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FLASH GENE

Symbol

WNK4

contributors: mct/pgu - updated : 17-08-2009

HGNC name	WNK lysine deficient protein kinase 4
HGNC id	14544

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	PHA2B familial hypertension and hyperkalemia, type 2 B
Location	17q21.31      Physical location : 40.932.648 - 40.949.079
Genatlas name	with-no-lysine (K) kinase-4
Synonym name	putative protein kinase WNK4
	protein kinase, lysine deficient 4
	protein kinase with no lysine 4
Synonym symbol(s)	PRKWNK4
EC.number	2.7.11.1

DNA

TYPE	functioning gene
STRUCTURE	16.39 kb     19 Exon(s)

MAPPING

cloned

Y

linked

N

status

provisional

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_032387 19 - 4147 NP_115763 - 1243 - 2001 11498583

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   kidney tubule collecting duct   predominantly

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

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
	plays an important role in the regulation of renal ion transport
	stimulates caveola-mediated endocytosis of TRPV5

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

cell & other

REGULATION

activated by

autophosphorylation

ASSOCIATED DISORDERS

corresponding disease(s)

PHA2B

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