Serine/threonine kinase which plays an important role in the regulation of electrolyte homeostasis, cell signaling, survival and proliferation. Acts as an activator and inhibitor of sodium-coupled chloride cotransporters and potassium-coupled chloride cotransporters respectively. Activates SCNN1A, SCNN1B, SCNN1D, SGK1, TRPV5 and TRPV6. Regulates the activity of the thiazide-sensitive Na-Cl cotransporter, SLC12A3, by phosphorylation which appears to prevent membrane trafficking of SLC12A3. Also inhibits the renal K(+) channel, KCNJ1, via a kinase-independent mechanism by which it induces clearance of the protein from the cell surface by clathrin-dependent endocytosis. WNK4 appears to act as a molecular switch that can vary the balance between NaCl reabsorption and K(+) secretion to maintain integrated homeostasis. Acts as a scaffold to inhibit SLC4A4 as well as CFTR activities and surface expression, recruits STK39 which mediates the inhibition. Phosphorylates NEDD4L (By similarity). ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-[protein] ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-threonyl-[protein] Activation requires autophosphorylation of Ser-332. Phosphorylation of Ser-328 also promotes increased activity (By similarity). Interacts with the C-terminal region of KCNJ1. Interacts with WNK1 and WNK3. Interacts with KLHL3. Present exclusively in intercellular junctions in the distal convoluted tubule and in both the cytoplasm and intercellular junctions in the cortical collecting duct. WNK4 is part of the tight junction complex. Phosphorylated by WNK1 and WNK3. Ubiquitinated by the BCR(KLHL3) complex, leading to its degradation and increased expression of KCNJ1 at the cell surface. Ubiquitinated by the BCR(KLHL2) complex (By similarity). Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. WNK subfamily. Was named WNK/'with no lysine(K)' because key residues for catalysis, including the lysine involved in ATP binding, are either not conserved or differ compared to the residues described in other kinase family proteins.