The DUSP26 Phosphatase Activator Adenylate Kinase 2 Regulates FADD Phosphorylation and Cell Growth

Nat Commun. 2014;5:3351. doi: 10.1038/ncomms4351.

Abstract

Adenylate kinase 2 (AK2), which balances adenine nucleotide pool, is a multi-functional protein. Here we show that AK2 negatively regulates tumour cell growth. AK2 forms a complex with dual-specificity phosphatase 26 (DUSP26) phosphatase and stimulates DUSP26 activity independently of its AK activity. AK2/DUSP26 phosphatase protein complex dephosphorylates fas-associated protein with death domain (FADD) and regulates cell growth. AK2 deficiency enhances cell proliferation and induces tumour formation in a xenograft assay. This anti-growth function of AK2 is associated with its DUSP26-stimulating activity. Downregulation of AK2 is frequently found in tumour cells and human cancer tissues showing high levels of phospho-FADD(Ser194). Moreover, reconstitution of AK2 in AK2-deficient tumour cells retards both cell proliferation and tumourigenesis. Consistent with this, AK2(+/-) mouse embryo fibroblasts exhibit enhanced cell proliferation with a significant alteration in phospho-FADD(Ser191). These results suggest that AK2 is an associated activator of DUSP26 and suppresses cell proliferation by FADD dephosphorylation, postulating AK2 as a negative regulator of tumour growth.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenylate Kinase / genetics
  • Adenylate Kinase / metabolism*
  • Animals
  • Cell Line
  • Cell Proliferation / genetics
  • Cell Proliferation / physiology
  • Dual-Specificity Phosphatases / genetics
  • Dual-Specificity Phosphatases / metabolism*
  • Electrophoresis, Gel, Two-Dimensional
  • Fas-Associated Death Domain Protein / genetics
  • Fas-Associated Death Domain Protein / metabolism
  • HeLa Cells
  • Humans
  • In Vitro Techniques
  • MCF-7 Cells
  • Male
  • Mice
  • Mice, Nude
  • Mitogen-Activated Protein Kinase Phosphatases / genetics
  • Mitogen-Activated Protein Kinase Phosphatases / metabolism*
  • Phosphorylation
  • Tandem Mass Spectrometry
  • Xenograft Model Antitumor Assays

Substances

  • FADD protein, human
  • Fas-Associated Death Domain Protein
  • Adenylate Kinase
  • adenylate kinase 2
  • Mitogen-Activated Protein Kinase Phosphatases
  • DUSP26 protein, human
  • Dual-Specificity Phosphatases