Biological cross-talk between WNK1 and the transforming growth factor beta-Smad signaling pathway.
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.
Lee
Byung-Hoon
BH
Department of Pharmacology, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9041.
Chen
Wei
W
Department of Pharmacology, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9041.
Stippec
Steve
S
Department of Pharmacology, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9041.
Cobb
Melanie H
MH
Department of Pharmacology, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9041. Electronic address: Cobb@UTSouthwestern.edu.
D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism*; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D015778:Minor Histocompatibility Antigens; D008954:Models, Biological; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D000076204:WNK Lysine-Deficient Protein Kinase 1
D047908:Intracellular Signaling Peptides and Proteins; D015778:Minor Histocompatibility Antigens; D034741:RNA, Small Interfering; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000076204:WNK Lysine-Deficient Protein Kinase 1; C498743:WNK1 protein, human; C498744:Wnk1 protein, mouse