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Wnk1

Domain

The RFXV motifs mediate recognition with downstream kinases OXSR1/OSR1 and STK39/SPAK.

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 WNK1-SPAK/OSR1 kinase cascade, which acts as a key regulator of blood pressure and regulatory volume increase by promoting ion influx (PubMed:12671053, PubMed:14610273). 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 (By similarity). 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 (By similarity). Following activation, OXSR1/OSR1 and STK39/SPAK catalyze phosphorylation of ion cotransporters SLC12A1/NKCC2, SLC12A2/NKCC1, SLC12A5/KCC2 and SLC12A6/KCC3, regulating their activity (By similarity). 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 (By similarity). Also acts as a regulator of angiogenesis in endothelial cells (PubMed:19644017). Also acts independently of the WNK1-SPAK/OSR1 kinase cascade by catalyzing phosphorylation of other substrates, such as SYT2, PCF11 and NEDD4L (By similarity). Mediates phosphorylation of SYT2, regulating SYT2 association with phospholipids and membrane-binding (By similarity). 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 (By similarity). Acts as a negative regulator of autophagy (By similarity). Required for the abscission step during mitosis, independently of the WNK1-SPAK/OSR1 kinase cascade (By similarity). WNK1 may also play a role in actin cytoskeletal reorganization (By similarity). 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 (PubMed:21317537, PubMed:23542070). 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 (By similarity). 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 (By similarity).

Isoform 7

Kinase-defective isoform specifically expressed in kidney, which acts as a dominant-negative regulator of the longer isoform 1 (PubMed:21131289). Does not directly inhibit WNK4 and has no direct effect on sodium and chloride ion transport (By similarity). Down-regulates sodium-chloride cotransporter activity indirectly by inhibiting isoform 1, it associates with isoform 1 and attenuates its kinase activity (By similarity). In kidney, may play an important role regulating sodium and potassium balance (By similarity).

Post-translational modifications

Autophosphorylated at Ser-378 and Ser-382, promoting its activity (By similarity). Autophosphorylation at Ser-382 is inhibited by intracellular calcium (By similarity). Phosphorylation at Thr-58 increases ability to activate SGK1 (By similarity).

Ubiquitinated by the BCR(KLHL3) complex, leading to its degradation (By similarity). Also ubiquitinated by the BCR(KLHL2) complex (By similarity).

May be O-glycosylated.

Sequence Similarities

Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. WNK subfamily.

Tissue Specificity

Widely expressed in both adult and embryonic tissue, with highest levels observed in the testis and lower levels in heart, lung, kidney, placenta, brain and skeletal muscle (PubMed:11498583, PubMed:12522152, PubMed:14514722). Expressed in pancreatic duct (PubMed:21317537). Two isoforms are expressed in heart, a single shorter isoform in the kidney (PubMed:14514722). Locates to the distal convoluted tubule, the medullary collecting duct and the cortical collecting duct of the kidney (PubMed:14514722).

Isoform 2

Restricted to the nervous system, expressed preferentially in sensory neurons than in motor neurons and in general more abundant in axons than in cell bodies (at protein level) (PubMed:18521183). In the DRG, predominantly expressed in the satellite cells that envelop sensory neurons, but low expression also observed in the cell bodies of neurons (at protein level) (PubMed:18521183). In the sciatic nerve, expressed in the Schwann cells that surround axons and in a mosaic distribution of axons (at protein level) (PubMed:18521183). In the spinal cord, expressed in superficial layers (LI and LII), as well as in the fibers of the Lissauer tract (at protein level) (PubMed:18521183). Also detected in the axon fibers of dorsolateral funiculus and lateral funiculus (at protein level) (PubMed:18521183).

Isoform 3

Restricted to the nervous system, expressed preferentially in sensory neurons than in motor neurons and in general more abundant in axons than in cell bodies (at protein level) (PubMed:18521183). In the DRG, predominantly expressed in the satellite cells that envelop sensory neurons, but low expression also observed in the cell bodies of neurons (at protein level) (PubMed:18521183). In the sciatic nerve, expressed in the Schwann cells that surround axons and in a mosaic distribution of axons (at protein level) (PubMed:18521183). In the spinal cord, expressed in superficial layers (LI and LII), as well as in the fibers of the Lissauer tract (at protein level) (PubMed:18521183). Also detected in the axon fibers of dorsolateral funiculus and lateral funiculus (at protein level) (PubMed:18521183).

Cellular localization

Alternative names

Hsn2, Prkwnk1, Sncg, Serine/threonine-protein kinase WNK1, Protein kinase lysine-deficient 1, Protein kinase with no lysine 1

swissprot:P83741