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FLASH GENE

Symbol

WNK4

contributors: mct/pgu - updated : 23-09-2018

HGNC name	WNK lysine deficient protein kinase 4
HGNC id	14544

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

EXPRESSION

Type	restricted

expressed in

(based on citations)

organ(s)

System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Cardiovascular heart       predominantly Digestive intestine large intestine colon     Nervous brain       predominantly reproductive epididymis         Urinary kidney tubule convoluted tubule   predominantly Mus musculus   kidney nephron     predominantly Homo sapiens   kidney tubule Henles loop     Mus musculus Visual eye lens       Homo sapiens

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Epithelial absorptive excretory digestive epithelium

cells

System Cell Pubmed Species Stage Rna symbol Cardiovascular endothelial Urinary podocyte Mus musculus

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	N-terminal fragment (1-620 WNK4) containing the acidic motif retains full activity in inhibiting KCNJ1 currents, and is crucial for its interaction with KCNJ1,
	a &
	8764;270-amino acid conserved kinase domain located near the amino terminus (Cha 2010)
	a catalytic domain containing a cysteine in place of a lysine in catalytic subdomain II
	the WNK sequence signature within the subdomain I and II
	several phospharylation sites
	regulatory C-terminal including a highly conserved acidic motif and two coil-coil domains

HOMOLOGY

interspecies	homolog to murine Wnk4 (87.8pc)
	homolog to rattus Wnk4 (87.9pc)

Homologene

FAMILY	protein kinase superfamily
	Ser/Thr protein kinase family
	WNK subfamily

CATEGORY

enzyme

SUBCELLULAR LOCALIZATION	plasma membrane,junction,tight
	intracellular
	intracellular,cytoplasm
text	present exclusively in intercellular junction in the distal convoluted tubule and in both the cytoplasm and intercelullar junction in the cortical collecting duct

basic FUNCTION	playing a role in cell adhesion and tissue-formation
	multifunctional regulator of diverse ions transporters, regulating the balance between renal NaCl reabsorption and K+ secretion
	involved in the regulation of electrolytes flux in diverses epithelia
	controls blood pressure and potassium homeostasis via regulation of mass and activity of the distal convoluted tubule
	enhancing TRPV5-mediated Ca2+ transport through increasing surface level of TRPV5 without a significant effect on TRPV6 (action of WNK4 on TRPV5 is likely in the secretory pathway for TRPV5 delivery to the plasma membrane)
	playing an important role through the acidic motif of WNK4 in its protein/protein interaction with the KCNJ1 channel
	with WNK2, WNK3, WNK4, have vital roles in the control of salt homeostasis and blood pressure
	when activated, subsequently phosphorylate and activate the related protein kinases STK39 and OXSR1
	involved in the signaling pathway between Angiotensin II and SLC12A3 (provide a mechanism by which hypovolemia maximizes renal salt reabsoprtion without concomitantly increasing K+ secretion)
	inhibits SLC12A3 activity by diverting the cotransporer to the lysosomee for degradation by way of an AP-3 transport carrier
	WNK4 promotes SLC12A3 targeting to the lysosome for degradation via a mechanism involving sortilin
	plays an important role in the regulation of renal ion transport
	stimulates caveola-mediated endocytosis of TRPV5
	is a target for KLHL3-mediated ubiquitination, and the impaired ubiquitination of WNK4 is a common mechanism of human hereditary hypertension
	plays a critical role in the expression of membrane proteins in the cell surface

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

a component

INTERACTION

DNA

RNA

small molecule	cofactor, nucleotide,
	ATP binding
	Mg2+ as a cofactor

protein	SLC26A6 (regulating SLC26A6)
	SLC12A3 and KCNJ1 (inhibition of activity of SLC12A3 and KCNJ1)
	activating STK39 and OSR1
	interactingw ith ITSN1, leading to endocytosis of KCNJ1
	interacts with WNK3 and WNK1 to regulate SLC12A3 in both human kidney cells and Xenopus oocytes
	interaction between WNK4 and PKC regulation of TRPV5 may be important for physiological regulation of renal Ca2+ reabsorption by parathyroid hormones or the tissue kallikrein
	enhances the surface expression of epithelial Ca2+ channel TRPV5, which plays a key role in the fine tuning of renal Ca2+ reabsorption
	SLC9A3R2 acts synergistically with WNK4 by stabilizing TRPV5 at the plasma membrane to maintain the positive regulation of WNK4 on TRPV5
	inhibits KCNMA1 activity by reducing KCNMA1 protein at the membrane, but the inhibition is not due to an increase in clathrin-mediated endocytosis of KCNMA1, but likely due to enhancing its lysosomal degradation
	modulates the activity of the renal Na(+)Cl(-) cotransporter SLC12A3
	KLHL3 inhibited the positive effect of WNK4 on Na(+)-Cl(-) cotransporter (NCC) by decreasing WNK4 protein abundance
	inhibits large conductance, Ca2+-activated K+ channels activity, in part, by increasing channel degradation through an ubiquitin-dependent pathway
	WNK4 is a substrate for KLHL3-CUL3 E3 ubiquitin ligase complexes
	attenuates plasma membrane targeting of SLC12A3 through regulation of STX12 SNARE complex formation with VAMP2 in recycling and sorting endosome
	WNK1 and WNK4 are the targets for the KLHL3-CUL3 complex and modulate the activity of SLC12A5 by means of intermediary Ste20-type kinases known as STK39 or OSR1
	WNK4 and PP1 regulate SLC12A7 activity as part of a common signaling module, but that they do not exert their effects through STK39 or carrier dephosphorylation
	CLDN7 plays an important role in salt balance in renal collecting duct (CD) cells and modulating WNK4 and SCNN1A expression levels that are vital in controlling salt-sensitive hypertension

cell & other

REGULATION

activated by

autophosphorylation

ASSOCIATED DISORDERS

corresponding disease(s)

PHA2B

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional     --low   markedly augmented TRPC3-mediated Ca(2+) influx in vascular smooth muscle cells (VSMCs), which is the pathological hallmark of hypertension in resistance arteries

Susceptibility

to essential hypertension to osteoporosis

Variant & Polymorphism SNP	polymorphism rs56116165 is a rare allelic variant in a candidate gene with a biological function in renal calcium homeostasis that may contribute to a genetic predisposition to osteoporosis

Candidate gene

Marker

Therapy target

ANIMAL & CELL MODELS