Identification of STAT2 Serine 287 as a Novel Regulatory Phosphorylation Site in Type I Interferon-induced Cellular Responses

Steen, Håkan C.; Nogusa, Shoko; Thapa, Roshan J.; Basagoudanavar, Suresh H.; Gill, Amanda L.; Merali, Salim; Barrero, Carlos; Balachandran, Siddharth; Gamero, Ana M.

doi:10.1074/jbc.m112.402529

Cited by 29 publications

(23 citation statements)

References 40 publications

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“…Serine 287 was identified as phosphorylated in response to IFN-α treatment 34 . Sequence alignment revealed no conservation of S287 between human and mouse STAT2.…”

Section: Stat2 Serine/threonine Phosphorylationmentioning

confidence: 96%

STAT2 phosphorylation and signaling

Steen

Gamero

2013

JAK-STAT

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STAT2 is an essential transcription factor in type I IFN mediated anti-viral and anti-proliferative signaling. STAT2 function is regulated by tyrosine phosphorylation, which is the trigger for STAT-dimerization, subsequent nuclear translocation, and transcriptional activation of IFN stimulated genes. Evidence of additional STAT2 phosphorylation sites has emerged as well as novel roles for STAT2 separate from the classical ISGF3-signaling. This review aims to summarize knowledge of phosphorylation-mediated STAT2-regulation and future avenues of related STAT2 research.

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“…Serine 287 was identified as phosphorylated in response to IFN-α treatment 34 . Sequence alignment revealed no conservation of S287 between human and mouse STAT2.…”

Section: Stat2 Serine/threonine Phosphorylationmentioning

confidence: 96%

STAT2 phosphorylation and signaling

Steen

Gamero

2013

JAK-STAT

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“…This post-translational event is important for signaling and results in enhanced antiproliferative and antiviral response to IFN-a. This finding suggests the presence of a regulatory serine residue in STAT2 that affects the response to IFN treatment (Steen et al, 2012). We did not investigate the specific nature of STAT2 phosphorylation that occurs in response to HPP1 overexpression with or without IFN-a treatment in our colon cancer model.…”

Section: Discussionmentioning

confidence: 97%

“…In this regard, our results are similar to those demonstrated in IFN-a-treated hepatoma cells, including pSTAT2 recruitment and resultant expression of OAS-1 and IFI-44 (Testoni et al, 2011a). Interestingly, in a fibrosarcoma cell line, the functional activity of STAT2 is augmented with serine phosphorylation in an IFN-dependent manner (Steen et al, 2012). This post-translational event is important for signaling and results in enhanced antiproliferative and antiviral response to IFN-a.…”

Section: Discussionmentioning

confidence: 99%

The Tumor Suppressive Effects of HPP1 Are Mediated Through JAK-STAT-Interferon Signaling Pathways

Hernandez

Elahi

Clark

et al. 2015

DNA and Cell Biology

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1HPP1, a novel tumor suppressive epidermal growth factor (EGF)-like ligand, mediates its effects through signal transducer and activators of transcription (STAT) activation. We previously demonstrated the importance of STAT1 activation for HPP1 function; however the contribution of STAT2 remains unclear. We sought to delineate the components of JAK-STAT-interferon (IFN) signaling specifically associated with HPP1s biological effects. Using stable HPP1-HCT116 transfectants, expression analyses were performed by polymerase chain reaction (PCR)/western blotting while expression knockdowns were achieved using siRNA. Growth parameters evaluated included proliferation, cell cycle distribution, and anchorage-independent growth. STAT dimerization, translocation, and DNA binding were examined by reporter assays, fluorescent microscopy, and chromatin immunoprecipitation (ChIP), respectively. Forced expression of HPP1 in colon cancer cell lines results in the upregulation of total and activated levels of STAT2. We have also determined that JAK1 and JAK2 are activated in response to HPP1 overexpression, and are necessary for subsequent STAT activation. Overexpression of HPP1 was associated with significant increases in STAT1:STAT1 ( p = 0.007) and STAT1:STAT2 ( p = 0.036) dimer formation, as well as subsequent nuclear translocation. By ChIP, binding of activated STAT1 and STAT2 to the interferon-signaling regulatory element promoter sites of the selected genes, protein kinase RNA-activated (PKR), IFI44, and OAS1 was demonstrated. STAT2 knockdown resulted in partial abrogation of HPP1s growth suppressive activity with increased proliferation ( p < 0.0001), reduced G1/G0 phase cell cycle fraction, and a restoration of growth potential in soft agar ( p < 0.01). Presumably as a consequence of upregulation of IFN signaling elements, HPP1 overexpression resulted in an acquisition of exogenous IFN sensitivity. Physiologic doses of IFN-a resulted in a significant reduction in proliferation ( p < 0.001) and increase in G1/G0 cell cycle arrest in HPP1 transfectants. STAT2 is necessary for HPP1-associated growth suppression, and mediates these effects through activation of IFN-a pathways. Given the interest in therapeutic targeting of oncogenic erbB proteins, further understanding of HPP1s role as a tumor suppressive EGF-like ligand is warranted.

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“…The first serine phosphorylation of STAT2 (S287) was revealed by the work of Steen et al (2013). Phosphorylation-defective mutants of S287 of STAT2 enhanced the ability of ISGF3 to bind to DNA, revealing that this phosphorylation is a negative regulatory event.…”

Section: Stat2mentioning

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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Identification of STAT2 Serine 287 as a Novel Regulatory Phosphorylation Site in Type I Interferon-induced Cellular Responses

Cited by 29 publications

References 40 publications

STAT2 phosphorylation and signaling

STAT2 phosphorylation and signaling

The Tumor Suppressive Effects of HPP1 Are Mediated Through JAK-STAT-Interferon Signaling Pathways

Responses to Cytokines and Interferons that Depend upon JAKs and STATs

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