scholarly journals Are STATS Arginine-methylated?

2005 ◽  
Vol 280 (23) ◽  
pp. 21700-21705 ◽  
Author(s):  
Waraporn Komyod ◽  
Uta-Maria Bauer ◽  
Peter C. Heinrich ◽  
Serge Haan ◽  
Iris Behrmann
Keyword(s):  
Arginine Methylation ◽  
Signaling Cascades ◽  
Post Translational Modification ◽  
Protein Arginine Methyltransferases ◽  
Stat Proteins ◽  
Fibrosarcoma Cells ◽  
Catalytically Active ◽  
Interferon Resistance ◽  
Stat Pathway

Transcription factors of the STAT (signal transducer and activator of transcription) family are important in signal transduction of cytokines. They are subject to post-translational modification by phosphorylation on tyrosine and serine residues. Recent evidence suggested that STATs are methylated on a conserved arginine residue within the N-terminal region. STAT arginine methylation has been described to be important for STAT function and loss of arginine methylation was discussed to be involved in interferon resistance of cancer cells. Here we provide several independent lines of evidence indicating that the issue of arginine methylation of STATs has to be reassessed. First, we show that treatment of melanoma and fibrosarcoma cells with inhibitors used to suppress methylation (N-methyl-2-deoxyadenosine, adenosine, dl-homocysteine) had profound and rapid effects on phosphorylation of STAT1 and STAT3 but also on p38 and Erk signaling cascades which are known to cross-talk with the Jak/STAT pathway. Second, we show that anti-methylarginine antibodies did not precipitate specifically STAT1 or STAT3. Third, we show that mutation of Arg31 to Lys led to destabilization of STAT1 and STAT3, implicating an important structural role of Arg31. Finally, purified catalytically active protein arginine methyltransferases (PRMT1, -2, -3, -4, and -6) did not methylate STAT proteins, and cotransfection with PRMT1 did not affect STAT1-controlled reporter gene activity. Taken together, our data suggest the absence of arginine methylation of STAT1 and STAT3.

scholarly journals Role of Protein Arginine Methyltransferases and Inflammation in Muscle Pathophysiology

2021 ◽  
Vol 12 ◽  
Author(s):  
Hyun-Kyung So ◽  
Sunghee Kim ◽  
Jong-Sun Kang ◽  
Sang-Jin Lee
Keyword(s):  
Skeletal Muscle ◽  
Chronic Inflammation ◽  
Muscle Mass ◽  
Skeletal Muscle Mass ◽  
Current Knowledge ◽  
Arginine Methylation ◽  
Muscle Physiology ◽  
Post Translational Modification ◽  
Protein Arginine Methyltransferases

Arginine methylation mediated by protein arginine methyltransferases (PRMTs) is a post-translational modification of both histone and non-histone substrates related to diverse biological processes. PRMTs appear to be critical regulators in skeletal muscle physiology, including regeneration, metabolic homeostasis, and plasticity. Chronic inflammation is commonly associated with the decline of skeletal muscle mass and strength related to aging or chronic diseases, defined as sarcopenia. In turn, declined skeletal muscle mass and strength can exacerbate chronic inflammation. Thus, understanding the molecular regulatory pathway underlying the crosstalk between skeletal muscle function and inflammation might be essential for the intervention of muscle pathophysiology. In this review, we will address the current knowledge on the role of PRMTs in skeletal muscle physiology and pathophysiology with a specific emphasis on its relationship with inflammation.

scholarly journals The Role of the PRMT5–SND1 Axis in Hepatocellular Carcinoma

Epigenomes ◽  
2021 ◽  
Vol 5 (1) ◽  
pp. 2
Author(s):  
Tanner Wright ◽  
Yalong Wang ◽  
Mark T. Bedford
Keyword(s):  
Hepatocellular Carcinoma ◽  
Staphylococcal Nuclease ◽  
Arginine Methylation ◽  
Effector Protein ◽  
Cancer Type ◽  
Post Translational Modification ◽  
Protein Arginine Methyltransferases ◽  
Disease Phenotypes ◽  
Tudor Domain

Arginine methylation is an essential post-translational modification (PTM) deposited by protein arginine methyltransferases (PRMTs) and recognized by Tudor domain-containing proteins. Of the nine mammalian PRMTs, PRMT5 is the primary enzyme responsible for the deposition of symmetric arginine methylation marks in cells. The staphylococcal nuclease and Tudor domain-containing 1 (SND1) effector protein is a key reader of the marks deposited by PRMT5. Both PRMT5 and SND1 are broadly expressed and their deregulation is reported to be associated with a range of disease phenotypes, including cancer. Hepatocellular carcinoma (HCC) is an example of a cancer type that often displays elevated PRMT5 and SND1 levels, and there is evidence that hyperactivation of this axis is oncogenic. Importantly, this pathway can be tempered with small-molecule inhibitors that target PRMT5, offering a therapeutic node for cancer, such as HCC, that display high PRMT5–SND1 axis activity. Here we summarize the known activities of this writer–reader pair, with a focus on their biological roles in HCC. This will help establish a foundation for treating HCC with PRMT5 inhibitors and also identify potential biomarkers that could predict sensitivity to this type of therapy.

scholarly journals Characterization of the Drosophila protein arginine methyltransferases DART1 and DART4

2004 ◽  
Vol 379 (2) ◽  
pp. 283-289 ◽  
Author(s):  
Marie-Chloé BOULANGER ◽  
Tina Branscombe MIRANDA ◽  
Steven CLARKE ◽  
Marco di FRUSCIO ◽  
Beat SUTER ◽  
...  
Keyword(s):  
Rna Binding ◽  
Developmental Stages ◽  
Rna Binding Proteins ◽  
Genetic System ◽  
Arginine Methylation ◽  
Type I ◽  
Protein Arginine Methyltransferases ◽  
Arginine Residues ◽  
Drosophila Protein

The role of arginine methylation in Drosophila melanogaster is unknown. We identified a family of nine PRMTs (protein arginine methyltransferases) by sequence homology with mammalian arginine methyltransferases, which we have named DART1 to DART9 (Drosophilaarginine methyltransferases 1–9). In keeping with the mammalian PRMT nomenclature, DART1, DART4, DART5 and DART7 are the putative homologues of PRMT1, PRMT4, PRMT5 and PRMT7. Other DART family members have a closer resemblance to PRMT1, but do not have identifiable homologues. All nine genes are expressed in Drosophila at various developmental stages. DART1 and DART4 have arginine methyltransferase activity towards substrates, including histones and RNA-binding proteins. Amino acid analysis of the methylated arginine residues confirmed that both DART1 and DART4 catalyse the formation of asymmetrical dimethylated arginine residues and they are type I arginine methyltransferases. The presence of PRMTs in D. melanogaster suggest that flies are a suitable genetic system to study arginine methylation.

scholarly journals Receptors for interleukin-3 (IL-3) and growth hormone mediate an IL-6- type transcriptional induction in the presence of JAK2 or STAT3

Blood ◽  
1995 ◽  
Vol 86 (5) ◽  
pp. 1671-1679 ◽  
Author(s):  
Y Wang ◽  
KK Morella ◽  
J Ripperger ◽  
CF Lai ◽  
DP Gearing ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Expression Vectors ◽  
Protein Activation ◽  
Stat Proteins ◽  
Interleukin 3 ◽  
Dose Dependent ◽  
Transcriptional Induction ◽  
Stimulation Of ◽  
Stat Pathway

To determine the specificity of signal transducer and activator of transcription (STAT) protein activation by box 3 motif-deficient hematopoietin receptors, expression vectors encoding the receptors for growth hormone, interleukin-3 (IL-3), and IL-4 were transiently transfected into COS-1 cells, together with expression vectors for Janus kinases (JAKs) and STAT proteins. Each receptor mediated a dose- dependent activation of STAT1 and STAT3, and for IL-3R and GHR this process was enhanced by JAK2. The data suggest that a box 3 motif in the cytoplasmic domain of the signal-transducing receptor to the JAK/STAT pathway. Transfection of the receptors, in combination with STAT3, into HepG2 cells reconstituted a cytokine-dependent stimulation of gene transcription through IL-6 response elements, providing evidence for a functional role of STAT3 in controlling gene expression.

scholarly journals Targeting Signal Transducer and Activator of Transcription Signaling Pathway in Leukemias

2009 ◽  
Vol 27 (26) ◽  
pp. 4422-4432 ◽  
Author(s):  
Mustafa Benekli ◽  
Heinz Baumann ◽  
Meir Wetzler
Keyword(s):  
Potential Role ◽  
Cellular Transformation ◽  
Therapeutic Strategies ◽  
Signal Transducer ◽  
Stat Proteins ◽  
Constitutive Activation ◽  
Targeting Signal ◽  
Novel Therapeutic Strategies ◽  
Stat Pathway

Signal transducer and activator of transcription (STAT) proteins comprise a seven-member family of latent cytoplasmic transcription factors that are activated through tyrosine phosphorylation by a variety of cytokines and growth factors. Aberrant activation of STATs accompanies malignant cellular transformation with resultant leukemogenesis. Constitutive activation of STATs has been demonstrated in various leukemias. A better understanding of the mechanisms of dysregulation of the STAT pathway and understanding of the cause and effect relationship in leukemogenesis may serve as a basis for designing novel therapeutic strategies directed against STATs. Mechanisms of STAT activation, the potential role of STAT signaling in leukemogenesis, and recent advances in drug discovery targeting the STAT pathway are the focus of this review.

Biochemical and Computational Approaches for the Large-Scale Analysis of Protein Arginine Methylation by Mass Spectrometry

2020 ◽  
Vol 21 (7) ◽  
pp. 725-739
Author(s):  
Daniele Musiani ◽  
Enrico Massignani ◽  
Alessandro Cuomo ◽  
Avinash Yadav ◽  
Tiziana Bonaldi
Keyword(s):  
Mass Spectrometry ◽  
Large Scale ◽  
High Resolution Mass Spectrometry ◽  
Arginine Methylation ◽  
Research Field ◽  
Scale Analysis ◽  
Post Translational Modification ◽  
Large Scale Analysis ◽  
Protein Arginine Methylation

: The absence of efficient mass spectrometry-based approaches for the large-scale analysis of protein arginine methylation has hindered the understanding of its biological role, beyond the transcriptional regulation occurring through histone modification. In the last decade, however, several technological advances of both the biochemical methods for methylated polypeptide enrichment and the computational pipelines for MS data analysis have considerably boosted this research field, generating novel insights about the extent and role of this post-translational modification. : Here, we offer an overview of state-of-the-art approaches for the high-confidence identification and accurate quantification of protein arginine methylation by high-resolution mass spectrometry methods, which comprise the development of both biochemical and bioinformatics methods. The further optimization and systematic application of these analytical solutions will lead to ground-breaking discoveries on the role of protein methylation in biological processes.

Altered expression of STAT genes in periodontitis

2021 ◽  
pp. 1-8
Author(s):  
Leila Gholami ◽  
Abolfazl Movafagh ◽  
Elham Badrlou ◽  
Naghme Nazer ◽  
Mohsen Yari ◽  
...  
Keyword(s):  
Blood Levels ◽  
P Value ◽  
Related Condition ◽  
Altered Expression ◽  
Stat Proteins ◽  
Periodontal Tissues ◽  
Inflammatory Conditions ◽  
Total Control ◽  
Stat Pathway

Signal Transducer and Activator of Transcription (STAT) pathway is functionally located downstream of Janus kinases proteins and can integrate signals from diverse pathways, thus regulating several aspects of immune responses. Although contribution of STAT proteins in the pathogenesis of several inflammatory conditions has been confirmed, their role in the development of periodontitis has been less appraised. Thus, we assessed levels of STAT transcripts in the periodontal tissues and circulation of affected individuals compared with the corresponding controls. Expression of STAT1 was remarkably lower in tissues samples of patients compared with control tissues (Ratio of mean expression (RME) = 0.15, SE = 0.99, P value = 0.01). Expression of STAT3 was lower in total periodontitis tissues compared with total control tissues (RME = 0.20, SE = 0.95, P value = 0.02). Expression of STAT6 was higher in total periodontitis tissues compared with total control tissues (RME = 0.5.38, SE = 0.74, P value < 0.001). Expressions of other STAT genes were statistically similar in tissues obtained from cases and controls. Moreover, blood levels of all STAT genes were statistically similar between patients and controls. Correlation analysis demonstrated significant correlations between tissues levels of individual STAT genes as well as between their blood levels. However, tissue and blood levels of each STAT gene were not correlated. The current investigation potentiates the role of certain STAT genes in the development of this immune-related condition and warrants functional assays to clarify the mechanism.

scholarly journals Protein arginine methyltransferases: promising targets for cancer therapy

2021 ◽  
Author(s):  
Jee Won Hwang ◽  
Yena Cho ◽  
Gyu-Un Bae ◽  
Su-Nam Kim ◽  
Yong Kee Kim
Keyword(s):  
Cell Cycle ◽  
Cancer Therapy ◽  
Phase 1 ◽  
Cell Types ◽  
Arginine Methylation ◽  
Protein Methylation ◽  
Post Translational Modification ◽  
Nonhistone Proteins ◽  
Protein Arginine Methyltransferases ◽  
Protein Arginine Methylation

AbstractProtein methylation, a post-translational modification (PTM), is observed in a wide variety of cell types from prokaryotes to eukaryotes. With recent and rapid advancements in epigenetic research, the importance of protein methylation has been highlighted. The methylation of histone proteins that contributes to the epigenetic histone code is not only dynamic but is also finely controlled by histone methyltransferases and demethylases, which are essential for the transcriptional regulation of genes. In addition, many nonhistone proteins are methylated, and these modifications govern a variety of cellular functions, including RNA processing, translation, signal transduction, DNA damage response, and the cell cycle. Recently, the importance of protein arginine methylation, especially in cell cycle regulation and DNA repair processes, has been noted. Since the dysregulation of protein arginine methylation is closely associated with cancer development, protein arginine methyltransferases (PRMTs) have garnered significant interest as novel targets for anticancer drug development. Indeed, several PRMT inhibitors are in phase 1/2 clinical trials. In this review, we discuss the biological functions of PRMTs in cancer and the current development status of PRMT inhibitors in cancer therapy.

The role of protein arginine methyltransferases in kidney diseases

2020 ◽  
Vol 134 (15) ◽  
pp. 2037-2051
Author(s):  
Chunyun Zhang ◽  
Shougang Zhuang
Keyword(s):  
Kidney Diseases ◽  
Kidney Injury ◽  
Renal Tumors ◽  
Post Translational Modification ◽  
Protein Arginine Methyltransferases ◽  
Extracellular Signaling ◽  
Metabolic Products ◽  
Arginine Residues ◽  
And Oxidative Stress

Abstract The methylation of arginine residues by protein arginine methyltransferases (PRMTs) is a crucial post-translational modification for many biological processes, including DNA repair, RNA processing, and transduction of intra- and extracellular signaling. Previous studies have reported that PRMTs are extensively involved in various pathologic states, including cancer, inflammation, and oxidative stress reaction. However, the role of PRMTs has not been well described in kidney diseases. Recent studies have shown that aberrant function of PRMTs and its metabolic products—symmetric dimethylarginine (SDMA) and asymmetric dimethylarginine (ADMA)—are involved in several renal pathological processes, including renal fibrosis, acute kidney injury (AKI), diabetic nephropathy (DN), hypertension, graft rejection and renal tumors. We aim in this review to elucidate the possible roles of PRMTs in normal renal function and various kidney diseases.

scholarly journals A systematic survey of PRMT interactomes reveals key roles of arginine methylation in the global control of RNA splicing and translation

2019 ◽  
Author(s):  
Huan-Huan Wei ◽  
Xiao-Juan Fan ◽  
Yue Hu ◽  
Xiao-Xu Tian ◽  
Meng Guo ◽  
...  
Keyword(s):  
Rna Splicing ◽  
Ribosomal Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Arginine Methylation ◽  
Mrna Splicing ◽  
Post Translational Modification ◽  
Protein Arginine Methyltransferases ◽  
Full Picture ◽  
Catalytic Network

AbstractThousands of proteins undergo arginine methylation, a widespread post-translational modification catalyzed by various protein arginine methyltransferases (PRMTs). However, a full picture of the catalytic network for each PRMT is lacking and the global understanding of their biological roles remains limited. Here we systematically identified interacting proteins for all human PRMTs and demonstrated that they are functionally important for mRNA splicing and translation. We showed that the interactomes of human PRMTs are significantly overlapped with the known methylarginine containing proteins, and different PRMTs are functionally complementary with a high degree of overlap in their substrates and high similarities between their putative methylation motifs. Importantly, arginine methylation is significantly enriched in RNA binding proteins involved in regulating RNA splicing and translation, and inhibition of PRMTs leads to global alteration of alternative splicing and suppression of translation. In particular, ribosomal proteins are pervasively modified with methylarginine, and mutations on their methylation sites suppress ribosome assembly, translation, and eventually cell growth. Collectively, our study provides a novel global view of different PRMT networks and uncovers critical functions of arginine methylation in the regulation of mRNA splicing and translation.

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