Ser/Thr-protein kinase WNK4 regulates the activity of the thiazide-sensitive Na-Cl cotransporter SLC12A3 by phosphorylation, which prevents membrane trafficking of SLC12A3. WNK4 also inhibits the renal potassium channel KCNJ1 via a kinase-independent mechanism by which it induces clearance of the protein from the cell surface by clathrin-dependent endocytosis. WNK4 acts as a molecular switch that can vary the balance between NaCl reabsorption and K+ secretion to maintain integrated homeostasis. WNK4 is exclusively present in intercellular junctions in th edistal convoluted tubule and in both the cytoplasm and intercellular junctions in the cortical collecting duct. Defects in WNK4 are a cause of pseudohypoaldosteronism type II (PHAII).