The role of KSRP in mRNA decay and microRNA precursor maturation

Advanced Review

Roberto Gherzi, Ching‐Yi Chen, Michele Trabucchi, Andres Ramos, Paola Briata

Published Online: May 06 2010

DOI: 10.1002/wrna.2

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Abstract KH‐type splicing regulatory protein (KSRP)/FBP2, a single‐strand nucleic acid binding protein originally identified as both an RNA‐binding protein and a transcription factor, affects RNA fates at multiple levels. In this review we will discuss the ability of KSRP to (1) promote decay of labile mRNAs by interacting with some components of the mRNA decay machinery and (2) favor the maturation of a select group of microRNA precursors. We also discuss how its peculiar modular structure allows KSRP to specifically interact with a wide spectrum of RNA sequences and how post‐translational modifications influence KSRP functions in cell proliferation and differentiation. Copyright © 2010 John Wiley & Sons, Ltd. This article is categorized under: RNA Evolution and Genomics > Ribonomics RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications RNA Turnover and Surveillance > Regulation of RNA Stability

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Schematic representation of the primary structure of human KH‐type splicing regulatory protein (KSRP). NLS is for nuclear localization signal. S193 is the AKT1/2 phosphorylation site while T692 is the MAPK p38 phosphorylation site.

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KSRP interacts with the TL of a class of miRNA precursors and participates in both nuclear Drosha and cytoplasmic Dicer complexes. As a consequence, the maturation of select miRNAs is favored. Lin‐28 interacts with a partly overlapping group of miRNA precursors and inhibits their maturation.

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The mRNA decay‐promoting function of KSRP is regulated by phosphorylation. (a) In myoblasts, differentiative cues induce p38 MAPK activation that phosphorylates KSRP at T692. Phosphorylation by p38 impairs the ability of KSRP to interact with some mRNAs (including myogenin) leading to their stabilization and accumulation. This mechanism, cooperating with transcriptional events, leads to myoblast differentiation into myofibers. GM is for Growth Medium, DM is for differentiation medium. (b) PI3K‐AKT signaling pathway is activated by growth factors. AKT phosphorylates KSRP at S193 and impairs its ability to promote the decay of unstable mRNAs. As a consequence, the inherently labile β‐catenin mRNA is stabilized and the protein accumulates in the nucleus where it exerts its cellular functions.

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KSRP recruits to the ARE‐containing mRNAs the enzymatic machines responsible for the decay of inherently unstable transcripts.

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