Wnk4
Domain
The RFXV motif mediates recognition with downstream kinases OXSR1/OSR1 and STK39/SPAK.
Function
Serine/threonine-protein kinase component of the WNK4-SPAK/OSR1 kinase cascade, which acts as a key regulator of ion transport in the distal nephron and blood pressure (PubMed:12515852, PubMed:14608358, PubMed:16964266, PubMed:17360470, PubMed:17488636, PubMed:17975670, PubMed:19240212, PubMed:19633012, PubMed:21486947). The WNK4-SPAK/OSR1 kinase cascade is composed of WNK4, which mediates phosphorylation and activation of downstream kinases OXSR1/OSR1 and STK39/SPAK (PubMed:21486947). Following activation, OXSR1/OSR1 and STK39/SPAK catalyze phosphorylation of ion cotransporters, such as SLC12A1/NKCC2, SLC12A2/NKCC1, SLC12A3/NCC, SLC12A5/KCC2 or SLC12A6/KCC3, regulating their activity (PubMed:17488636, PubMed:19633012, PubMed:21486947). Acts as a molecular switch that regulates the balance between renal salt reabsorption and K(+) secretion by modulating the activities of renal transporters and channels, including the Na-Cl cotransporter SLC12A3/NCC and the K(+) channel, KCNJ1/ROMK (PubMed:14608358, PubMed:16964266, PubMed:17975670). Regulates NaCl reabsorption in the distal nephron by activating the thiazide-sensitive Na-Cl cotransporter SLC12A3/NCC in distal convoluted tubule cells of kidney: activates SLC12A3/NCC in a OXSR1/OSR1- and STK39/SPAK-dependent process (PubMed:14608358, PubMed:17488636, PubMed:17975670, PubMed:19633012, PubMed:21486947). Also acts as a scaffold protein independently of its protein kinase activity: negatively regulates cell membrane localization of various transporters and channels (CFTR, KCNJ1/ROMK, SLC4A4, SLC26A9 and TRPV4) by clathrin-dependent endocytosis (PubMed:14608358, PubMed:16403833, PubMed:17673510, PubMed:21317537). Also inhibits the activity of the epithelial Na(+) channel (ENaC) SCNN1A, SCNN1B, SCNN1D in a inase-independent mechanism (PubMed:17360470). May also phosphorylate NEDD4L (By similarity).
Post-translational modifications
Autophosphorylated at Ser-328 and Ser-332, promoting its activation (By similarity). Phosphorylated by WNK1 and WNK3 (PubMed:17975670). Phosphorylated at Ser-572 in a MAP3K15/ASK3-dependent process in response to osmotic stress or hypotonic low-chloride stimulation (By similarity).
Ubiquitinated by the BCR(KLHL3) complex, leading to its degradation. Also ubiquitinated by the BCR(KLHL2) complex.
Sequence Similarities
Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. WNK subfamily.
Tissue Specificity
Locates to the distal convoluted tubule, the medullary collecting duct and the cortical collecting duct of the kidney (PubMed:11498583). Expressed in pancreatic duct (PubMed:21317537).
Cellular localization
- Cell junction
- Tight junction
- Present exclusively in intercellular junctions in the distal convoluted tubule and in both the cytoplasm and intercellular junctions in the cortical collecting duct (PubMed:11498583). WNK4 is part of the tight junction complex (PubMed:11498583).
Alternative names
Prkwnk4, Wnk4, Serine/threonine-protein kinase WNK4, Protein kinase lysine-deficient 4, Protein kinase with no lysine 4