title: Evolutionarily conserved WNK and Ste20 kinases are essential for acute volume recovery and survival after hypertonic shrinkage in Caenorhabditis elegans.
abstract: Members of the germinal center kinase (GCK)-VI subfamily of Ste20 kinases regulate a Caenorhabditis elegans ClC anion channel and vertebrate SLC12 cation-Cl(-) cotransporters. With no lysine (K) (WNK) protein kinases interact with and activate the mammalian GCK-VI kinases proline-alanine-rich Ste20-related kinase (PASK) and oxidative stress-responsive 1 (OSR1). We demonstrate here for the first time that GCK-VI kinases play an essential role in whole animal osmoregulation. RNA interference (RNAi) knockdown of the single C. elegans GCK-VI kinase, GCK-3, dramatically inhibits systemic volume recovery and survival after hypertonic shrinkage. Tissue-specific RNAi suggests that GCK-3 functions primarily in the hypodermis and intestine to mediate volume recovery. The single C. elegans WNK kinase, WNK-1, binds to GCK-3, and wnk-1 knockdown gives rise to a phenotype qualitatively similar to that of gck-3(RNAi) worms. Knockdown of the two kinases together has no additive effect, suggesting that WNK-1 and GCK-3 function in a common pathway. We postulate that WNK-1 functions upstream of GCK-3 in a manner similar to that postulated for its mammalian homologs. Phylogenetic analysis of kinase functional domains suggests that the interaction between GCK-VI and WNK kinases first occurred in an early metazoan and therefore likely coincided with the need of multicellular animals to tightly regulate transepithelial transport processes that mediate systemic osmotic homeostasis.
authors.affiliation: Vanderbilt Univ. Medical Center, T-4202 Medical Center North, Nashville, TN 37232-2520, USA.
authors.forename: Keith P
authors.initials: KP
authors.lastname: Choe
authors.forename: Kevin
authors.initials: K
authors.lastname: Strange
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000201:enzymology / Q000235:genetics*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000378:metabolism; D019143:Evolution, Molecular; D000081410:Germinal Center Kinases; D049452:Green Fluorescent Proteins / Q000235:genetics; D007422:Intestines / Q000201:enzymology; D008969:Molecular Sequence Data; D009997:Osmotic Pressure; D010802:Phylogeny; D011494:Protein Kinases / Q000235:genetics* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D012462:Saline Solution, Hypertonic / Q000494:pharmacology; D040521:Subcutaneous Tissue / Q000201:enzymology; D000076204:WNK Lysine-Deficient Protein Kinase 1; D014882:Water-Electrolyte Balance / Q000502:physiology*
chemical_list: D029742:Caenorhabditis elegans Proteins; D000081410:Germinal Center Kinases; D012462:Saline Solution, Hypertonic; D049452:Green Fluorescent Proteins; D011494:Protein Kinases; C420464:sterile 20-like protein kinase nerve injury-associated kinase; D017346:Protein Serine-Threonine Kinases; D000076204:WNK Lysine-Deficient Protein Kinase 1; C523715:wnk-1 protein, C elegans