MicroRNA: master controllers of intracellular signaling pathways

Signaling pathways are essential intracellular networks that coordinate molecular outcomes to external stimuli. Tight regulation of these pathways is essential to ensure an appropriate response. MicroRNA (miRNA) is a class of small, non-coding RNA that regulates gene expression at a post-transcriptional level by binding to the complementary sequence on target mRNA, thus limiting protein translation. Intracellular pathways are controlled by protein regulators, such as suppressor of cytokine signaling and A20. Until recently, expression of these classical protein regulators was thought to be controlled solely by transcriptional induction and proteasomal degradation; however, there is a growing body of evidence describing their regulation by miRNA. This new information has transformed our understanding of cell signaling by adding a previously unknown layer of regulatory control. This review outlines the miRNA regulation of these classical protein regulators and describes their broad effects at both cellular and disease levels. We review the regulation of three important signaling pathways, including the JAK/STAT, NF-κB, and TGF-β pathways, and summarize an extensive catalog of their regulating miRNAs. This information highlights the importance of the miRNA regulon and reveals a previously unknown regulatory landscape that must be included in the identification and development of novel therapeutic targets for clinical disorders.