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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
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)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein 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