Interleukin 4 Regulates Phosphorylation of Serine 756 in the Transactivation Domain of Stat6

Wang, Yuling; Malabarba, Maria Grazia; Nagy, Zsuzsanna; Kirken, Robert A.

doi:10.1074/jbc.m313668200

Cited by 46 publications

(36 citation statements)

References 59 publications

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“…1A). IL-4 signaling is transduced via STAT6 (25)(26)(27), suggesting that OC-STAMP expression requires STAT6. We did not detect STAT6 phosphorylation in M-CSF-or GM-CSF-treated BMMs, but we observed strong STAT6 phosphorylation in GM-CSF plus IL-4-treated FBGCs (Fig.…”

Section: Oc-stamp Expression In Fbgcs Requires Stat6-dc-mentioning

confidence: 99%

An Essential Role for STAT6-STAT1 Protein Signaling in Promoting Macrophage Cell-Cell Fusion

Miyamoto

Katsuyama

Miyauchi

et al. 2012

Journal of Biological Chemistry

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Background:The signaling leading to macrophage fusion remains largely unknown. Results: STAT6 deficiency completely inhibited macrophage fusion, although STAT1 deficiency or OC-STAMP/DC-STAMP co-expression was sufficient to promote macrophage fusion. Conclusion: The STAT6-STAT1-OC-STAMP/DC-STAMP axis is required for macrophage fusion. Significance: The STAT6-STAT1-OC-STAMP/DC-STAMP axis is a novel pathway leading to macrophage fusion.

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Section: Oc-stamp Expression In Fbgcs Requires Stat6-dc-mentioning

confidence: 99%

An Essential Role for STAT6-STAT1 Protein Signaling in Promoting Macrophage Cell-Cell Fusion

Miyamoto

Katsuyama

Miyauchi

et al. 2012

Journal of Biological Chemistry

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“…Phosphorylation of both S725 and S779 of STAT5A and of S730 of STAT5B negatively regulate transactivation in response to stimulation of mammary glands with prolactin (Yamashita et al 1998;Benitah et al 2003). Wang et al (2004) showed that IL-4 and IL-13 promote STAT6 phosphorylation on S756 in human T cells. However, the contribution of this phosphorylation to function is not yet clear.…”

Section: Carboxy-terminal Serine Phosphorylationsmentioning

confidence: 99%

Responses to Cytokines and Interferons that Depend upon JAKs and STATs

Stark

Cheon

Wang

2017

Cold Spring Harb Perspect Biol

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Many cytokines and all interferons activate members of a small family of kinases (the Janus kinases [JAKs]) and a slightly larger family of transcription factors (the signal transducers and activators of transcription [STATs]), which are essential components of pathways that induce the expression of specific sets of genes in susceptible cells. JAK-STAT pathways are required for many innate and acquired immune responses, and the activities of these pathways must be finely regulated to avoid major immune dysfunctions. Regulation is achieved through mechanisms that include the activation or induction of potent negative regulatory proteins, posttranslational modification of the STATs, and other modulatory effects that are cell-type specific. Mutations of JAKs and STATs can result in gains or losses of function and can predispose affected individuals to autoimmune disease, susceptibility to a variety of infections, or cancer. Here we review recent developments in the biochemistry, genetics, and biology of JAKs and STATs. Because the basic biochemistry of Janus kinase -signal transducers and activators of transcription (JAK-STAT) signaling pathways has been frequently and extensively reviewed (see, for example, Stark and Darnell 2012;Cai et al. 2015;O'Shea et al. 2015;Villarino et al. 2015), we present here only a brief summary. After a cytokine or interferon binds to its specific receptor, the receptor forms homodimers, heterodimers, or trimers, depending on the cytokine, thus activating the tightly bound JAKs to cross-phosphorylate each other. The activated JAKs then phosphorylate specific tyrosine residues in the cytoplasmic domains of the receptors, providing binding sites for the STATs through their highly conserved SH2 domains. The receptor-bound STATs are phosphorylated, each on a highly conserved tyrosine residue, after which they leave the receptor as homo-or heterodimers whose association is strengthened by SH2-phosphotyrosine interactions. The phosphorylated STAT dimers are then transported to the nucleus, where they bind to and activate specific promoters. The basic outline of JAK-STAT signaling (Fig. 1) shows that interferon (IFN)-g (type II IFN) and all of the cytokines primarily drive the formation of specific STAT homodimers, which then bind to DNA directly. However, in some cases, heterodimers involving STAT1 and STAT3 or STAT5A and STAT5B can also form. In contrast, IFN-b and the subtypes of IFN-a (collectively type I IFNs) and the subtypes of IFN-l (collectively type III IFNs) drive the formation of STAT1-STAT2 heterodimers, which then associate with the DNA-binding interferon regulatory protein 9 (IRF9) to form in-

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“…Ser-707 Phosphorylation of STAT6 Negatively Regulates Its Transcriptional Activity-Small molecule inhibitors of PP2A, a Ser/Thr-protein phosphatase, are known to induce multiple serine phosphorylations in the transactivation domain of STAT6, which repress its transcriptional activity (20,24). Serine phosphorylations in the transactivation domains of STAT1 and STAT3 also regulate their transcriptional activities.…”

Section: Cell Stress Induces Phosphorylation Of Stat6 In Hela Cells-mentioning

confidence: 99%

“…Serine phosphorylation of STAT6 has also been demonstrated. Following IL-4 stimulation, Ser-756 in the transactivation domain of STAT6 is concurrently phosphorylated with Tyr-641, which is essential for the activation of STAT6 (24). However, the biological significance of this phosphorylation remains unclear.…”

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confidence: 99%

Deactivation of STAT6 through Serine 707 Phosphorylation by JNK

Shirakawa

Kawazoe

Tsujikawa

et al. 2011

Journal of Biological Chemistry

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Signal transducer and activator of transcription 6 (STAT6), which plays a critical role in immune responses, is activated by interleukin-4 (IL-4). Activity of STAT family members is regulated primarily by tyrosine phosphorylations and possibly also by serine phosphorylations. Here, we report a previously undescribed serine phosphorylation of STAT6, which is activated by cell stress or by the pro-inflammatory cytokine, interleukin-1␤ (IL-1␤). Our analyses suggest that Ser-707 is phosphorylated by c-Jun N-terminal kinase (JNK). Phosphorylation decreases the DNA binding ability of IL-4-stimulated STAT6, thereby inhibiting the transcription of STAT6-responsive genes. Inactivation of STAT6 by JNK-dependent Ser-707 phosphorylation may be one mechanism of controlling the balance between IL-1␤ and IL-4 signals.STAT proteins are transcription factors that are activated by a variety of cytokines and growth factors. Seven mammalian STAT proteins have been identified, which contain a conserved structure composed of SH2, DNA binding, and transactivation domains. Extracellular binding of cytokines or growth factors to the receptors of these STAT proteins induces the activation of intracellular Janus kinases (JAK), which phosphorylate STAT proteins on a specific tyrosine residue. The phosphorylated STAT proteins promote formation of homo-or heterodimers from the phosphorylated tyrosine residue and its partner SH2 domains. The dimers are transported into the nucleus, where they induce transcription of the target genes (1-4). One of the seven STAT proteins, STAT6, was originally cloned as an IL-4-activated transcription factor (5). Studies of STAT6-deficient mice showed that STAT6 plays key roles in the differentiation of TH2 cells, the switching of B-cell immunoglobulin isotype to IgE, and the induction of allergic disease (6 -9).The mitogen-activated protein kinases (MAPK) include three families of serine/threonine-protein kinases: extracellular signal-regulated kinase (ERK), JNK, and p38. JNK and p38 are activated by environmental stress and pro-inflammatory cytokines. JNK, also known as stress-activated protein kinase (SAPK), is activated by IL-1, tumor necrosis factor (TNF), UV radiation, osmotic stress, anisomycin, and other stress factors (10 -14). JNK activation leads to Ser/Thr phosphorylation of several transcription factors and other cellular substrates that are implicated in cell survival, insulin receptor signaling, and mRNA stabilization (15)(16)(17)(18)(19).In addition to the tyrosine phosphorylations, those of serine residues are also important for regulation of STAT activities. The serine residue in a conserved Pro-X-Ser-Pro sequence at the COOH termini of STAT1, STAT3, STAT4, STAT5a, and STAT5b is phosphorylated in response to cytokines and growth factors (20 -23). Serine phosphorylation of STAT6 has also been demonstrated. Following IL-4 stimulation, Ser-756 in the transactivation domain of STAT6 is concurrently phosphorylated with Tyr-641, which is essential for the activation of STAT6 (24). However, the biol...

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Interleukin 4 Regulates Phosphorylation of Serine 756 in the Transactivation Domain of Stat6

Cited by 46 publications

References 59 publications

An Essential Role for STAT6-STAT1 Protein Signaling in Promoting Macrophage Cell-Cell Fusion

An Essential Role for STAT6-STAT1 Protein Signaling in Promoting Macrophage Cell-Cell Fusion

Responses to Cytokines and Interferons that Depend upon JAKs and STATs

Deactivation of STAT6 through Serine 707 Phosphorylation by JNK

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