scholarly journals RBM4a-SRSF3-MAP4K4 Splicing Cascade Constitutes a Molecular Mechanism for Regulating Brown Adipogenesis

2018 ◽  
Vol 19 (9) ◽  
pp. 2646 ◽  
Author(s):  
Hui-Yu Peng ◽  
Yu-Chih Liang ◽  
Tse-Hua Tan ◽  
Huai-Chia Chuang ◽  
Ying-Ju Lin ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Molecular Mechanism ◽  
Rna Binding ◽  
Mitogen Activated Protein Kinase ◽  
Binding Motif ◽  
Brown Adipose ◽  
Study Results ◽  
Mitogen Activated Protein ◽  
Alternatively Spliced ◽  
Brown Adipogenesis

An increase in mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) reportedly attenuates insulin-mediated signaling which participates in the development of brown adipose tissues (BATs). Nevertheless, the effect of MAP4K4 on brown adipogenesis remains largely uncharacterized. In this study, results of a transcriptome analysis (also referred as RNA-sequencing) showed differential expressions of MAP4K4 or SRSF3 transcripts isolated from distinct stages of embryonic BATs. The discriminative splicing profiles of MAP4K4 or SRSF3 were noted as well in brown adipocytes (BAs) with RNA-binding motif protein 4-knockout (RBM4−/−) compared to the wild-type counterparts. Moreover, the relatively high expressions of authentic SRSF3 transcripts encoding the splicing factor functioned as a novel regulator toward MAP4K4 splicing during brown adipogenesis. The presence of alternatively spliced MAP4K4 variants exerted differential effects on the phosphorylation of c-Jun N-terminal protein kinase (JNK) which was correlated with the differentiation or metabolic signature of BAs. Collectively, the RBM4-SRSF3-MAP4K4 splicing cascade constitutes a novel molecular mechanism in manipulating the development of BAs through related signaling pathways.

scholarly journals Phosphorylation of the ARE-binding protein DAZAP1 by ERK2 induces its dissociation from DAZ

2006 ◽  
Vol 399 (2) ◽  
pp. 265-273 ◽  
Author(s):  
Simon Morton ◽  
Huei-Ting Yang ◽  
Ntsane Moleleki ◽  
David G. Campbell ◽  
Philip Cohen ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Rna Binding ◽  
Binding Protein ◽  
Mitogen Activated Protein Kinase ◽  
Raw 264.7 ◽  
Raw 264.7 Macrophages ◽  
Hek 293 ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

A protein in RAW 264.7 macrophages, which became phosphorylated in response to LPS (lipopolysaccharide), was identified as the RNA-binding protein called DAZAP1 [DAZ (deleted in azoospermia)-associated protein 1]. The phosphorylation of this protein was prevented by specific inhibition of MKK1 [MAPK (mitogen-activated protein kinase) kinase 1], indicating that it was phosphorylated via the classical MAPK cascade. Further experiments showed that DAZAP1 was phosphorylated stoichiometrically in vitro by ERK2 (extracellular-signal-regulated protein kinase 2) at two Thr-Pro sequences (Thr269 and Thr315), and that both sites became phosphorylated in HEK-293 (human embryonic kidney 293) cells in response to PMA or EGF (epidermal growth factor), or RAW 264.7 macrophages in response to LPS. Phosphorylation induced by each stimulus was prevented by two structurally distinct inhibitors of MKK1 (PD184352 and U0126), demonstrating that DAZAP1 is a physiological substrate for ERK1/ERK2. The mutation of Thr269 and Thr315 to aspartate or the phosphorylation of these residues caused DAZAP1 to dissociate from its binding partner DAZ. DAZ interacts with PABP [poly(A)-binding protein] and thereby stimulates the translation of mRNAs containing short poly(A) tails [Collier, Gorgoni, Loveridge, Cooke and Gray (2005) EMBO J. 24, 2656–2666]. In the present study we have shown that DAZ cannot bind simultaneously to DAZAP1 and PABP, and suggest that the phosphorylation-induced dissociation of DAZ and DAZAP1 may allow the former to stimulate translation by interacting with PABP.

scholarly journals Mitogen-Activated Protein Kinase Phosphatase 1 Disrupts Proinflammatory Protein Synthesis in Endotoxin-Adapted Monocytes

2013 ◽  
Vol 20 (9) ◽  
pp. 1396-1404 ◽  
Author(s):  
Laura Brudecki ◽  
Donald A. Ferguson ◽  
Charles E. McCall ◽  
Mohamed El Gazzar
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Rna Binding ◽  
Multiorgan Failure ◽  
Mitogen Activated Protein Kinase ◽  
Necrosis Factor Alpha ◽  
Translational Repressor ◽  
Proinflammatory Mediators ◽  
Tnf Α ◽  
Mitogen Activated Protein

ABSTRACTAutotoxic production of proinflammatory mediators during early sepsis induces excessive inflammation, and their later suppression may limit the immune response. We previously reported that sepsis differentially represses transcription and translation of tumor necrosis factor alpha (TNF-α) and interleukin 1β (IL-1β) to reprogram sepsis inflammation. This switch is gene specific and plays a crucial role in the clinically relevant syndrome of endotoxin adaptation/tolerance, multiorgan failure, and poor sepsis outcome. To further define the mechanisms responsible for translation disruption that follows inflammation induction, we used THP-1 human promonocytes as a model of Toll-like receptor 4 (TLR4) responses found in sepsis. We showed that phosphorylation-dependent activation of p38 mitogen-activated protein kinase (MAPK) and translation disruption of TNF-α and IL-6 follow increased MAPK phosphatase 1 (MKP-1) expression and that MKP-1 knockdown rephosphorylates p38 and restores the capacity to translate TNF-α and IL-6 mRNAs. We also observed that the RNA-binding protein motif 4 (RBM4), a p38 MAPK target, accumulates in an unphosphorylated form in the cytosol in endotoxin-adapted cells, suggesting that dephosphorylated RBM4 may function as a translational repressor. Moreover, MKP-1 knockdown promotes RBM4 phosphorylation, blocks its transfer from the nucleus to the cytosol, and reverses translation repression. We also found that microRNA 146a (miR-146a) knockdown prevents and miR-146a transfection induces MKP-1 expression, which lead to increases or decreases in TNF-α and IL-6 translation, respectively. We conclude that a TLR4-, miR-146a-, p38 MAPK-, and MKP-1-dependent autoregulatory pathway regulates the translation of proinflammatory genes during the acute inflammatory response by spatially and temporally modifying the phosphorylation state of RBM4 translational repressor protein.

scholarly journals Role of the RNA-binding Protein Nrd1 and Pmk1 Mitogen-activated Protein Kinase in the Regulation of Myosin mRNA Stability in Fission Yeast

2009 ◽  
Vol 20 (9) ◽  
pp. 2473-2485 ◽  
Author(s):  
Ryosuke Satoh ◽  
Takahiro Morita ◽  
Hirofumi Takada ◽  
Ayako Kita ◽  
Shunji Ishiwata ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Fission Yeast ◽  
Mrna Stability ◽  
Rna Binding ◽  
Binding Protein ◽  
Myosin Ii ◽  
Rna Binding Protein ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein

Myosin II is an essential component of the actomyosin contractile ring and plays a crucial role in cytokinesis by generating the forces necessary for contraction of the actomyosin ring. Cdc4 is an essential myosin II light chain in fission yeast and is required for cytokinesis. In various eukaryotes, the phosphorylation of myosin is well documented as a primary means of activating myosin II, but little is known about the regulatory mechanisms of Cdc4. Here, we isolated Nrd1, an RNA-binding protein with RNA-recognition motifs, as a multicopy suppressor of cdc4 mutants. Notably, we demonstrated that Nrd1 binds and stabilizes Cdc4 mRNA, thereby suppressing the cytokinesis defects of the cdc4 mutants. Importantly, Pmk1 mitogen-activated protein kinase (MAPK) directly phosphorylates Nrd1, thereby negatively regulating the binding activity of Nrd1 to Cdc4 mRNA. Consistently, the inactivation of Pmk1 MAPK signaling, as well as Nrd1 overexpression, stabilized the Cdc4 mRNA level, thereby suppressing the cytokinesis defects associated with the cdc4 mutants. In addition, we demonstrated the cell cycle–dependent regulation of Pmk1/Nrd1 signaling. Together, our results indicate that Nrd1 plays a role in the regulation of Cdc4 mRNA stability; moreover, our study is the first to demonstrate the posttranscriptional regulation of myosin expression by MAPK signaling.

Control of mRNA decay by phosphorylation of tristetraprolin

2008 ◽  
Vol 36 (3) ◽  
pp. 491-496 ◽  
Author(s):  
Heike Sandler ◽  
Georg Stoecklin
Keyword(s):  
Protein Kinase ◽  
Untranslated Region ◽  
Rna Binding ◽  
Rna Binding Protein ◽  
Mitogen Activated Protein Kinase ◽  
Interacting Proteins ◽  
Mitogen Activated Protein ◽  
Kinase Cascade ◽  
Transient Stabilization ◽  
Cytokine Mrnas

TTP (tristetraprolin) is an RNA-binding protein that suppresses inflammation by accelerating the degradation of cytokine mRNAs. TTP binds to an AU-rich element in the 3′-untranslated region of its target mRNAs. In macrophages, the induction of cytokine expression requires activation of the p38-MAPK (mitogen-activated protein kinase)–MK2 [MAPKAP (MAPK-activated protein) kinase-2] kinase cascade. MK2 directly phosphorylates TTP and thereby contributes to transient stabilization of cytokine mRNAs. In the present review, we address the target specificity of TTP, summarize TTP-interacting proteins and discuss how phosphorylation regulates the activity, localization and stability of TTP.

scholarly journals p38 Mitogen-activated protein kinase stabilizes SMN mRNA through RNA binding protein HuR

2009 ◽  
Vol 18 (21) ◽  
pp. 4035-4045 ◽  
Author(s):  
Faraz Farooq ◽  
Sylvia Balabanian ◽  
Xuejun Liu ◽  
Martin Holcik ◽  
Alex MacKenzie
Keyword(s):  
Protein Kinase ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein

scholarly journals BRO1, a novel gene that interacts with components of the Pkc1p-mitogen-activated protein kinase pathway in Saccharomyces cerevisiae.

1996 ◽  
Vol 16 (6) ◽  
pp. 2585-2593 ◽  
Author(s):  
M E Nickas ◽  
M P Yaffe
Keyword(s):  
Protein Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Yeast Cells ◽  
Growth Defect ◽  
Binding Motif ◽  
Temperature Sensitive ◽  
Cell Integrity ◽  
Gene Encoding ◽  
Mitogen Activated Protein ◽  
Kinase Pathway

Yeast cells with mutations in BRO1 display phenotypes similar to those caused by deletion of BCK1, a gene encoding a MEK kinase that functions in a mitogen-activated protein kinase pathway mediating maintenance of cell integrity. bro1 cells exhibit a temperature-sensitive growth defect that is suppressed by the addition of osmotic stabilizers or Ca2+ to the growth medium or by additional copies of the BCK1 gene. At permissive temperatures, bro1 mutants are sensitive to caffeine and respond abnormally to nutrient limitation. A null mutation in BRO1 is synthetically lethal with null mutations in BCK1, MPK1, which encodes a mitogen-activated protein kinase that functions downstream of Bck1p, or PKC1, a gene encoding a protein kinase C homolog that activates Bck1p. Analysis of the isolated BRO1 gene revealed that it encodes a novel, 97-kDa polypeptide which contains a putative SH3 domain-binding motif and is homologous to a protein of unknown function in Caenorhabditis elegans.

scholarly journals Angiotensin II Influences Pre-mRNA Splicing Regulation by Enhancing RBM20 Transcription Through Activation of the MAPK/ELK1 Signaling Pathway

2019 ◽  
Vol 20 (20) ◽  
pp. 5059 ◽  
Author(s):  
Hanfang Cai ◽  
Chaoqun Zhu ◽  
Zhilong Chen ◽  
Rexiati Maimaiti ◽  
Mingming Sun ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Protein Kinase ◽  
Rna Binding ◽  
Mapk Signaling ◽  
Mrna Splicing ◽  
Mitogen Activated Protein Kinase ◽  
Binding Motif ◽  
Cardiac Diseases ◽  
Ang Ii ◽  
The Impact

RNA binding motif 20 (RBM20) is a key regulator of pre-mRNA splicing of titin and other genes that are associated with cardiac diseases. Hormones, like insulin, triiodothyronine (T3), and angiotensin II (Ang II), can regulate gene-splicing through RBM20, but the detailed mechanism remains unclear. This study was aimed at investigating the signaling mechanism by which hormones regulate pre-mRNA splicing through RBM20. We first examined the role of RBM20 in Z-, I-, and M-band titin splicing at different ages in wild type (WT) and RBM20 knockout (KO) rats using RT-PCR; we found that RBM20 is the predominant regulator of I-band titin splicing at all ages. Then we treated rats with propylthiouracil (PTU), T3, streptozotocin (STZ), and Ang II and evaluated the impact of these hormones on the splicing of titin, LIM domain binding 3 (Ldb3), calcium/calmodulin-dependent protein kinase II gamma (Camk2g), and triadin (Trdn). We determined the activation of mitogen-activated protein kinase (MAPK) signaling in primary cardiomyocytes treated with insulin, T3, and Ang II using western blotting; MAPK signaling was activated and RBM20 expression increased after treatment. Two downstream transcriptional factors c-jun and ETS Transcription Factor (ELK1) can bind the promoter of RBM20. A dual-luciferase activity assay revealed that Ang II, but not insulin and T3, can trigger ELK1 and thus promote transcription of RBM20. This study revealed that Ang II can trigger ELK1 through activation of MAPK signaling by enhancing RBM20 expression which regulates pre-mRNA splicing. Our study provides a potential therapeutic target for the treatment of cardiac diseases in RBM20-mediated pre-mRNA splicing.

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