Recruitment of Stat1 to chromatin is required for interferon-induced serine phosphorylation of Stat1 transactivation domain

Sadzak, Iwona; Schiff, Melanie; Gattermeier, Irene; Glinitzer, Reingard; Sauer, IM; Saalmüller, Armin; Yang, Edward; Schaljo, Barbara; Kovarik, Pavel

doi:10.1073/pnas.0801794105

Cited by 137 publications

(131 citation statements)

References 43 publications

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“…In addition, the well-known IL-6-induced phosphorylation of STAT3 on S727, which lies in the transactivation domain and is required for function, occurs only when the tyrosinephosphorylated protein can enter the nucleus and bind to DNA [8]. This finding is similar to the previous observations [40] that the recruitment of STAT1 to chromatin is required for interferon-induced phosphorylation of the S727 transactivation domain. Furthermore, the methylation of STAT3 K140 is prevented by the S727A mutation, suggesting that phosphorylation precedes methylation [8].…”

Section: Methylation Of Nfκb and Stat3 Takes Place After They Bind Tosupporting

confidence: 82%

Lysine methylation of promoter-bound transcription factors and relevance to cancer

2010

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p53, NFκB, STAT3, and several other transcription factors are reversibly methylated on lysine residues by enzymes that also modify histones. The methylations of NFκB and STAT3 take place when they are bound to promoters, suggesting a more general model in which the binding of inducible transcription factors to DNA helps to recruit chromatin-modification machinery, which then may modify not only histones but also the bound transcription factors. Mutations of some histone-lysine methyltransferases and demethylases are linked to cancer, and these mutations may alter the methylation not only of histones but also of transcription factors, and thus may be tumorigenic through more than one mechanism. In recent years, much attention has been focused on posttranslational modification of chromatin because of its critical role in regulating gene expression [1]. The N-terminal tails of histones, as well as positions in the globular domains, carry methylations, acetylations, phosphorylations, ADP ribosylations, ubiquitinations, sumoylations, and other modifications [2]. Many different amino acid residues of each of the four core histones have been identified as modification sites [3] and some lysine side chains can be methylated or acetylated alternatively. These modifications provide entry sites for accessory proteins that help to determine higher order chromatin organization, leading to the activation or inactivation of specific genes. The lysine ε-amino groups can receive one, two, or three methyl groups and the extent of lysine methylation at a single lysine residue can be read differently by different effector proteins [4]. H3K4 methylation is associated with an early-elongating form of RNA polymerase II at actively transcribed genes, H3K9 and H3K27 methylation are linked to heterochromatin formation, while H3K36 methylation provides a stable molecular mechanism for establishing chromatin context throughout the genome by distinguishing potential regulatory regions from transcribed chromatin [5]. Moreover, increasing evidence indicates that nonhistone proteins are subject to reversible acetylation or methylation by histone-modifying enzymes. Among these nonhistone targets are transcription factors, hormone receptors, signal transducers, chaperones, and proteins of the cytoskeleton [6][7][8][9][10][11][12]. Although the acetylation of nonhistone proteins has been appreciated for some time [9,13,14], their methylation has been recognized only more recently. Here, we provide a summary of recent work showing lysine methylation of transcription factors that have well-recognized roles in tumorigenesis and of the effects of mutations of lysine methyltransferases and demethylases in cancer, and we cite evidence that at least some modifications take place only on promoter-bound transcription factors. Lysine methylation of nonhistone proteinsReversible modification of histones by methylation and demethylation, which occur at both lysine and arginine residues, plays an important role in many biological processes, including transcri...

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Section: Methylation Of Nfκb and Stat3 Takes Place After They Bind Tosupporting

confidence: 82%

Lysine methylation of promoter-bound transcription factors and relevance to cancer

2010

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“…By contrast, the increase in OVA-specific CTL activity caused by administration of pulsed, STAT-1-deficient myeloid DC was ϳ2-fold. To test whether Stat1S727 phosphorylation in myeloid DC contributed to CD8 ϩ T cell activation and whether DC activity could be enhanced by treatment with IFN-I, 10 5 myeloid DC from wt, STAT-1 Ϫ/Ϫ or Stat1S727A animals were used to immunize wt recipient mice. Before injection the cells were either left untreated, or treated with IFN-␤ for 24 h. Under these conditions, wt DC stimulated CTL activity to be 6-fold greater than in naive mice and this was increased to 8-fold by IFN-I treatment (Fig.…”

Section: Stat-1 Is Required In DC For the Generation Of Ova-specific mentioning

confidence: 99%

Dendritic Cells Require STAT-1 Phosphorylated at Its Transactivating Domain for the Induction of Peptide-Specific CTL

Pilz

Kratky

Stockinger

et al. 2009

The Journal of Immunology

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Phosphorylation of transcription factor STAT-1 on Y701 regulates subcellular localization whereas phosphorylation of the transactivating domain at S727 enhances transcriptional activity. In this study, we investigate the impact of STAT-1 and the importance of transactivating domain phosphorylation on the induction of peptide-specific CTL in presence of the TLR9-dependent immune adjuvant IC31. STAT-1 deficiency completely abolished CTL induction upon immunization, which was strongly reduced in animals carrying the mutation of the S727 phospho-acceptor site. A comparable reduction of CTL was found in mice lacking the type I IFN (IFN-I) receptor, whereas IFN-γ-deficient mice behaved like wild-type controls. This finding suggests that S727-phosphorylated STAT-1 supports IFN-I-dependent induction of CTL. In adoptive transfer experiments, IFN-I- and S727-phosphorylated STAT-1 were critical for the activation and function of dendritic cells. Mice with a T cell-specific IFN-I receptor ablation did not show impaired CTL responses. Unlike the situation observed for CTL development S727-phosphorylated STAT-1 restrained proliferation of naive CD8+ T cells both in vitro and following transfer into Rag-deficient mice. In summary, our data reveal a dual role of S727-phosphorylated STAT-1 for dendritic cell maturation as a prerequisite for the induction of CTL activity and for T cell autonomous control of activation-induced or homeostatic proliferation.

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“…3C suggesting that STAT1 could modulate HSC70/SHPS-1 association. Because STAT1 was dissociated from SHPS-1 upon IGF-I stimulation, we investigated whether IGF-I induces STAT1 phosphorylation at Tyr-701 and Ser-727, which is a prerequisite for transport of STAT1 to the nucleus from the cytoplasm (41,42). As shown in Fig.…”

Section: The Novel Role Of Shps-1 In Mediating Igf-i Signalingmentioning

confidence: 99%

Identification of Novel SHPS-1-associated Proteins and Their Roles in Regulation of Insulin-like Growth Factor-dependent Responses in Vascular Smooth Muscle Cells

Shen

Radhakrishnan

et al. 2009

Molecular & Cellular Proteomics

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Tyrosine phosphatase non-receptor type substrate-1 (SHPS-1), a transmembrane protein, plays a vital role in cell migration and proliferation. Our previous studies have shown that insulin-like growth factor-I (IGF-I) stimulates SHPS-1 phosphorylation, leading to recruitment of SHP-2, c-Src, Shc, and Grb2⅐p85 to phosphorylated SHPS-1. Assembly of this signaling complex is required for optimal stimulation of both mitogen-activated protein and phosphatidylinositol 3-kinase pathways. The main aim of the present study was to identify novel proteins that interacted with the cytoplasmic domain of SHPS-1 (SHPS-1/CD) in response to IGF-I stimulation and define the role of these interactions in mediating specific biological functions. We performed a functional proteomic screening to identify SHPS-1 binding partners using combination of mRNA display and the tandem affinity purification-tag methods. Screening identified a number of proteins not previously known to interact with phosphorylated SHPS-1/CD. These novel SHPS-1 binding partners represent several functional categories including heat shock proteins, protein kinases and phosphatases, and proteins that regulate transcription or translation. In Vivo and in vitro studies suggested that most of the proteins bound to SHPS-1 via binding to one of the four SH2 domain containing proteins, SHP-2, CTK, SUPT6H, and STAT1, that directly bound to SHPS-1. Although the binding of most of these proteins to SHPS-1 was positively regulated by IGF-I, a few were negatively regulated, suggesting differential regulation of protein complexes assembled on SHPS-1/CD in response to IGF-I. Further studies showed that truncation of SHPS-1/CD significantly impaired IGF-I-dependent AKT signal transduction and subsequent biological functions including cell survival, protein synthesis, protein aggregation, and prevention of apoptosis. The results emphasize the importance of formation of SHPS-1 signaling complex induced by IGF-I and provide novel insights into our knowledge of the role of this molecular scaffold in regulation of IGF

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Recruitment of Stat1 to chromatin is required for interferon-induced serine phosphorylation of Stat1 transactivation domain

Cited by 137 publications

References 43 publications

Lysine methylation of promoter-bound transcription factors and relevance to cancer

Lysine methylation of promoter-bound transcription factors and relevance to cancer

Dendritic Cells Require STAT-1 Phosphorylated at Its Transactivating Domain for the Induction of Peptide-Specific CTL

Identification of Novel SHPS-1-associated Proteins and Their Roles in Regulation of Insulin-like Growth Factor-dependent Responses in Vascular Smooth Muscle Cells

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