Translational control of ERK signalling pathway by the mRNA cap-binding protein 4EHP
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA421497 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6359211.fastq.gz | Fastqsanger.gz | |||
| SRR6359212.fastq.gz | Fastqsanger.gz | |||
| SRR6359213.fastq.gz | Fastqsanger.gz | |||
| SRR6359214.fastq.gz | Fastqsanger.gz | |||
| SRR6359215.fastq.gz | Fastqsanger.gz |
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Project description:microRNA (miRNA)-mediated gene silencing is commonly deregulated in a wide variety of diseases. Therefore, a better understanding of how miRNAs govern the translation and stability of mRNAs is of paramount importance. We recently demonstrated that the cap-binding protein 4EHP is recruited by the miRNA machinery to effect translational repression. However, the impact of 4EHP on regulation of endogenous mRNAs and its role in cell biology is debated. Herein, using the ribosome profiling assay, we identify a subset of endogenous mRNAs that are sensitive to translational repression by 4EHP. We show that expression of DUSP6, a phosphatase that reverses ERK1/2 phosphorylation, is regulated by 4EHP. This regulation, which occurs exclusively at the level of mRNA translation, without affecting the stability of Dusp6 mRNA, is engendered through 4EHP- and miRNA-dependent elements in Dusp6 3´UTR. Consequently, 4EHP protein controls ERK1/2 phosphorylation, promotes cell growth and inhibits apoptosis. Our data reveal a crucial role for translational control mechanisms in the regulation of the ERK pathway.
2018-02-20 | GSE107826 | GEO
Project description:Although canonical mRNA degradation is generally recognized to be translation dependent, our understanding of the molecular events that coordinate ribosome movement with the decay machinery is still limited. Here, we show that the 4EHP–GIGYF1/2 complex triggers co-translational mRNA decay as a result of altered ribosome activity during elongation. Human cells lacking 4EHP and GIGYF1 and 2 proteins accumulate transcripts known to be degraded in a translation dependent manner or with prominent ribosome pausing. These include mRNAs encoding secretory and membrane-bound proteins or specific tubulin isotypes, among others. 4EHP–GIGYF1/2 fails to reduce target mRNA levels in the absence of ribosome stalling or upon disruption of its interaction with the cap structure, DDX6 and a GYF domain-associated protein. Our studies reveal how a repressor complex linked to neurological disorders minimizes the protein output of a subset of mRNAs.
2020-10-23 | GSE144841 | GEO
Project description:Although canonical mRNA degradation is generally recognized to be translation dependent, our understanding of the molecular events that coordinate ribosome movement with the decay machinery is still limited. Here, we show that the 4EHP–GIGYF1/2 complex triggers co-translational mRNA decay as a result of altered ribosome activity during elongation. Human cells lacking 4EHP and GIGYF1 and 2 proteins accumulate transcripts known to be degraded in a translation dependent manner or with prominent ribosome pausing. These include mRNAs encoding secretory and membrane-bound proteins or specific tubulin isotypes, among others. 4EHP–GIGYF1/2 fails to reduce target mRNA levels in the absence of ribosome stalling or upon disruption of its interaction with the cap structure, DDX6 and a GYF domain-associated protein. Our studies reveal how a repressor complex linked to neurological disorders minimizes the protein output of a subset of mRNAs.
2020-10-06 | GSE149279 | GEO
Project description:Cells adapt to proteostatic and metabolic stresses, in part, by triggering the phosphorylation of eIF2alpha and the subsequent synthesis of ATF4. eIF2alpha phosphorylation facilitates translational induction of ATF4 by regulating reinitiation of the scanning ribosomes at the ATF4 mRNA’s 5’ leader. In addition to eIF2alpha, ATF4 induction requires other regulators that remain poorly understood. Here, we report an ATF4 regulatory network consisting of eIF4E-Homologous Protein (4EHP), NELF-E, the 40S ribosome, and eIF3 subunits. Specifically, 4EHP was required for ATF4 signaling in the Drosophila larval fat body and in disease models associated with abnormal ATF4 signaling. 4EHP’s mRNA cap-binding domain specifically interacted with NELF-E mRNA, which encodes a regulator of pol II-mediated transcription. Both NELF-E and 4EHP were required for the expression of ATF4 and enzymes that mediate the serine-one-carbon pathway. Knockdown of NELF-E also reduced several subunits of the 40S ribosome and the eIF3 translation initiation factor complex. Reduction of Rps12 and eif3h suppressed physiological ATF4 induction. These results uncover a previously unrecognized ATF4 regulatory network that impacts stress adaptation and pathological outcomes.
2025-11-19 | GSE309407 | GEO
Project description:MicroRNAs (miRNAs) exert a broad influence over gene expression by directing effector activities that impinge on translation and stability of mRNAs. We recently discovered that the cap-binding protein 4EHP is a key component of the mammalian miRNA-Induced Silencing Complex (miRISC), which mediates gene silencing. However, little is known about the mRNA repertoire that is controlled by the 4EHP/miRNA mechanism or its biological importance. Here, using ribosome profiling, we identify a subset of mRNAs that are translationally controlled by 4EHP. We show that the Dusp6 mRNA, which encodes an ERK1/2 phosphatase, is translationally repressed by 4EHP and a specific miRNA, miR-145. This promotes ERK1/2 phosphorylation, resulting in augmented cell growth and reduced apoptosis. Our findings thus empirically define the integral role of translational repression in miRNA-induced gene silencing and reveal a critical function for this process in the control of the ERK signaling cascade in mammalian cells.
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Project description:The EGFR/Ras/ERK signalling pathway is a primary driver of cancer cell proliferation and metastasis in tumours that exhibit high cell-to-cell heterogeneity. While the signalling activity of this pathway is frequently amplified in tumours, it is not understood how the kinetic aspects of its activation in tumours differ from normal cellular signalling. We explored these single-cell kinetic differences using live-cell reporters of ERK signalling in the breast cancer progression series HMT-3522 and found that ERK activity in invasive cells is similar in amplitude to non-malignant cells but is highly dynamic and more disordered, leading to more heterogeneous expression of ERK target genes. We traced this variability to a high degree of amphiregulin-mediated autocrine signalling by invasive cells. Dynamic ERK activity could be transferred from invasive to pre-malignant cells through paracrine signalling in co-culture, and could drive temporal variation in the expression of genes including Fra-1, c-Myc, and Egr1 at the single-cell level. Our findings establish a mechanism for the generation of tumour cell plasticity, in which paracrine signalling in the microenvironment is translated into continually shifting diversity in gene expression profiles, helping drive the phenotypic heterogeneity of tumour cells.
2020-08-01 | GSE118312 | GEO
Project description:The consolidation of learned information into long-lasting memories requires the strengthening of synaptic connections through de novo protein synthesis. Translation initiation factors play a cardinal role in gating the production of new proteins thereby regulating memory formation. Both positive and negative regulators of translation play a critical role in learning and memory consolidation. The eukaryotic initiation factor 4E (eIF4E) homologous protein (4EHP, encoded by the gene Eif4e2) is a pivotal negative regulator of translation but its role in learning and memory is unknown. To address this gap in knowledge, we generated excitatory (glutamatergic: CaMKIIα-positive) and inhibitory (GABAergic: GAD65-positive) conditional knockout mice for 4EHP, which were analyzed in various behavioral memory tasks. Knockout of 4EHP in Camk2a-expressing neurons (4EHP-cKOexc) did not impact long-term memory in either contextual fear conditioning or Morris water maze tasks. Similarly, long-term contextual fear memory was not altered in Gad2-directed 4EHP knockout mice (4EHP-cKOinh). However, when subjected to a short-term T-maze working memory task, both mouse models exhibited impaired cognition. We therefore tested the hypothesis that de novo protein synthesis plays a direct role in working memory. We discovered that phosphorylation of ribosomal protein S6, a measure of mTORC1 activity, is dramatically reduced in the CA1 hippocampus of 4EHP-cKOexc mice. Consistently, genetic reduction of mTORC1 activity in either excitatory or inhibitory neurons was sufficient to impair working memory. Taken together, these findings indicate that translational control by 4EHP and mTORC1 in both excitatory and inhibitory neurons are necessary for working memory.
| S-EPMC9847188 | biostudies-literature
Project description:Fibroblast Growth Factor (FGF) signalling via ERK exerts diverse roles in development and disease. In mammalian preimplantation embryos and naïve pluripotent stem cells ERK promotes differentiation, whereas in primed pluripotent states closer to somatic differentiation ERK sustains self-renewal. How can the same pathway produce different outcomes in two related cell types? To explore context-dependent ERK signalling in embryonic development and differentiation we generated cell and mouse lines that allow for tissue- and time-specific cell intrinsic ERK activation. Using these tools, we find variations in response to ERK are mostly mediated by repression of transcriptional targets that occur in tandem with reductions in chromatin accessibility at regulatory regions. Furthermore, immediate early ERK responses are largely shared by different cell types but become refined producing cell-specific programs as increasing durations of signalling interface with cell specific gene regulatory networks. Induction in naïve pluripotency is accompanied by chromatin changes, whereas in later stages it is not, suggesting that chromatin context doesn’t shape signalling response. Altogether, our data suggest that cell-type specific responses to ERK signalling exploit the same immediate early response, but then sculpt it to specific lineages via repression of distinct cellular programs and downstream indirect stimulation of available enhancer networks.
2024-03-05 | GSE259233 | GEO
Project description:Fibroblast Growth Factor (FGF) signalling via ERK exerts diverse roles in development and disease. In mammalian preimplantation embryos and naïve pluripotent stem cells ERK promotes differentiation, whereas in primed pluripotent states closer to somatic differentiation ERK sustains self-renewal. How can the same pathway produce different outcomes in two related cell types? To explore context-dependent ERK signalling in embryonic development and differentiation we generated cell and mouse lines that allow for tissue- and time-specific cell intrinsic ERK activation. Using these tools, we find variations in response to ERK are mostly mediated by repression of transcriptional targets that occur in tandem with reductions in chromatin accessibility at regulatory regions. Furthermore, immediate early ERK responses are largely shared by different cell types but become refined producing cell-specific programs as increasing durations of signalling interface with cell specific gene regulatory networks. Induction in naïve pluripotency is accompanied by chromatin changes, whereas in later stages it is not, suggesting that chromatin context doesn’t shape signalling response. Altogether, our data suggest that cell-type specific responses to ERK signalling exploit the same immediate early response, but then sculpt it to specific lineages via repression of distinct cellular programs and downstream indirect stimulation of available enhancer networks.
2024-03-05 | GSE259232 | GEO
Project description:Fibroblast Growth Factor (FGF) signalling via ERK exerts diverse roles in development and disease. In mammalian preimplantation embryos and naïve pluripotent stem cells ERK promotes differentiation, whereas in primed pluripotent states closer to somatic differentiation ERK sustains self-renewal. How can the same pathway produce different outcomes in two related cell types? To explore context-dependent ERK signalling in embryonic development and differentiation we generated cell and mouse lines that allow for tissue- and time-specific cell intrinsic ERK activation. Using these tools, we find variations in response to ERK are mostly mediated by repression of transcriptional targets that occur in tandem with reductions in chromatin accessibility at regulatory regions. Furthermore, immediate early ERK responses are largely shared by different cell types but become refined producing cell-specific programs as increasing durations of signalling interface with cell specific gene regulatory networks. Induction in naïve pluripotency is accompanied by chromatin changes, whereas in later stages it is not, suggesting that chromatin context doesn’t shape signalling response. Altogether, our data suggest that cell-type specific responses to ERK signalling exploit the same immediate early response, but then sculpt it to specific lineages via repression of distinct cellular programs and downstream indirect stimulation of available enhancer networks.
2024-03-05 | GSE259236 | GEO