WNK Family Kinases and the Regulation of Ion Flux

The four mammalian examples of the with no K (lysine) or WNK family of serine/threonine protein kinases have an unusual arrangement of their catalytic lysines. WNK1 and WNK4 have been genetically linked to a rare type of hypertension. Studies demonstrate that these kinases regulate the activity of a diverse group of proteins that in toto suggest WNKs are involved in ionic homeostasis by means of constitutively regulated endocytosis of ion transporters and channels. The mechanism is reliant on an amino terminal fragment of WNK that does not include the kinase domain. How WNK1 exerts this effect, however, remains unclear. This dissertation will detail the examination of the amino terminal fragment of WNK1, its interaction with predicted molecular adaptor proteins, and how these interactions may modulate the activation of the serum- and glucocorticoid-inducible kinase 1, SGK1, leading to the internalization of the epithelial Na+ channel, ENaC via the ubiquitin ligase neuronal precursor cell- expressed, developmentally downregulated protein 4-2, or Nedd4-2.