RNA-binding proteins as a point of convergence of the PI3K and p38 MAPK pathways

BackgroundEpilepsy is one of the most common neurological diseases characterized by excessive hyperexcitability of neurons. Molecular mechanisms of epilepsy are diverse and not really understood. All in common is the misregulation of proteins that determine excitability such as potassium and sodium channels as well as GABA receptors; which are all known as biomarkers for epilepsy. Two recently identified key pathways involve the kinases mechanistic target of rapamycin (mTOR) and mitogen-activated protein kinases (MAPK). Interestingly, mRNAs coding for those biomarkers are found to be localized at or near synapses indicating a local misregulation of synthesis and activity.ResultsResearch in the last decade indicates that RNA-binding proteins (RBPs) responsible for mRNA localization, stability and translation mediate local expression control. Among others, they are affected by mTOR and MAPK to guide expression of epileptic factors. These results suggest that mTOR/MAPK act on RBPs to regulate the fate of mRNAs, indicating a misregulation of protein expression at synapses in epilepsy.ConclusionWe propose that mTOR and MAPK regulate RBPs, thereby guiding the local expression of their target-mRNAs encoding for markers of epilepsy. Thus, misregulated mTOR/MAPK-RBP interplay may result in excessive local synthesis of ion channels and receptors thereby leading to hyperexcitability. Continuous stimulation of synapses further activates mTOR/MAPK pathway reinforcing their effect on RBP-mediated expression control establishing the basis for epilepsy. Here, we highlight findings showing the tight interplay between mTOR as well as MAPK with RBPs to control expression for epileptic biomarkers.

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“…In this context, kinases regulate those proteins and, therewith, their ability to control posttranscriptional gene expression [22, 46]. …”

Section: Expression Control By the Mapk Pathway: A Regulator Of Epilementioning

confidence: 99%

mTOR and MAPK: from localized translation control to epilepsy

Pernice¹,

Schieweck²,

Kiebler³

et al. 2016

BMC Neurosci

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“…TIS11 family proteins are distal targets for signaling pathways, allowing transfer of external stimuli to the mRNA decay machinery (Venigalla and Turner, 2012). The p38 MAP kinase (MAPK) and its downstream kinase MAPK-activated protein kinase 2 (MK2) play a pivotal role in ARE-mediated mRNA decay.…”

Section: Introductionmentioning

confidence: 99%

“…The conserved C-terminal sequence between TIS11b and TIS11d is indicated between dotted lines. Other phosphoserines have been identified in vitro and in phosphoproteomic studies of ectopically expressed TTP (reviewed in Venigalla and Turner, 2012). However, the relevance of these phosphosites remains to be validated experimentally.…”

Section: Introductionmentioning

confidence: 99%

The cAMP pathway regulates mRNA decay through phosphorylation of the RNA-binding protein TIS11b/BRF1

Rataj

Planel

Desroches-Castan

et al. 2016

MBoC

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“…A single p38-ATF/CREB signal transduction pathway of fission yeast can coordinately induce (promote transcription and RNA stability) and repress (promote RNA decay) distinct sets of RNA transcripts, as is required for developmental decisions in response to stress and other stimuli. Pathway-mediated regulation of RNA stability and decay are probably conserved, because p38 SAPKs help to regulate RNA stability and decay in metazoans (51,52) and budding yeast (67), whose lineage diverged from that of fission yeast more than a billion years ago (68). It remains to be seen if the regulation of RNA decay in other species involves ATF/CREB family proteins and the corresponding RNA sequence motifs, as it does in fission yeast.…”

Section: Discussionmentioning

confidence: 99%

“…Such indirect control by p38 family kinases has been implicated previously (51,52), but cannot explain satisfactorily the interdependent regulation of posttranscriptional RNA decay by M26 sequence motifs and the Atf1-Pcr1 heterodimer (Fig. 2, 3, and 5).…”

Section: Discussionmentioning

confidence: 99%

A Stress-Activated, p38 Mitogen-Activated Protein Kinase–ATF/CREB Pathway Regulates Posttranscriptional, Sequence-Dependent Decay of Target RNAs

Gao

Wagnon

Protacio

et al. 2013

Molecular and Cellular Biology

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Broadly conserved, mitogen-activated/stress-activated protein kinases (MAPK/SAPK) of the p38 family regulate multiple cellular processes. They transduce signals via dimeric, basic leucine zipper (bZIP) transcription factors of the ATF/CREB family (such as Atf2, Fos, and Jun) to regulate the transcription of target genes. We report additional mechanisms for gene regulation by such pathways exerted through RNA stability controls. The Spc1 (Sty1/Phh1) kinase-regulated Atf1-Pcr1 (Mts1-Mts2) heterodimer of the fission yeast Schizosaccharomyces pombe controls the stress-induced, posttranscriptional stability and decay of sets of target RNAs. Whole transcriptome RNA sequencing data revealed that decay is associated nonrandomly with transcripts that contain an M26 sequence motif. Moreover, the ablation of an M26 sequence motif in a target mRNA is sufficient to block its stress-induced loss. Conversely, engineered M26 motifs can render a stable mRNA into one that is targeted for decay. This stress-activated RNA decay (SARD) provides a mechanism for reducing the expression of target genes without shutting off transcription itself. Thus, a single p38-ATF/CREB signal transduction pathway can coordinately induce (promote transcription and RNA stability) and repress (promote RNA decay) transcript levels for distinct sets of genes, as is required for developmental decisions in response to stress and other stimuli.

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RNA-binding proteins as a point of convergence of the PI3K and p38 MAPK pathways

Cited by 40 publications

References 94 publications

mTOR and MAPK: from localized translation control to epilepsy

mTOR and MAPK: from localized translation control to epilepsy

The cAMP pathway regulates mRNA decay through phosphorylation of the RNA-binding protein TIS11b/BRF1

A Stress-Activated, p38 Mitogen-Activated Protein Kinase–ATF/CREB Pathway Regulates Posttranscriptional, Sequence-Dependent Decay of Target RNAs

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