| Post Translational Modifications | Autophosphorylated at Ser-378 and Ser-382, promoting its activity. Autophosphorylation at Ser-382 is inhibited by intracellular calcium. Phosphorylation at Thr-60 increases ability to activate SGK1. Ubiquitinated by the BCR(KLHL3) complex, leading to its degradation. Also ubiquitinated by the BCR(KLHL2) complex. May be O-glycosylated. |
| Function | Serine/threonine-protein kinase component of the WNK1-SPAK/OSR1 kinase cascade, which acts as a key regulator of blood pressure and regulatory volume increase by promoting ion influx. WNK1 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. The membraneless compartment concentrates WNK1 with its substrates, OXSR1/OSR1 and STK39/SPAK, promoting WNK1-dependent phosphorylation and activation of downstream kinases OXSR1/OSR1 and STK39/SPAK. Following activation, OXSR1/OSR1 and STK39/SPAK catalyze phosphorylation of ion cotransporters SLC12A1/NKCC2, SLC12A2/NKCC1, SLC12A5/KCC2 and SLC12A6/KCC3, regulating their activity. Phosphorylation of Na-K-Cl cotransporters SLC12A2/NKCC1 and SLC12A2/NKCC1 promote their activation and ion influx.simultaneously, phosphorylation of K-Cl cotransporters SLC12A5/KCC2 and SLC12A6/KCC3 inhibit their activity, blocking ion efflux. Also acts as a regulator of angiogenesis in endothelial cells via activation of OXSR1/OSR1 and STK39/SPAK: activation of OXSR1/OSR1 regulates chemotaxis and invasion, while STK39/SPAK regulates endothelial cell proliferation. Also acts independently of the WNK1-SPAK/OSR1 kinase cascade by catalyzing phosphorylation of other substrates, such as SYT2, PCF11 and NEDD4L. Mediates phosphorylation of SYT2, regulating SYT2 association with phospholipids and membrane-binding. Regulates mRNA export in the nucleus by mediating phosphorylation of PCF11, thereby decreasing the association between PCF11 and POLR2A/RNA polymerase II and promoting mRNA export to the cytoplasm. Acts as a negative regulator of autophagy. Required for the abscission step during mitosis, independently of the WNK1-SPAK/OSR1 kinase cascade. May also play a role in actin cytoskeletal reorganization. Also acts as a scaffold protein independently of its protein kinase activity: negatively regulates cell membrane localization of various transporters and channels, such as SLC4A4, SLC26A6, SLC26A9, TRPV4 and CFTR. Involved in the regulation of epithelial Na(+) channel (ENaC) by promoting activation of SGK1 in a kinase-independent manner: probably acts as a scaffold protein that promotes the recruitment of SGK1 to the mTORC2 complex in response to chloride, leading to mTORC2-dependent phosphorylation and activation of SGK1. Acts as an assembly factor for the ER membrane protein complex independently of its protein kinase activity: associates with EMC2 in the cytoplasm via its amphipathic alpha-helix, and prevents EMC2 ubiquitination and subsequent degradation, thereby promoting EMC2 stabilization. Isoform 3: Kinase-defective isoform specifically expressed in kidney, which acts as a dominant-negative regulator of the longer isoform 1. 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. |
| Protein Name | Serine/Threonine-Protein Kinase Wnk1Erythrocyte 65 Kda ProteinP65Kinase Deficient ProteinProtein Kinase Lysine-Deficient 1Protein Kinase With No Lysine 1Hwnk1 |
| Database Links | Reactome: R-HSA-2672351 |
| Cellular Localisation | CytoplasmNucleusCytoskeletonSpindleMediates Formation And Localizes To Cytoplasmic Membraneless Compartment In Response To Hyperosmotic StressAlso Localizes To The NucleusLocalizes To The Mitotic Spindle During Mitosis |
| Alternative Protein Names | Serine/Threonine-Protein Kinase Wnk1 proteinErythrocyte 65 Kda Protein proteinP65 proteinKinase Deficient Protein proteinProtein Kinase Lysine-Deficient 1 proteinProtein Kinase With No Lysine 1 proteinHwnk1 proteinWNK1 proteinHSN2 proteinKDP proteinKIAA0344 proteinPRKWNK1 protein |
Information sourced from Uniprot.org
