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Protein kinase WNK2 inhibits cell proliferation by negatively modulating the activation of MEK1/ERK1/2

S Moniz1, F Veríssimo, P Matos

  • 1Centre of Human Genetics, Instituto Nacional de Saúde Dr Ricardo Jorge, Lisbon, Portugal.

Oncogene
|August 2, 2007
PubMed

Insights

WNK2 protein kinase depletion activates ERK1/2 signaling, promoting cancer cell proliferation. This suggests WNK2 acts as a tumor suppressor, regulating cell growth via the MEK1/ERK1/2 pathway.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • WNK (With No Lysine) protein kinases represent a recently identified subfamily with unique catalytic domain variations.
  • Four human WNK genes have been identified, highlighting their importance in cellular processes.

Purpose of the Study:

  • To clone and functionally analyze the human WNK2 gene.
  • To investigate the role of WNK2 in regulating cell proliferation and signaling pathways.

Main Methods:

  • RNA interference (RNAi) was used to deplete endogenous WNK2 expression in human cancer cell lines (HeLa and HT29).
  • Kinase-dead WNK2 mutant (WNK2-K207M) was expressed to assess the requirement of WNK2 catalytic activity.
  • Extracellular signal-regulated kinase (ERK)1/2 and ERK5 activation, cell cycle progression (G1/S), and response to epidermal growth factor (EGF) were analyzed.
  • MEK1 phosphorylation and activity were examined to elucidate the molecular mechanism of ERK1/2 activation.

Main Results:

  • WNK2 depletion activated ERK1/2 mitogen-activated protein kinases but not ERK5.
  • Expression of a kinase-dead WNK2 mutant also activated ERK1/2, indicating WNK2's catalytic activity is essential.
  • WNK2 depletion enhanced G1/S cell cycle progression and potentiated cellular responses to low EGF concentrations.
  • ERK1/2 activation in WNK2-depleted cells occurred downstream of Raf kinases, involving MEK1 phosphorylation at serine 298 and subsequent MEK1 upregulation.

Conclusions:

  • WNK2 modulates growth factor-induced cancer cell proliferation through the MEK1/ERK1/2 pathway.
  • WNK2 functions as a candidate tumor suppressor gene.
  • WNK kinases may exhibit coordinated activity in regulating cell proliferation.

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