With No Lysine (WNK) Family Proteins and Their Interaction with Downstream Kinases




Wedin, Kyle Edward

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With no lysine (WNK) kinases are a family of protein kinases characterized by unusual kinase domain architecture. These large proteins, divergent outside of a kinase core and protein-protein interaction motifs, have been associated with pseudohypoaldosteronism 2, a form of Mendelian-inherited hypertension, and numerous downstream effectors that regulate vesicle trafficking, membrane protein localization, and ion handling. This study shows that WNK2 is also a functioning protein kinase with the same unusual kinase domain architecture and regulation by an autoinhibitory region. Like WNK1, WNK2 is able to signal to the extracellular-signal regulated kinase 5 (ERK5) pathway. One effector for WNK1 is oxidative stress responsive 1 (OSR1), a sterile20-like kinase. All four WNKs are able to phosphorylate OSR1 and stimulate its activity toward an ion transporter substrate, to roughly a similar degree. The WNKs have similar kinetic properties, with Km toward OSR1 in the micromolar range and kcat¬ near 1 min-1. No significant differences in activity toward OSR1 were seen for a mutant kinase domain at a site divergent among the WNKs that shows differential binding to substrate. Analysis of the phosphorylation sites of OSR1 reveals multiple sites along the activation loop that can promote increased activation if carrying a negative charge. It is unknown if these sites are phosphorylated in vivo. However, a second site of WNK1 phosphorylation just outside of the OSR1 kinase domain does not seem to affect WNK-OSR interactions. Further studies of interactions of the WNKs with their downstream effectors will reveal unusual functions for this unique family of proteins.

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