Biological cross-talk between WNK1 and the transforming growth factor beta-Smad signaling pathway

J Biol Chem. 2007 Jun 22;282(25):17985-96. doi: 10.1074/jbc.M702664200. Epub 2007 Mar 28.


WNKs (with no lysine (K)), unique serine/threonine protein kinases, have been best studied in the context of cell volume regulation and ion homeostasis. Here we describe a biological link between WNKs and transforming growth factor (TGF) beta-Smad signaling. Both WNK1 and WNK4 directly bind to and phosphorylate Smad2. Knockdown of WNK1 in HeLa cells using small interfering RNA reduces Smad2 protein expression; this decrease is at least partially due to down-regulation of Smad2 transcription. In contrast, phosphorylated Smad2 significantly accumulated in the nucleus as a consequence of depletion of WNK1, resulting in Smad-mediated transcriptional responses. In addition, TGFbeta-induced target gene transcripts were increased in WNK1 small interfering RNA cells. These findings suggest WNK1 as a dual modulator of TGFbeta-Smad signaling pathways.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Nucleus / metabolism
  • Fibroblasts / metabolism*
  • Gene Expression Regulation
  • HeLa Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Mice
  • Minor Histocompatibility Antigens
  • Models, Biological
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / metabolism*
  • RNA, Small Interfering / metabolism
  • Signal Transduction
  • Smad Proteins / metabolism*
  • Transforming Growth Factor beta / metabolism*
  • WNK Lysine-Deficient Protein Kinase 1


  • Intracellular Signaling Peptides and Proteins
  • Minor Histocompatibility Antigens
  • RNA, Small Interfering
  • Smad Proteins
  • Transforming Growth Factor beta
  • Protein-Serine-Threonine Kinases
  • WNK Lysine-Deficient Protein Kinase 1
  • WNK1 protein, human
  • Wnk1 protein, mouse