Alternative Translation Initiation Generates a Functionally Distinct Isoform of the Stress-Activated Protein Kinase MK2

Cell Rep. 2019 Jun 4;27(10):2859-2870.e6. doi: 10.1016/j.celrep.2019.05.024.

Abstract

Alternative translation is an important mechanism of post-transcriptional gene regulation leading to the expression of different protein isoforms originating from the same mRNA. Here, we describe an abundant long isoform of the stress/p38MAPK-activated protein kinase MK2. This isoform is constitutively translated from an alternative CUG translation initiation start site located in the 5' UTR of its mRNA. The RNA helicase eIF4A1 is needed to ensure translation of the long and the known short isoforms of MK2, of which the molecular properties were determined. Only the short isoform phosphorylated Hsp27 in vivo, supported migration and stress-induced immediate early gene (IEG) expression. Interaction profiling revealed short-isoform-specific binding partners that were associated with migration. In contrast, the long isoform contains at least one additional phosphorylatable serine in its unique N terminus. In sum, our data reveal a longer isoform of MK2 with distinct physiological properties.

Keywords: 5′ UTR; MAPKAPK2; alternative translation initiation; eIF4A1; ribosome footprinting.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Gene Expression Regulation
  • HEK293 Cells
  • Heat-Shock Proteins / genetics
  • Heat-Shock Proteins / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins / chemistry
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • MAP Kinase Signaling System / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Molecular Chaperones / genetics
  • Molecular Chaperones / metabolism
  • Peptide Chain Initiation, Translational*
  • Phosphorylation
  • Protein Isoforms / chemistry
  • Protein Isoforms / metabolism
  • Protein Serine-Threonine Kinases / chemistry
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • RAW 264.7 Cells
  • RNA Helicases / antagonists & inhibitors
  • RNA Helicases / metabolism
  • RNA, Messenger / metabolism
  • RNA, Small Interfering
  • p38 Mitogen-Activated Protein Kinases / metabolism*

Substances

  • HSPB1 protein, human
  • Heat-Shock Proteins
  • Intracellular Signaling Peptides and Proteins
  • Molecular Chaperones
  • Protein Isoforms
  • RNA, Messenger
  • RNA, Small Interfering
  • MAP-kinase-activated kinase 2
  • Protein Serine-Threonine Kinases
  • p38 Mitogen-Activated Protein Kinases
  • RNA Helicases