Activation of Different Stat5 Isoforms Contributes to Cell-Type-Restricted Signaling in Response to Interferons

Meinke, Andreas; Barahmand‐pour, Fariba; Wöhrl, S; Stoiber, Dagmar; Decker, Thomas

doi:10.1128/mcb.16.12.6937

Cited by 165 publications

(114 citation statements)

References 68 publications

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“…10,12,32 Our data presented in this study suggest a novel mechanism for IFNg-mediated activation of PI3K, involving interactions between STAT5b, Gab2 and the Src kinase Fyn (summarized in Figure 9). Whereas STAT5b can be phosphorylated in monocyte and T-cell lines in response to IFNg, 33 here we show activation of STAT5, a previously undocumented activity of IFNg in intestinal epithelial cells. This STAT5 phosphorylation in response to IFNg was inhibited by use of the broad-spectrum JAK kinase inhibitor, AG490, and was also STAT1 dependent, being significantly reduced by STAT1-specific siRNA.…”

Section: Discussionmentioning

confidence: 80%

Interferon-γ-induced increases in intestinal epithelial macromolecular permeability requires the Src kinase Fyn

Smyth

Phan

Wang

et al. 2011

Laboratory Investigation

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Interferon-g (IFNg) is an important immunoregulatory cytokine that can also decrease intestinal epithelial barrier function. Little is known about the intracellular signalling events immediately subsequent to IFNg/IFNg receptor interaction that mediate increases in epithelial permeability; data that could be used to ablate this effect of IFNg while leaving its immunostimulatory effects intact. This study assessed the potential involvement of Src family kinases in IFNg-induced increases in epithelial permeability using confluent filter-grown monolayers of the human colon-derived T84 epithelial cell line. Inhibition of Src kinase with the pharmacologic PP1 and use of Fyn kinase-specific siRNA significantly reduced IFNg-induced increases in epithelial permeability as gauged by translocation of noninvasive E. coli (HB101 strain) and flux of horseradish peroxidase (HRP) across monolayers of T84 cells. However, the drop in transepithelial resistance elicited by IFNg was not affected by either treatment. Immunoblotting revealed that IFNg activated the transcription factor STAT5 in T84 cells, and immunoprecipitation studies identified an IFNg-inducible interaction between STAT5b and the PI3K regulatory subunit p85a through formation of a complex requiring the adaptor molecule Gab2. siRNA targeting STAT5b and Gab2 reduced IFNg-induced increases in epithelial permeability and phosphorylation of PI3K(p85a). PP1 and Fyn siRNA reduced IFNg-induced PI3K activity (indicated by decreased phospho-Akt) and the formation of the STAT5b/PI3K(p85a) complex. Collectively, the results suggest the formation of a Fyn-dependent STAT5b/Gab2/PI3K complex that links IFNg to PI3K signalling and the regulation of macromolecular permeability in a model enteric epithelium.

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Section: Discussionmentioning

confidence: 80%

Interferon-γ-induced increases in intestinal epithelial macromolecular permeability requires the Src kinase Fyn

Smyth

Phan

Wang

et al. 2011

Laboratory Investigation

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“…We do not know the functional implication of this finding, but several works have already described a discrimination of Stat5a and Stat5b activation after specific stimuli. In this sense, stimulation of the promonocytic U937 cells with IFN-␣ and IFN-␥ leads to tyrosine phosphorylation and transactivation of Stat5a but not Stat5b (Meinke et al, 1996). The same study reported that IFN-␥ did not activate either Stat5a or Stat5b in HeLa cells despite the expression of both Stat5 isoforms at similar levels (Meinke et al, 1996).…”

Section: Discussionmentioning

confidence: 80%

“…In this sense, stimulation of the promonocytic U937 cells with IFN-␣ and IFN-␥ leads to tyrosine phosphorylation and transactivation of Stat5a but not Stat5b (Meinke et al, 1996). The same study reported that IFN-␥ did not activate either Stat5a or Stat5b in HeLa cells despite the expression of both Stat5 isoforms at similar levels (Meinke et al, 1996). Furthermore, granulocyte-monocyte colony-stimulating factor stimulates Stat5a but not Stat5b activation in human peripheral-blood monocytes (Rosen et al, 1996), whereas the same stimulus in human neutrophils activates Stat5b and not Stat5a (AlShami et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

STAT5a Activation Mediates the Epithelial to Mesenchymal Transition Induced by Oncogenic RhoA.

Benitah¹,

Valerón²,

Rui

et al. 2003

MBoC

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The involvement of Rho GTPases in signal transduction pathways leading to transcription activation is one of the major roles of this family of GTPases. Thus, the identification of transcription factors regulated by Rho GTPases and the understanding of the mechanisms of their activation and its biological outcome are of great interest. Here, we provide evidence that Rho GTPases modulate Stat5a, a transcription factor of the family of signal transducers and activators of transcription. RhoA triggers tyrosine phosphorylation (Y696) of Stat5a via a JAK2-dependent mechanism and promotes DNA-binding activity of Stat5a. Tyrosine phosphorylation of Stat5a is also stimulated physiologically by lysophosphatidic acid (LPA) in a Rho-dependent manner. Simultaneously, RhoA reduces serine phosphorylation of Stat5a at both serine residues S726 and S780, resulting in a further increase of activity as defined by mutagenesis experiments. Furthermore, serine dephosphorylation of Stat5a by RhoA does not take place by down-modulation of either JNK1, MEK1, or p38 MAP kinases, as determined by transfection experiments or chemical inhibition of both MEK1, p38, and JNK serine kinases. Thus, RhoA regulates Stat5a via tyrosine phosphorylation and via a yet to be determined novel down-modulating pathway that involves serine dephosphorylation. Finally, we provide evidence for a role of Stat5a in RhoA-induced epithelial-to-mesenchymal transition with concomitant increase in vimentin expression, E-cadherin down-regulation, and cell motility

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“…46 Besides the canonical activation of STAT1, IFNγ induces activation of STAT5. 47 Given our findings of STAT5 as a regulator of miR-155 expression, it is tempting to speculate that STAT5 is also involved in IFNγ-mediated miR-155 expression. We looked for, but did not find, involvement of NFkB in miR-155 expression in malignant CTCL T cells.…”

Section: Methodsmentioning

confidence: 99%

STAT5-mediated expression of oncogenic miR-155 in cutaneous T-cell lymphoma

et al. 2013

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Activation of Different Stat5 Isoforms Contributes to Cell-Type-Restricted Signaling in Response to Interferons

Cited by 165 publications

References 68 publications

Interferon-γ-induced increases in intestinal epithelial macromolecular permeability requires the Src kinase Fyn

Interferon-γ-induced increases in intestinal epithelial macromolecular permeability requires the Src kinase Fyn

STAT5a Activation Mediates the Epithelial to Mesenchymal Transition Induced by Oncogenic RhoA.

STAT5-mediated expression of oncogenic miR-155 in cutaneous T-cell lymphoma

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