No lysine? No problem: the surprising roles of WNK kinases in physiology and disease

WNK (With No lysine K) protein kinases gained early attention because gain-of-function mutations in genes encoding two of them cause hypertension. They differ from other kinases due to the unusual location of the catalytic lysine, hence the name WNK. These kinases control many aspects of ion transport in the kidney and are essential for development and maintenance of the cardiovascular system. In the present review, we describe WNK proteins and selected substrates, in particular, the kinases oxidative stress-responsive kinase 1 and SPS1-related proline/alanine-rich kinase, and their regulation. We spotlight findings that emphasize the broad relevance of WNKs in normal physiology and disease. Our overview focuses on basic aspects of ion transport that occur in many cell types and tissues, functions in the endothelial system, interactions with insulin-dependent and metabolic pathways, the importance in the brain in part through controlling chloride ion balance, and the whirlwind of findings in cancer that reveal how WNK signaling can be repurposed. Other actions that may be of equal importance, e.g., influences on the immune system, are touched on only briefly. We also note a few genome-wide association studies that have uncovered multiple SNPs in genes encoding WNKs and downstream effectors in an array of diseases, in anticipation of more to come in the future.