Signaling by p38 MAPK stimulates nuclear localization of the microprocessor component p68 for processing of selected primary MicroRNAs

Academic Article


  • The importance of microRNAs (miRNAs) in biological and disease processes necessitates a better understanding of the mechanisms that regulate miRNA abundance. We showed that the activities of the mitogen-activated protein kinase (MAPK) p38 and its downstream effector kinaseMAPK-activated protein kinase 2 (MK2) were necessary for the efficient processing of a subset of primary miRNAs (pri-miRNAs). Through yeast two-hybrid screening, we identified p68 (also known as DDX5), a key component of the Drosha complex that processes pri-miRNAs, as an MK2-interacting protein, and we found that MK2 phosphorylated p68 at Ser 197 in cells. In wild-type mouse embryonic fibroblasts (MEFs) treated with a p38 inhibitor or in MK2-deficient (MK2-/-) MEFs, expression of a phosphomimetic mutant p68 fully restored pri-miRNA processing, suggesting that MK2-mediated phosphorylation of p68 was essential for this process. We found that, whereas p68 was present in the nuclei of wild-type MEFs, it was found mostly in the cytoplasm of MK2-/- MEFs. Nuclear localization of p68 depended on MK2-mediated phosphorylation of Ser197. In addition, inhibition of p38 MAPK promoted the growth of wild-type MEFs and breast cancer MCF7 cells by enhancing the abundance of c-Myc through suppression of the biogenesis of the miRNA miR-145,which targets c-Myc.Because pri-miRNAprocessing occurs in the nucleus, our findings suggest that the p38 MAPK-MK2 signaling pathway promotes miRNA biogenesis by facilitating the nuclear localization of p68.
  • Authors

    Published In

  • Science Signaling  Journal
  • Digital Object Identifier (doi)

    Author List

  • Hong S; Noh H; Chen H; Padia R; Pan ZK; Su SB; Jing Q; Ding HF; Huang S
  • Volume

  • 6
  • Issue

  • 266