Activation of the Janus Kinase/Signal Transducer and Activator of Transcription Pathway by Osmotic Shock

Gatsios, Petros; Terstegen, Lara; Schliess, Freimut; Häussinger, Dieter; Kerr, Ian M.; Heinrich, Peter C.; Graeve, Lutz

doi:10.1074/jbc.273.36.22962

Cited by 78 publications

(76 citation statements)

References 54 publications

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Section: Figuresupporting

confidence: 55%

“…Sorbitol (600 mM) was required for effective Stat activation, which was independent of gp130 or Jaks, but seemed to depend upon cell shrinkage (68,69). We did not detect Stat activation when 400 mM sorbitol was used, possibly secondary to low levels of Stat activation at this concentration, as previously reported (68,69). Our results are consistent with the experience from a large number of laboratories that physiologic activators of stress kinases, such as IL-1 and TNF, do not typically activate Stat tyrosine phosphorylation or DNA binding (70).…”

Section: Figurementioning

confidence: 99%

“…When cells are treated with high concentrations of sorbitol, stress kinases can contribute to Stat activation (68,69). Sorbitol (600 mM) was required for effective Stat activation, which was independent of gp130 or Jaks, but seemed to depend upon cell shrinkage (68,69).…”

Section: Figurementioning

confidence: 99%

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Inhibition of IL-6 and IL-10 Signaling and Stat Activation by Inflammatory and Stress Pathways

Ahmed¹,

Ivashkiv

2000

The Journal of Immunology

120

110

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The development and resolution of an inflammatory process are regulated by a complex interplay among cytokines that have pro- and anti-inflammatory effects. Effective and sustained action of a proinflammatory cytokine depends on synergy with other inflammatory cytokines and antagonism of opposing cytokines that are often highly expressed at inflammatory sites. We analyzed the effects of the inflammatory and stress agents, IL-1, TNF-α, LPS, sorbitol, and H2O2, on signaling by IL-6 and IL-10, pleiotropic cytokines that activate the Jak-Stat signaling pathway and have both pro- and anti-inflammatory actions. IL-1, TNF-α, and LPS blocked the activation of Stat DNA binding and tyrosine phosphorylation by IL-6 and IL-10, but not by IFN-γ, in primary macrophages. Inhibition of Stat activation correlated with inhibition of expression of IL-6-inducible genes. The inhibition was rapid and independent of de novo gene induction and occurred when the expression of suppressor of cytokine synthesis-3 was blocked. Inhibition of IL-6 signaling was mediated by the p38 subfamily of stress-activated protein kinases. Jak1 was inhibited at the level of tyrosine phosphorylation, indicating that inhibition occurred at least in part upstream of Stats in the Jak-Stat pathway. Experiments using Stat3 mutated at serine 727 and using truncated IL-6Rs suggested that the target of inhibition is contained within the membrane-proximal region of the cytoplasmic domain of the gp130 subunit of the IL-6 receptor and is different from the SH2 domain-containing protein-tyrosine phosphatase/suppressor of cytokine synthesis-3 docking site. These results identify a new level at which IL-1 and TNF-α modulate signaling by pleiotropic cytokines such as IL-6 and IL-10 and provide a molecular basis for the previously described antagonism of certain IL-6 actions by IL-1.

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Section: Figuresupporting

confidence: 55%

Section: Figurementioning

confidence: 99%

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Inhibition of IL-6 and IL-10 Signaling and Stat Activation by Inflammatory and Stress Pathways

Ahmed¹,

Ivashkiv

2000

The Journal of Immunology

120

110

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“…Dictyostelium STATc, like metazoan STATs 1 and 3 (12), can be activated by either ligand stimulation or hyperosmotic stress (13,14). The activating ligand for STATc is differentiation inducing factor (DIF-1), a chlorinated polyketide that is produced by the prespore cells and that induces prestalk-specific gene expression (15,16).…”

mentioning

confidence: 99%

Identification of the kinase that activates a nonmetazoan STAT gives insights into the evolution of phosphotyrosine-SH2 domain signaling

Araki

Kawata

Williams

2012

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

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SH2 domains are integral to many animal signaling pathways. By interacting with specific phosphotyrosine residues, they provide regulatable protein-protein interaction domains. Dictyostelium is the only nonmetazoan with functionally characterized SH2 domains, but the cognate tyrosine kinases are unknown. There are no orthologs of the animal tyrosine kinases, but there are very many tyrosine kinase-like kinases (TKLs), a group of kinases which, despite their family name, are classified mainly as serine-threonine kinases. STATs are transcription factors that dimerize via phosphotyrosine-SH2 domain interactions. STATc is activated by phosphorylation on Tyr922 when cells are exposed to the prestalk inducer differentiation inducing factor (DIF-1), a chlorinated hexaphenone. We show that in a null mutant for Pyk2, a tyrosine-specific TKL, exposure to DIF-1 does not activate STATc. Conversely, overexpression of Pyk2 causes constitutive STATc activation. Pyk2 phosphorylates STATc on Tyr922 in vitro and complexes with STATc both in vitro and in vivo. This demonstration that a TKL directly activates a STAT has significant implications for understanding the evolutionary origins of SH2 domain-phosphotyrosine signaling. It also has mechanistic implications. Our previous work suggested that a predicted constitutive STATc tyrosine kinase activity is counterbalanced in vivo by the DIF-1-regulated activity of PTP3, a Tyr922 phosphatase. Here we show that the STATc-Pyk2 complex is formed constitutively by an interaction between the STATc SH2 domain and phosphotyrosine residues on Pyk2 that are generated by autophosphorylation. Also, as predicted, Pyk2 is constitutively active as a STATc kinase. This observation provides further evidence for this highly atypical, possibly ancestral, STAT regulation mechanism. S H2 domains form part of a paradigmatic "writer/reader/ eraser" control module (1, 2) in which the writers are tyrosine kinases (TKs), the readers are SH2 domains, and the erasers are protein tyrosine phosphatases (PTPs). In principle no one element of such a three-component system can function usefully independently of the other two. So how could such a three-component system have evolved? Here the fungi and the amoebozoan Dictyostelium have been informative.Metazoa possess large numbers of TKs, but the only unicellular organisms known to possess them are choanoflagellates, unicellular close relatives of the Metazoa (3, 4). Although neither Dictyostelium nor fungi possess TKs, they do have PTPs, thus suggesting that tyrosine phosphorylation arose in a common ancestor of fungi and Amoebozoa, mediated perhaps by dualspecificity kinases and regulated by dephosphorylation via PTPs (2). There are no phosphotyrosine-binding SH2 domains in fungi, but there is a sequence-related domain within the SPT6 protein that binds phospho-serine and that may have been ancestral to modern SH2 domains (5). In the fungi, therefore, phosphorylation of tyrosine appears to be used solely as a direct modulator of enzymatic function, but in Dictyoste...

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“…Although the phosphorylation of NHE1 itself does not change upon a cell volume decrease (Grinstein et al, 1992), it is known that several kinases are activated by decreased cell volume and tyrosine phosphorylation is increased (Krump et al, 1997;Hoffmann et al, 2009). One tyrosine kinase activated by decreased cell volume is Janus kinase 2 (Jak2) (Gatsios et al, 1998). Jak2 has been found to be required for full activation of NHE1 by decreased cell volume in Chinese Hamster Ovary (CHO) cells, where Jak2 activates NHE1 through phosphorylating and activating Calmodulin (CaM), which then binds to and activates NHE1 (Garnovskaya et al, 2003).…”

Section: Acute Cell Volume Regulation By Inorganic Ion Transport In Ementioning

confidence: 99%

Cell volume regulation in mammalian oocytes and preimplantation embryos

Baltz

Zhou

2012

Molecular Reproduction Devel

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SUMMARYThe earliest stages of preimplantation embryos are particularly sensitive to increased osmolarity, even within the physiological range. This sensitivity contributed to persistent developmental arrest, even when embryos were cultured in vitro in older, conditioned culture media, and seems to arise when embryos at the 1-and 2-cell stages accumulate inorganic ions used for cell volume homeostasis at too high a level, through activation of coupled Na þ /H þ and HCO 3 À /Cl À exchange. Such accumulation of inorganic ions can be disruptive since, above a certain level, the increased ionic strength disrupts cellular biochemistry and macromolecular functions and alters membrane potential. To counter this, embryos have evolved mechanisms of cell volume regulation that are unique to early preimplantation embryogenesis. The primary role of these is glycine accumulation via the GLYT1 transporter, with a secondary contribution by betaine accumulation via the SIT1 transporter. Independent cell-volume regulation first arises in the oocyte only after ovulation is triggered, when the strong oocyte-zona pellucida adhesion present in germinal vesicle stage oocytes in the ovarian follicle is released and GLYT1 becomes activated to begin accumulating glycine. Open questions still remain regarding how these processes are regulated.Mol. Reprod. Dev. 79: 821-831, 2012. ß

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Activation of the Janus Kinase/Signal Transducer and Activator of Transcription Pathway by Osmotic Shock

Cited by 78 publications

References 54 publications

Inhibition of IL-6 and IL-10 Signaling and Stat Activation by Inflammatory and Stress Pathways

Inhibition of IL-6 and IL-10 Signaling and Stat Activation by Inflammatory and Stress Pathways

Identification of the kinase that activates a nonmetazoan STAT gives insights into the evolution of phosphotyrosine-SH2 domain signaling

Cell volume regulation in mammalian oocytes and preimplantation embryos

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