With No Lysine 1 (WNK1): A Potential Regulator of The Lysosomal Degradation Pathway
With no Lysine (K) 1 (WNK1) is an atypical serine/threonine protein kinase that has its catalytic lysine positioned in a unique location. This kinase, along with another member of the WNK family, WNK4, has been genetically linked to pseudohypoaldosteronism type II (PHAII), which is characterized by both hypertension and hyperkalemia. Several groups have used reconstitution assays in Xenopus oocytes and mammalian cell lines to show WNKs regulate the surface expression and/or activity of various ion transporters and channels, including the epithelial sodium channel (ENaC) and the sodium chloride co-transporter (NCCT). Although the mechanisms for regulating these cell surface proteins are not well defined, it appears that WNKs may modulate the intracellular trafficking of these channels and transporters. To help define the mechanisms WNK1 utilizes to influence blood pressure and to characterize this kinase biochemically, I performed a WNK1 kinase activation screen and a WNK1 yeast-two-hybrid screen. I have shown that WNK1 kinase activity increases in response to osmotic stress, which may imply its kinase activity is important for regulating ion homeostasis in response to a change in cell volume. I have also shown that a proline-rich region of WNK1 interacts with vacuolar protein sorting 4a (VPS4a), an ATPase that helps sort cargo from the plasma membrane to lysosomes. Cells expressing a VPS4 ATP-hydrolysis mutant trap cargo from the cell surface in an aberrant endosomal structure, slowing protein degradation via the lysosomal pathway. I hypothesize that WNK1 delivers cargo to VPS4a to facilitate the degradation of plasma membrane proteins.
Epithelial Cells, Hypertension, Protein-Serine-Threonine Kinases
University of Texas Southwestern Medical Center
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