WNK3
Description
The WNK3 (WNK lysine deficient protein kinase 3) is a protein-coding gene located on chromosome X.
WNK3 is a protein that in humans is encoded by the WNK3 gene. WNK3 is a member of the 'with no lysine' family of serine-threonine protein kinases. These family members lack the catalytic lysine in subdomain II, and instead have a conserved lysine in subdomain I. This family member functions as a positive regulator of the transcellular Ca2+ transport pathway, and it plays a role in the increase of cell survival in a caspase 3 dependent pathway.
WNK3 is a serine/threonine protein kinase that plays a crucial role in the WNK3-SPAK/OSR1 kinase cascade, which regulates electrolyte balance and cell volume in response to changes in osmotic pressure. WNK3 acts as a molecular crowding sensor, detecting cell shrinkage and forming a membraneless compartment through liquid-liquid phase separation. This compartment concentrates WNK3 and its substrates, OXSR1/OSR1 and STK39/SPAK, promoting their phosphorylation and activation. Activated OXSR1/OSR1 and STK39/SPAK then phosphorylate ion cotransporters, including SLC12A1/NKCC2, SLC12A2/NKCC1, SLC12A3/NCC, SLC12A4/KCC1, SLC12A5/KCC2, and SLC12A6/KCC3, regulating their activity. Phosphorylation of Na-K-Cl cotransporters, such as SLC12A2/NKCC1, promotes their activation and ion influx, while phosphorylation of K-Cl cotransporters like SLC12A4/KCC1 inhibits their activity, blocking ion efflux. WNK3 also phosphorylates WNK4, potentially regulating SLC12A3/NCC activity, and may phosphorylate NEDD4L. Additionally, WNK3 acts as a scaffold protein, independently of its kinase activity, negatively regulating the membrane localization of transporters and channels like KCNJ1 and SLC26A9. WNK3 also increases Ca(2+) influx mediated by TRPV5 and TRPV6 by enhancing their membrane expression through a kinase-dependent pathway.
WNK3 is also known as MRXS2, PRKWNK3, PRS.
