WNK2 modulates MEK1 activity through the Rho GTPase pathway

Cell Signal. 2008 Oct;20(10):1762-8. doi: 10.1016/j.cellsig.2008.06.002. Epub 2008 Jun 14.

Abstract

WNK protein kinases form a kinase subfamily expressed in multi-cellular organisms and the human genome encodes four distinct WNK genes. Human WNK2 has been recently identified as a cell growth regulator that modulates activation of the ERK1/2 protein kinase and is epigenetically silenced in gliomas. Here we provide mechanistic insight into how WNK2 affects ERK activation. We found that WNK2 depletion decreased RhoA activation and promoted GTP-loading of Rac1, leading to stimulation of the Rac1-effector PAK1, which is the kinase responsible for subsequent phosphorylation of MEK1 at serine 298, thereby increasing MEK affinity towards ERK1/2. We propose that WNK2 controls a RhoA-mediated cross-talk mechanism that regulates the efficiency with which MEK1 can activate ERK1/2 upon growth factor stimulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Enzyme Activation
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Gene Silencing
  • Humans
  • MAP Kinase Kinase 1 / metabolism*
  • Phosphoserine / metabolism
  • Protein Serine-Threonine Kinases / deficiency
  • Protein Serine-Threonine Kinases / metabolism*
  • Recombinant Proteins / metabolism
  • p21-Activated Kinases / metabolism
  • rac1 GTP-Binding Protein / metabolism
  • rhoA GTP-Binding Protein / metabolism*

Substances

  • Recombinant Proteins
  • Phosphoserine
  • WNK2 protein, human
  • Protein Serine-Threonine Kinases
  • p21-Activated Kinases
  • Extracellular Signal-Regulated MAP Kinases
  • MAP Kinase Kinase 1
  • rac1 GTP-Binding Protein
  • rhoA GTP-Binding Protein