scholarly journals The Molecular Basis of Drug Discovery Targeting the Regulatory Mechanism of MAPK Signaling via the Spatial Regulation of RNA-binding Proteins

2019 ◽  
Vol 139 (1) ◽  
pp. 7-12
Author(s):  
Ryosuke Satoh
Cell Cycle ◽  
2017 ◽  
Vol 16 (8) ◽  
pp. 723-724 ◽  
Author(s):  
Kaloyan M. Tsanov ◽  
George Q. Daley

2017 ◽  
Vol 9 (415) ◽  
pp. eaah5436 ◽  
Author(s):  
Daisuke Ito ◽  
Mami Hatano ◽  
Norihiro Suzuki

Advanced genetic approaches have accelerated the identification of causative genes linked to the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Most of the disease-related proteins encoded by these genes form aggregates in the cellular machineries that regulate RNA and protein quality control in cells. Cross-talk among the signaling pathways governing these machineries leads to pathological cascades mediated by the accumulation of mutant RNA binding proteins. We outline the molecular basis of ALS and FTD pathogenesis and discuss the prospects for therapeutic strategies to treat these diseases.


2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Reiko Sugiura ◽  
Ryosuke Satoh ◽  
Shunji Ishiwata ◽  
Nanae Umeda ◽  
Ayako Kita

Mitogen-activated protein kinases (MAPKs), which are found in all eukaryotes, are signal transducing enzymes playing a central role in diverse biological processes, such as cell proliferation, sexual differentiation, and apoptosis. The MAPK signaling pathway plays a key role in the regulation of gene expression through the phosphorylation of transcription factors. Recent studies have identified several RNA-binding proteins (RBPs) as regulators of MAPK signaling because these RBPs bind to the mRNAs encoding the components of the MAPK pathway and regulate the stability of their transcripts. Moreover, RBPs also serve as targets of MAPKs because MAPK phosphorylate and regulate the ability of RBPs to bind and stabilize target mRNAs, thus controlling various cellular functions. In this review, we present evidence for the significance of the MAPK signaling in the regulation of RBPs and their target mRNAs, which provides additional information about the regulatory mechanism underlying gene expression. We further present evidence for the clinical importance of the posttranscriptional regulation of mRNA stability and its implications for drug discovery.


2021 ◽  
Author(s):  
Meghna Sobti ◽  
Benjamin J. Mead ◽  
Cátia Igreja ◽  
Alastair G. Stewart ◽  
Mary Christie

AbstractThe GIGYF proteins associate with 4EHP and RNA-associated proteins to elicit transcript-specific translational repression. However, the mechanism by which the GIGYF1/2-4EHP complex is recruited to its target transcripts remain unclear. Here we report the crystal structures of the GYF domains from GIGYF1 and GIGYF2 in complex with proline-rich sequences from miRISC-binding proteins TNRC6C and TNRC6A, respectively. The TNRC6 proline-rich motifs bind to a conserved array of aromatic residues on the surface of the GIGYF1/2 GYF domain, bridging 4EHP to Argonaute-miRNA mRNA targets. Our structures also reveal a phenylalanine residue conserved from yeast to human GYF domains that contributes to GIGYF2 thermostability. The molecular details we outline here are likely to be conserved between GIGYF1/2 and other RNA-binding proteins to elicit 4EHP-mediated repression in different biological contexts.


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