Region 752–761 of STAT3 is critical for SRC-1 recruitment and Ser727 phosphorylation

Zhao, Hong; Nakajima, Ryota; Kunimoto, Hiroyuki; Sasaki, Takanori; Kojima, Hiroyuki; Nakajima, Kōichi

doi:10.1016/j.bbrc.2004.10.075

Cited by 10 publications

(17 citation statements)

References 36 publications

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“…Alternatively, phosphorylation of Ser-727 may inhibit Tyr-705 phosphorylation in naïve PC12 cells, similar to that observed in other cellular systems (19,21,22). Furthermore, Ser-727 of STAT3 is crucial for its recruitment of p300 upon cytokine stimulation (17,(37)(38)(39). Indeed, we found that NGFinduced phosphorylation of STAT3 at Ser-727 was accompanied by concomitant binding of STAT3 to p300.…”

Section: Discussionsupporting

confidence: 51%

“…Because Ser-727 of STAT3 is suggested to play a crucial role in the association of STAT3 with p300 upon cytokine stimulation (17,(37)(38)(39), the induction of STAT3 Ser-727 phosphorylation by NGF might affect the association of p300 with STAT3, thereby modulating its transcriptional activity. Consistent with this notion, we found that STAT3 associated with p300 after 15 min of NGF treatment, whereas no interaction between these two molecules was observed in the absence of NGF (Fig.…”

Section: Phosphorylation Of Stat3 Was Induced By Neurotrophins In Neuro-mentioning

confidence: 99%

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STAT3 as a Downstream Mediator of Trk Signaling and Functions

Cheung²,

2006

Journal of Biological Chemistry

107

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Neurotrophins are a family of trophic factors critical for the survival and development of neurons within the peripheral and central nervous systems. Members of the family include the prototypic member nerve growth factor (NGF), 3 brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and NT-4/5 in the mammals, and NT-6/7 in the fish species (1-4). The actions of neurotrophins are mediated by Trks, a family of receptor tyrosine kinases (RTKs). Binding of neurotrophins to their cognate receptors TrkA, TrkB, or TrKC induces rapid tyrosine phosphorylation of the receptors, resulting in their transactivation. Phosphorylated tyrosine residues on the receptors then serve as docking sites for various adaptor molecules, thereby activating multiple intracellular signal transduction pathways including Ras-mitogen-activated protein kinase, phosphatidylinositol 3-kinase, and phospholipase C␥.Although the intricate signaling cascade activated may directly take part in mediating the downstream functions of neurotrophins, initiation of gene transcription also plays an important role (3-5). Among the transcription factors triggered by Trk signaling, for example, phosphorylation of CREB (cAMP-response element-binding protein) is involved in neurotrophin-mediated neuronal differentiation and survival (6 -8). Activation of Egr-1 has been demonstrated to play crucial roles in the initiation of neurite outgrowth in PC12 cells (9). Induction of AP-1 activity, on the other hand, is implicated in the pro-survival property of NGF in serum-deprived PC12 cells (10). It is therefore of interest and importance to further elucidate the roles of various transcription factors in neurotrophin/Trk signaling.Recently, activation of STAT3, a member of the signal transducer and activator of transcription family, has been observed after activation of several RTKs such as ErbB and Eph receptors (11-13). The identification of STAT3 in neuregulin/ErbB (12) and ephrin/Eph signaling (13) in our laboratory prompted us to investigate if STAT3 activation also plays a role in neurotrophin/Trk signaling. STAT3 was originally identified as a crucial downstream component in cytokine signaling (13-15). The canonical STAT3 activation pathway involves recruitment of STAT3 to the cytokine receptors, such as gp130 and leukemia inhibitory factor receptor, upon cytokine stimulation. The phosphorylation of STAT3 by receptor-associated Janus kinases at tyrosine 705 (Tyr-705) subsequently leads to activation and homo-or heterodimerization of the STAT1/3 transcription factors. These homo-or heterodimers of STAT1/3 then translocate to the nucleus, activating multiple target gene transcription via interaction with specific DNA-response elements (14).In addition to Tyr-705 phosphorylation, phosphorylation of STAT3 at serine 727 (Ser-727) has also been demonstrated to play a regulatory role in STAT3 activation. The precise function of Ser-727 phosphorylation nonetheless remains obscure. It is generally believed that Ser-727 phosphorylation is required for STAT3 to ac...

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Section: Discussionsupporting

confidence: 51%

Section: Phosphorylation Of Stat3 Was Induced By Neurotrophins In Neuro-mentioning

confidence: 99%

STAT3 as a Downstream Mediator of Trk Signaling and Functions

Cheung²,

2006

Journal of Biological Chemistry

107

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“…1 A) and with NLK (29), we explored the role of STAT3 in the YXXQ-derived TAK1-NLK pathway. We used STAT3-knockdown HepG2 cells (HepG2-STAT3KD) and a derivative HepG2-STAT3KD cell line that was reconstituted with short interfering RNA-resistant STAT3 (HepG2-KD-STAT3R) (14). Stimulation with IL-6 at 1 and 100 ng͞ml caused TAK1 activation in the HepG2-STAT3KD cells to levels comparable to those obtained in the parental cells (Fig.…”

Section: Stat3 Is Required For Il-6-induced Nlk Activation But Not Fomentioning

confidence: 99%

“…IL-6 uses STAT3 in its major signaling pathway and concomitantly activates the Ras͞Raf͞ ERK and PI3-kinase pathways (7). IL-6, therefore, activates multiple genes, including acute-phase reactants, and the junB, tis11, stat3, c-myc, and c-fos genes, mostly through STAT3 (8)(9)(10)(11)(12)(13)(14). In the IL-6 receptor system, the tyrosine-phosphorylated YXXQ motif of gp130 is critical for recruiting STAT3 for subsequent phosphorylation at Tyr-705 by the associated Jak kinases (15).…”

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STAT3 regulates Nemo-like kinase by mediating its interaction with IL-6-stimulated TGFβ-activated kinase 1 for STAT3 Ser-727 phosphorylation

Kojima

Sasaki

Ishitani

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Signal transducer and activator of transcription 3 (STAT3) is activated by the IL-6 family of cytokines and growth factors. STAT3 requires phosphorylation on Ser-727, in addition to tyrosine phosphorylation on Tyr-705, to be transcriptionally active. In IL-6 signaling, the two major pathways that derive from the YXXQ and the YSTV motifs of gp130 cause Ser-727 phosphorylation. Here, we show that TGF-␤-activated kinase 1 (TAK1) interacts with STAT3, that the TAK1-Nemo-like kinase (NLK) pathway is efficiently activated by IL-6 through the YXXQ motif, and that this is the YXXQ-mediated H7-sensitive pathway that leads to STAT3 Ser-727 phosphorylation. Because NLK was recently shown to interact with STAT3, we explored the role of STAT3 in activating this pathway. Depletion of STAT3 diminished the IL-6-induced NLK activation by >80% without inhibiting IL-6-induced TAK1 activation or its nuclear entry. We found that STAT3 functioned as a scaffold for TAK1 and NLK in vivo through a region in its carboxyl terminus. Furthermore, the expression of the STAT3 534 -770 region in the nuclei of STAT3-knockdown cells enhanced the IL-6-induced NLK activation in a dose-dependent manner but not the TGF␤-induced NLK activation. TGF␤ did not cause STAT3 Ser-727 phosphorylation, even when the carboxyl region of STAT3 was expressed in the nuclei. Together, these results indicate that STAT3 enhances the efficiency of its own Ser-727 phosphorylation by acting as a scaffold for the TAK1-NLK kinases, specifically in the YXXQ motif-derived pathway.gp130 ͉ YXXQ motif ͉ signaling specificity T he signal transducer and activator of transcription (STAT) family plays pivotal roles in a variety of systems and in development, in response to cytokines and growth factors. STAT family members are activated in the cytoplasm by tyrosine phosphorylation, form dimers, and enter the nucleus, where they act as DNA-binding transcription factors (1). Of the seven known STATs, STAT1, 3, 5A, 5B, and 6 are phosphorylated at one or two serine residues in their carboxyl-terminal transactivation domain (1, 2) and at a critical tyrosine. The serine phosphorylation enhances the transcriptional activity in the case of STAT1 (3), STAT3 (3, 4), and STAT6 (5). STAT3 can be activated by a variety of cytokines, including the IL-6 family, by using gp130 as a common receptor subunit (6), Granulocyte colony-stimulating factor (G-CSF) and erythropoietin, and growth factors, EGF, platelet-derived growth factor, and hepatocyte growth factor, and cytoplasmic tyrosine kinases, including Src and v-Eyk (reviewed in ref. 7). IL-6 uses STAT3 in its major signaling pathway and concomitantly activates the Ras͞Raf͞ ERK and PI3-kinase pathways (7). IL-6, therefore, activates multiple genes, including acute-phase reactants, and the junB, tis11, stat3, c-myc, and c-fos genes, mostly through STAT3 (8-14). In the IL-6 receptor system, the tyrosine-phosphorylated YXXQ motif of gp130 is critical for recruiting STAT3 for subsequent phosphorylation at Tyr-705 by the associated Jak kinases (15). I...

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Spatiotemporal Regulation of c-Fos by ERK5 and the E3 Ubiquitin Ligase UBR1, and Its Biological Role

et al. 2006

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c-Fos is regulated by phosphorylation and multiple turnover mechanisms. We found that c-Fos was ubiquitylated in the cytoplasm during IL-6/gp130 stimulation under MEK inhibition and sought the mechanisms involved in the regulation. We show that sustained ERK5 activity and the E3 ligase UBR1 regulate the stability and subcellular localization of c-Fos. UBR1, rapidly induced by STAT3, interacts with and ubiquitylates c-Fos in the cytoplasm for its accelerated degradation. ERK5 inhibits the nuclear export of c-Fos by phosphorylating Thr232 in the c-Fos NES(221-233) and disrupts the interaction of c-Fos with UBR1 by phosphorylating Ser32. Moreover, UBR1 depletion in HeLa cells, which constitutively express UBR1 at a high level, enhances both c-Fos expression and cell growth, whereas ERK5 depletion reduces both of them. Interestingly, an NES mutant of c-Fos, but not wild-type, substitutes ERK5 activity for HeLa cell proliferation. Thus, this spatiotemporal regulation of c-Fos by ERK5 and UBR1 is critical for the regulation of c-Fos/AP-1.

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Region 752–761 of STAT3 is critical for SRC-1 recruitment and Ser727 phosphorylation

Cited by 10 publications

References 36 publications

STAT3 as a Downstream Mediator of Trk Signaling and Functions

STAT3 as a Downstream Mediator of Trk Signaling and Functions

STAT3 regulates Nemo-like kinase by mediating its interaction with IL-6-stimulated TGFβ-activated kinase 1 for STAT3 Ser-727 phosphorylation

Spatiotemporal Regulation of c-Fos by ERK5 and the E3 Ubiquitin Ligase UBR1, and Its Biological Role

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