TRAF2-mediated Lys63-linked ubiquitination of DUSP14/MKP6 is essential for its phosphatase activity

Cell Signal. 2016 Jan;28(1):145-51. doi: 10.1016/j.cellsig.2015.10.017. Epub 2015 Oct 28.


Dual-specificity phosphatase 14 (DUSP14, also known as MKP6) is a MAP kinase phosphatase that dephosphorylates JNK, ERK, and p38 in vitro. We recently reported that DUSP14 negatively regulates T-cell activation and immune responses by interfering activation of TAB1-TAK1 complex. However, the molecular mechanism that regulates the phosphatase activity of DUSP14 remains unclear. Here, we report the post-translational modification of DUSP14 by ubiquitination. Mass spectrometry and mutational analyses identified that DUSP14 was Lys63-linked ubiquitinated at lysine 103 residue. Furthermore, DUSP14 inducibly interacted with the E3 ligase TRAF2 during T-cell receptor (TCR) signaling; TRAF2 shRNA knockdown reduced the DUSP14 ubiquitination. We also show that ubiquitination of DUSP14 was required for its phosphatase activity during TCR signaling. Together, these findings reveal a novel mechanism by which TRAF2 mediates Lys63-linked ubiquitination of DUSP14, leading to DUSP14 activation in T cells.

Keywords: DUSP14/MKP6; T-cell receptor signaling; TRAF2; Ubiquitination.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dual-Specificity Phosphatases / genetics
  • Dual-Specificity Phosphatases / metabolism*
  • Humans
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Lymphocyte Activation / genetics
  • Lysine / metabolism*
  • MAP Kinase Kinase Kinases / metabolism
  • Mitogen-Activated Protein Kinase Phosphatases / metabolism*
  • NF-kappa B / metabolism
  • Phosphorylation
  • Protein Processing, Post-Translational / genetics*
  • T-Lymphocytes / immunology*
  • TNF Receptor-Associated Factor 2 / metabolism*
  • Ubiquitin / metabolism*
  • Ubiquitination


  • NF-kappa B
  • TNF Receptor-Associated Factor 2
  • Ubiquitin
  • JNK Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinases
  • Mitogen-Activated Protein Kinase Phosphatases
  • DUSP14 protein, human
  • Dual-Specificity Phosphatases
  • Lysine