WNK3
Domain
Disordered regions undergo liquid-liquid phase separation (LLPS) for the formation of a cytoplasmic membraneless compartment that concentrates WNK1 with its substrates, OXSR1/OSR1 and STK39/SPAK.
Function
Serine/threonine-protein kinase component of the WNK3-SPAK/OSR1 kinase cascade, which plays an important role in the regulation of electrolyte homeostasis and regulatory volume increase in response to hyperosmotic stress (PubMed:16275911, PubMed:16275913, PubMed:16501604, PubMed:22989884, PubMed:36318922). WNK3 mediates regulatory volume increase in response to hyperosmotic stress by acting as a molecular crowding sensor, which senses cell shrinkage and mediates formation of a membraneless compartment by undergoing liquid-liquid phase separation (PubMed:36318922). The membraneless compartment concentrates WNK3 with its substrates, OXSR1/OSR1 and STK39/SPAK, promoting WNK3-dependent phosphorylation and activation of downstream kinases OXSR1/OSR1 and STK39/SPAK (PubMed:22989884). Following activation, OXSR1/OSR1 and STK39/SPAK catalyze phosphorylation of ion cotransporters SLC12A1/NKCC2, SLC12A2/NKCC1, SLC12A3/NCC, SLC12A4/KCC1, SLC12A5/KCC2 or SLC12A6/KCC3, regulating their activity (PubMed:16275911, PubMed:16275913). Phosphorylation of Na-K-Cl cotransporters SLC12A2/NKCC1 and SLC12A2/NKCC1 promote their activation and ion influx; simultaneously, phosphorylation of K-Cl cotransporters SLC12A4/KCC1, SLC12A5/KCC2 and SLC12A6/KCC3 inhibits its activity, blocking ion efflux (PubMed:16275911, PubMed:16275913, PubMed:16357011, PubMed:19470686, PubMed:21613606). Phosphorylates WNK4, possibly regulating the activity of SLC12A3/NCC (PubMed:17975670). May also phosphorylate NEDD4L (PubMed:20525693). Also acts as a scaffold protein independently of its protein kinase activity: negatively regulates cell membrane localization of various transporters and channels, such as KCNJ1 and SLC26A9 (PubMed:16357011, PubMed:17673510). Increases Ca(2+) influx mediated by TRPV5 and TRPV6 by enhancing their membrane expression level via a kinase-dependent pathway (PubMed:18768590).
Involvement in disease
Prieto syndrome
PRS
An X-linked recessive disorder characterized by impaired intellectual development, developmental delay, autism spectrum disorder, variable epilepsy, craniofacial dysmorphism, and structural brain abnormalities including polymicrogyria and cerebral atrophy.
None
The disease is caused by variants affecting the gene represented in this entry.
Post-translational modifications
Autophosphorylated at Ser-304 and Ser-308, promoting its activity (PubMed:33439774). Phosphorylation at Thr-541 prevents interaction with KLHL3 and subsequent ubiquitination and degradation by the BCR(KLHL3) complex (Probable) (PubMed:35179207).
Ubiquitinated by the BCR(KLHL2) complex, leading to its degradation (PubMed:23838290). Ubiquitinated by the BCR(KLHL3) complex, leading to its degradation (PubMed:35179207).
Sequence Similarities
Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. WNK subfamily.
Tissue Specificity
Expressed in brain, lung, kidney, liver and pancreas, and in fetal tissues including placenta, fetal brain, lung and kidney. Very low levels of expression were also detected in fetal heart, thymus, liver and spleen. Isoform 1 is brain-specific. Isoform 3 is kidney-specific.
Cellular localization
- Cytoplasm
- Mediates formation and localizes to cytoplasmic membraneless compartment in response to hyperosmotic stress.
Alternative names
KIAA1566, PRKWNK3, WNK3, Serine/threonine-protein kinase WNK3, Protein kinase lysine-deficient 3, Protein kinase with no lysine 3