such mutants could be still activated through erythropoietin receptor. These results indicate that STATs are activated through cytokine receptors by two distinct mechanisms, one dependent on receptor tyrosine phosphorylation and the other mediated by the JAK ± STAT direct interaction.
STATs as critical mediators of signal transduction and transcription: lessons learned from STAT5
Cytokine & Growth Factor Reviews, 2004
Signal transducers and activators of transcription (Stats) comprise a family of seven transcription factors that are activated by a variety of cytokines, hormones and growth factors. Stats are activated through tyrosine phosphorylation, mainly by Jak kinases, that lead to their dimerization, nuclear translocation and regulation of target gene expression.
European Journal of Cancer, 2006
The Janus family of tyrosine kinases (JAK) and the signal transducer and activator of transcription (STAT) family are critical components of diverse signal transduction pathways that are actively involved in cellular survival, proliferation, differentiation, and apoptosis. Accumulating evidence also supports a role for STAT proteins in oncogenesis. STATs transduce signals emanating from the large haematopoietin subfamily of cytokines, including the interferon, the gp130, the cC and the single chain families of receptors. 1 STATs can also be activated by receptor tyrosine kinases, such as epidermal growth factor receptor (EGFR), colony stimulating factor-1 receptor (CSF-1R), and platelet derived growth factor receptor (PDGFR). Several members of the G-protein-coupled receptors have also been shown to signal through STATs. The binding of a cytokine to its receptor induces the receptor's oligomerisation which in turn triggers the activation of JAKs by either auto-or transphosphorylation. There are four members of the JAK family in mammals, Jak1, Jak2, Jak3 and Tyk2. Jak1, Jak2 and Tyk2 are expressed ubiquitously, whereas the expression of Jak3 is restricted to cells of the myeloid and lymphoid lineages. The activated JAKs phosphorylate the receptors on specific tyrosine sites, which generate docking sites for the recruitment of cytoplasmic monomeric STAT proteins via their SH2 (Src homology 2) domains. Subsequently, the recruited STATs are phosphorylated by activated JAKs and dimerise via reciprocal phosphotyrosine-SH2 domain interactions. STAT 3 is also regulated by phosphorylation on its serine residue 727. 4 This phosphorylation can be inhibitory and the kinase responsible is not clearly identified. The dimers translocate to the nucleus, where they bind to specific DNA response elements which regulate gene expression. 5 STAT signalling is thought to be terminated by dephosphorylation through nuclear tyrosine phosphatases and/or through proteolytic degradation. Moreover, few phosphatases such as SHP1 are known to dephosphorylate JAK/STAT proteins and SHP1 remains one of the phosphatases identified which downregulates STAT3. 6 Seven members of the STAT family encoded in distinct genes have been identified in mammalian cells: STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT 6. STAT1 and STAT3 exhibit two isoforms each resulting from alternative splicing 5 whereas STAT5a and STAT5b are encoded by distinct genes. STAT proteins have a well-defined structure including a DNA-binding domain, a conserved NH 2 -terminal domain, a COOH-terminal transactivation domain, and an SH2 domain. Concerning STAT signalling pathway, it is modulated by interacted molecules: among them, the SOCS protein and PIAS protein have been described to play a crucial role in the regulation of STAT signalling pathway. 7 The SOCS protein belongs to a group of cytokine-inducible genes that have been shown to inhibit STAT signalling by binding to JAKS. Some of the SOCS protein can also be regulated by STATS themselves, providing that STAT can regulate its own phosphorylation status. 8 For instance, SOCS-3 has been demonstrated as a negative regulator of STAT3 and STAT5 activation. As for PIAS proteins, they generally play a role by decreasing DNA activation via STAT DNA-binding activity. The overexpression of PIAS1 and PIAS3 represents a specific nuclear inhibition of STAT1 and STAT3 and by consequence prevents the activation of STAT-dependent gene transcription.
Signaling via the T Cell Antigen Receptor Induces Phosphorylation of Stat1 on Serine 727
Journal of Biological Chemistry, 2000
The Stat1 transcription factor plays a pivotal role in both, the antiviral and antigrowth actions of interferons. Stat1 acquires the ability to bind DNA by becoming phosphorylated on Tyr 701 . However, to effectively stimulate gene transcription, it must also be phosphorylated on Ser 727 . We show that engagement of T cell antigen receptor (TCR)/CD3 complex in either Jurkat cells or peripheral blood lymphocytes stimulates phosphorylation of Ser 727 but not Tyr 701 of Stat1. This process does not require the expression of tyrosine kinases Lck and Zap-70. Interestingly, pretreatment of T cells with the Src kinase inhibitor PP1 completely abrogated CD3-mediated serine phosphorylation of Stat1, whereas inhibitors to MEK1 and phosphatidylinositol 3-kinase had no effect. Phosphorylation of Ser 727 of Stat1 in T cells is not restricted to TCR/CD3 but also results when cells are stimulated via the costimulatory molecule CD28. The combination of CD3 and CD28 did not augment phosphorylation of Stat1 Ser 727 . Surprisingly, Stat1-mediated transcriptional activity in response to IFN-␣ was enhanced with CD3 stimulation, whereas CD3 alone had little effect. These findings suggest that Stat1 is a signaling molecule in TCR signaling and may play a role in T cell function.
STAT Signaling in Cancer: Insights into Pathogenesis and Treatment Strategies
The inappropriate survival and proliferation of cancer cells often arises from the activation of signaling pathways normally under the control of physiologic stimuli. The genetic alterations which occur in a tumor cell lead to the inappropriate activation of these signaling pathways, resulting in the persistent survival or growth of cells independent of the appropriate cues. A pathway which has been found to be important in mediating the effects of many physiologic stimuli is the STAT pathway. Originally identified as playing a key role in hematologic and immune cells, STATs are now recognized to play a prominent role in transducing signals from a wide variety of stimuli, in perhaps every tissue in the body. Given this prominent role in normal homeostasis, it is not surprising that STATs have been found to be activated inappropriately in a wide array of human cancers. This has provided important information about the molecular pathogenesis of cancer, and presents possible strategies...