WNK4

This gene encodes a member of the WNK family of serine-threonine protein kinases. The kinase is part of the tight junction complex in kidney cells, and regulates the balance between NaCl reabsorption and K(+) secretion. The kinase regulates the activities of several types of ion channels, cotransporters, and exchangers involved in electrolyte flux in epithelial cells. Mutations in this gene result in pseudohypoaldosteronism type IIB

Full Name

WNK lysine deficient protein kinase 4

Function

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. Phosphorylates NEDD4L. Acts as a scaffold to inhibit SLC4A4 as well as CFTR activities and surface expression, recruits STK39 which mediates the inhibition (By similarity).

Biological Process

Biological Process activation of protein kinase activity Source:Ensembl
Biological Process aldosterone secretion Source:Ensembl
Biological Process calcium ion homeostasis Source:Ensembl
Biological Process cellular cation homeostasis Source:UniProtKB
Biological Process cellular chloride ion homeostasis Source:Ensembl
Biological Process cellular response to xenobiotic stimulus Source:Ensembl
Biological Process chloride transport Source:Ensembl
Biological Process distal tubule morphogenesis Source:UniProtKB2 Publications
Biological Process ERK1 and ERK2 cascade Source:Ensembl
Biological Process gene expression Source:Ensembl
Biological Process inflammatory response Source:Ensembl
Biological Process intracellular signal transduction Source:UniProtKB
Biological Process ion homeostasis Source:UniProtKB2 Publications
Biological Process ion transport Source:UniProtKB
Biological Process macrophage activation Source:Ensembl
Biological Process negative regulation of pancreatic juice secretion Source:Ensembl
Biological Process negative regulation of protein kinase activity Source:Ensembl
Biological Process negative regulation of sodium ion transport Source:UniProtKB
Biological Process positive regulation of potassium ion import across plasma membrane Source:GO_Central1 Publication
Biological Process positive regulation of sodium ion transmembrane transporter activity Source:GO_Central1 Publication
Biological Process potassium ion transmembrane transport Source:Ensembl
Biological Process protein kinase C signaling Source:Ensembl
Biological Process protein localization Source:Ensembl
Biological Process protein phosphorylation Source:UniProtKB
Biological Process renal sodium ion absorption Source:UniProtKB2 Publications
Biological Process response to dietary excess Source:Ensembl
Biological Process sodium ion transmembrane transport Source:Ensembl

Cellular Location

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. WNK4 is part of the tight junction complex.

Involvement in disease

Pseudohypoaldosteronism 2B (PHA2B):
An autosomal dominant disorder characterized by hypertension, hyperkalemia, hyperchloremia, mild hyperchloremic metabolic acidosis, and correction of physiologic abnormalities by thiazide diuretics.

PTM

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.