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 and SGK1. Controls sodium and chloride ion transport by inhibiting the activity of WNK4, by either phosphorylating the kinase or via an interaction between WNK4 and the autoinhibitory domain of WNK1. WNK4 regulates the activity of the thiazide-sensitive Na-Cl cotransporter, SLC12A3, by phosphorylation. WNK1 may also play a role in actin cytoskeletal reorganization. Phosphorylates NEDD4L. Acts as a scaffold to inhibit SLC4A4, SLC26A6 as well as CFTR activities and surface expression, recruits STK39 which mediates the inhibition (PubMed:21317537, PubMed:23542070). Dominant-negative regulator of the longer isoform 1. Does not have kinase activity, does not directly inhibit WNK4 and has no direct effect on sodium and chloride ion transport. Down-regulates sodium-chloride cotransporter activity indirectly by inhibiting isoform 1, it associates with isoform 1 and attenuates its kinase activity. In kidney, may play an important role regulating sodium and potassium balance. ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-[protein] ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-threonyl-[protein] By hypertonicity. Activation requires autophosphorylation of Ser-382. Phosphorylation of Ser-378 also promotes increased activity (By similarity). Interacts with SYT2. Interacts with KLHL3, WNK3 and WNK4 (By similarity). Isoform 7: Interacts with isoform 1 (By similarity). Widely expressed in both adult and embryonic tissue, with highest levels observed in the testis and lower levels in heart, lung, kidney, placenta, brain and skeletal muscle. Expressed in pancreatic duct (PubMed:21317537). Two isoforms are expressed in heart, a single shorter isoform in the kidney. Locates to the distal convoluted tubule, the medullary collecting duct and the cortical collecting duct of the kidney. HSN2-containing isoform 2 and isoform 3 are restricted to the nervous system, expressed preferentially in sensory neurons than in motor neurons and in general more abundant in axons than in cell bodies (at protein level). In the DRG, predominantly expressed in the satellite cells that envelop sensory neurons, but low expression also observed in the cell bodies of neurons (at protein level). In the sciatic nerve, expressed in the Schwann cells that surround axons and in a mosaic distribution of axons (at protein level). In the spinal cord, expressed in superficial layers (LI and LII), as well as in the fibers of the Lissauer tract (at protein level). Also detected in the axon fibers of dorsolateral funiculus and lateral funiculus (at protein level). Autophosphorylation at Ser-382 is inhibited by intracellular calcium. Ubiquitinated in vitro by the BCR(KLHL3) complex and in vivo by a BCR(KLHL2) complex, leading to proteasomal degradation. This isoform which includes the HSN2 exon has been identified in human and mouse. The sequence shown here is the result of gene prediction. This isoform which includes the HSN2 exon has been identified in human and mouse. The sequence shown here is the result of gene prediction. May be due to intron retention. Kinase-defective isoform. Produced by alternative promoter usage and alternative splicing. 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. It is uncertain whether Met-1 or Met-214 is the initiator. HSN2 was originally thought to be an intronless gene lying within a WNK1 gene intron. It has been shown to be a nervous system-specific exon of WNK1 included in isoform 2 and isoform 3 (PubMed:18521183). Probable cloning artifact. Probable cloning artifact. Extended N-terminus. Includes 3' and 3' intronic sequences.