Mnk2 alternative splicing modulates the p38-MAPK pathway and impacts Ras-induced transformation

Cell Rep. 2014 Apr 24;7(2):501-513. doi: 10.1016/j.celrep.2014.03.041. Epub 2014 Apr 13.

Abstract

The kinase Mnk2 is a substrate of the MAPK pathway and phosphorylates the translation initiation factor eIF4E. In humans, MKNK2, the gene encoding for Mnk2, is alternatively spliced yielding two splicing isoforms with differing last exons: Mnk2a, which contains a MAPK-binding domain, and Mnk2b, which lacks it. We found that the Mnk2a isoform is downregulated in breast, lung, and colon tumors and is tumor suppressive. Mnk2a directly interacts with, phosphorylates, activates, and translocates p38α-MAPK into the nucleus, leading to activation of its target genes, increasing cell death and suppression of Ras-induced transformation. Alternatively, Mnk2b is pro-oncogenic and does not activate p38-MAPK, while still enhancing eIF4E phosphorylation. We further show that Mnk2a colocalization with p38α-MAPK in the nucleus is both required and sufficient for its tumor-suppressive activity. Thus, Mnk2a downregulation by alternative splicing is a tumor suppressor mechanism that is lost in some breast, lung, and colon tumors.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Active Transport, Cell Nucleus
  • Alternative Splicing*
  • Animals
  • Cell Nucleus / metabolism*
  • Cell Transformation, Neoplastic / metabolism*
  • MAP Kinase Signaling System*
  • Mice
  • Protein Binding
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • p38 Mitogen-Activated Protein Kinases / metabolism*
  • ras Proteins / metabolism

Substances

  • Mknk2 protein, mouse
  • Protein-Serine-Threonine Kinases
  • p38 Mitogen-Activated Protein Kinases
  • ras Proteins