Control of mRNA decay by phosphorylation of tristetraprolin

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.

Download Full-text

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

Molecular Biology of the Cell ◽

10.1091/mbc.e08-09-0893 ◽

2009 ◽

Vol 20 (9) ◽

pp. 2473-2485 ◽

Cited By ~ 25

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.

Download Full-text

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

Human Molecular Genetics ◽

10.1093/hmg/ddp352 ◽

2009 ◽

Vol 18 (21) ◽

pp. 4035-4045 ◽

Cited By ~ 60

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

Download Full-text

Molecular mechanisms of phosphorylation-regulated TTP (tristetraprolin) action and screening for further TTP-interacting proteins

Biochemical Society Transactions ◽

10.1042/bst0381632 ◽

2010 ◽

Vol 38 (6) ◽

pp. 1632-1637 ◽

Cited By ~ 6

Author(s):

Christopher Tiedje ◽

Alexey Kotlyarov ◽

Matthias Gaestel

Keyword(s):

Protein Kinase ◽

Mrna Stability ◽

Molecular Mechanisms ◽

Rna Binding ◽

Hybrid Approach ◽

Mitogen Activated Protein Kinase ◽

Interacting Proteins ◽

Interaction Partners ◽

Mitogen Activated Protein ◽

Dependent Interaction

TTP (tristetraprolin) is an RNA-binding protein which regulates mRNA stability or translation or both. The molecular mechanisms which are responsible and which discriminate between regulation of mRNA stability and translation are not completely understood so far, but are clearly dependent on p38 MAPK (mitogen-activated protein kinase)/MK (MAPK-activated protein kinase) 2/3-mediated phosphorylation of TTP. To learn more about these mechanisms, phosphorylation-dependent TTP-interacting proteins could be of great interest. Many interacting partners, which belong to the mRNA-processing and -regulating machinery, have been identified by hypothesis-driven co-immunoprecipitation and in the classical Y2H (yeast two-hybrid) approach, where TTP was identified as prey, and are summarized in the present paper. However, because of transactivating properties of TTP, an unbiased Y2H approach using TTP as bait was hindered. Since novel methods for the identification of phosphorylation-dependent interaction partners and of interactors of full-length auto-activating proteins in eukaryotic systems have evolved in the last few years, these methods should be applied to screen for additional phosphorylation-dependent interaction partners of TTP and could lead towards a complete understanding of TTP function at the molecular level.

Download Full-text

The RNA-Binding Protein PCBP1 Functions as a Tumor Suppressor in Prostate Cancer by Inhibiting Mitogen Activated Protein Kinase 1

Cellular Physiology and Biochemistry ◽

10.1159/000492315 ◽

2018 ◽

Vol 48 (4) ◽

pp. 1747-1754 ◽

Cited By ~ 8

Author(s):

Yingying Zhang ◽

Lin Meng ◽

Lin Xiao ◽

Ruiwang Liu ◽

Zhonghai Li ◽

...

Keyword(s):

Prostate Cancer ◽

Protein Kinase ◽

Rna Binding ◽

Binding Protein ◽

Rna Binding Protein ◽

Mitogen Activated Protein Kinase ◽

Mrna Levels ◽

Mitogen Activated Protein

Background/Aims: Poly r(C) binding protein (PCBP) 1 or heterogeneous ribonucleoprotein (hnRNP) E1 is a RNA binding protein functional in multiple biological processes. In prostate cancer (PCa), PCBP1 loss was shown to be involved with increased stemness in PCacells; however, the underlying mechanism remains unclear. Method: The role of PCBP1 in prostate tumor formationwas determined by xenograft assays. Immunoprecipitationand mass spectrometry were performed to find the pathways altered after PCBP1 knockdown. Cell proliferation, migration, invasion, and soft agar colony formationassays and xenograft assays were used to determine the role of target protein pathogenesis regulation and formation of PCa. QRT-PCR was performedto quantify relative mRNA expression. Results: The expression of mitogen activated protein kinase 1 (MAPK1) or extracellular signal regulated kinase 2 (ERK2) was increased following PCBP1 loss. Attenuation of MAPK1 inhibited in vitro and in vivo tumorigenicity and metastasis in PCa cell line, PC3. Overexpression of MAPK1 in the PC3 cells increased the tumorigenicity and metastasis. Analysis of PCBP1 and MAPK1 mRNA levels in 25 PCa patients compared to tumor-adjacent normal tissue confirmed an inverse correlation between PCBP1 and MAPK1 expression. Conclusions: PCBP1 can act as a suppressor of tumor in prostate epithelial cells by inhibiting MAPK1 expression.

Download Full-text