Maximal activation of transcription by statl and stat3 requires both tyrosine and serine phosphorylation

  title={Maximal activation of transcription by statl and stat3 requires both tyrosine and serine phosphorylation},
  author={Zilong Wen and Zhong Zhong and James E. Darnell},

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STATs in Cytokine-mediated Transcriptional Regulation
The current understanding of the functional domains, the regulation, and the physiological roles of STATs in cytokine signaling are reviewed.
Serine phosphorylation of STATs
This review addresses recent advances in understanding the regulation of STAT serine phosphorylation, as well as the kinases and other signal transducers implied in this process.
Serine Phosphorylation and Negative Regulation of Stat3 by JNK*
It is demonstrated that JNK1, activated by its upstream kinase MKK7, negatively regulated the tyrosine phosphorylation and DNA binding and transcriptional activities of Stat3 stimulated by EGF and pretreatment of cells with UV reduced the EGF-stimulated tyrosining and phosphotyrosine-dependent activities of stat3.
JAKs and STATs branch out.
Stat1 serine phosphorylation occurs independently of tyrosine phosphorylation and requires an activated Jak2 kinase
Evidence is presented that Stat1 tyrosineosphorylation is not a prerequisite for Stat1 serine phosphorylation, although an active Jak2 kinase is required for both phosphorylated events.
STAT3 Is a Serine Kinase Target in T Lymphocytes
The results show that STAT3 proteins are targets for multiple kinase pathways in T cells and can integrate signals from both cytokine receptors and antigen receptors, and it is shown that H-7-sensitive kinases do not regulate STAT3 tyrosine phosphorylation or phosphorylated of serine 727.
Simultaneous tyrosine and serine phosphorylation of STAT3 transcription factor is involved in Rho A GTPase oncogenic transformation.
Results indicate that Stat3 is an important player in RhoA-mediated oncogenic transformation, which requires simultaneous phosphorylation at both tyrosine and serine residues by specific signaling events triggered by Rho a effectors.
STAT2 phosphorylation and signaling
This review aims to summarize knowledge of phosphorylation-mediated STAT2-regulation and future avenues of related STAT2 research.
Inhibition of protein phosphatase 2A induces serine/threonine phosphorylation, subcellular redistribution, and functional inhibition of STAT3.
  • A. WoetmannM. Nielsen N. Odum
  • Biology, Chemistry
    Proceedings of the National Academy of Sciences of the United States of America
  • 1999
Evidence is provided that PP2A plays a crucial role in the regulation of STAT3 phosphorylation and subcellular distribution in T cells and suggests that the level of STAT2A phosphorylated is balanced between a staurosporine-sensitive kinase(s) and PP1/PP2A.
Stat5a Serine Phosphorylation
It is shown that mutagenesis of Ser725, Ser779, or a combination ofSer725/779 to an Ala had no effect on prolactin-induced transcriptional activation of a β-casein reporter construct, and the results suggest that Ser725 phosphorylation has an impact on signal duration.


Requirement of serine phosphorylation for formation of STAT-promoter complexes.
Serine phosphorylation appears to enhance or to be required for the formation of stable Stat3-Stat3, a member of the interleukin-6 family of cytokines, which binds to and activate receptors that contain a common subunit, gp130.
A single phosphotyrosine residue of Stat91 required for gene activation by interferon-gamma.
Interferon-gamma (IFN-gamma) stimulates transcription of specific genes by inducing tyrosine phosphorylation of a 91-kilodalton cytoplasmic protein (termed STAT for signal transducer and activator of
Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6.
A new family member, Stat3, becomes activated through phosphorylation on tyrosine as a DNA binding protein in response to epidermal growth factor and interleukin-6 but not interferon gamma (IFN-gamma).
Tyrosine-phosphorylated Stat1 and Stat2 plus a 48-kDa protein all contact DNA in forming interferon-stimulated-gene factor 3.
Evidence is presented that a heterodimer of Stat1 and Stat2 is present in ISGF3 and that Stat 1 and the 48-kDa protein make precise contact, while Stat2 makes general contact, with the interferon-stimulated response element, the binding site of the IsGF3.
Interferon-dependent tyrosine phosphorylation of a latent cytoplasmic transcription factor.
The interferon-alpha-stimulated gene factor 3 (ISGF3), a transcriptional activator, contains three proteins that reside in the cell cytoplasm until they are activated in response to IFN-alpha, and may link occupation of a specific polypeptide receptor with activation of transcription of a set of specific genes.
Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins.
A previously unrecognized direct signal transduction pathway to the nucleus has been uncovered: IFN-receptor interaction at the cell surface leads to the activation of kinases of the Jak family that phosphorylate substrate proteins called STATs (signal transducers and activators of transcription).
Stat3 and Stat4: members of the family of signal transducers and activators of transcription.
Comparison with the deduced protein sequence of the two previously described genes (Stat91 and Stat113), discovered because of their activation as transcription factors after interferon-induced tyrosine phosphorylation, shows several highly conserved regions, including the putative SH3 and SH2 domains.
STAT3 activation by cytokines utilizing gp130 and related transducers involves a secondary modification requiring an H7-sensitive kinase.
All cytokines using gp130 and related signal transducers consistently and preferentially induce the two forms of STAT3 as compared with STAT1; this characteristic STAT activation pattern is seen regardless of which Jak/Tyk kinases are used in a particular response, consistent with the notion that the receptor components themselves are the primary determinants of which STATs are activated.
Stat4, a novel gamma interferon activation site-binding protein expressed in early myeloid differentiation
The Stat4 gene, which is 52% identical to STAT1, is located on mouse chromosome 1 and is tightly linked to the Stat1 gene, suggesting that the genes arose by gene duplication.