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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
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, PHA2B
    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
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    19 - 4147 - 1243 - 2001 11498583
    EXPRESSION
    Type restricted
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart   predominantly
    Digestiveintestinelarge intestinecolon  
    Nervousbrain   predominantly
    reproductiveepididymis    
    Urinarykidneytubuleconvoluted tubule predominantly Mus musculus
     kidneynephron  predominantly Homo sapiens
     kidneytubuleHenles loop   Mus musculus
    Visualeyelens    Homo sapiens
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Epithelialabsorptive excretorydigestive epithelium  
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Cardiovascularendothelial
    Urinarypodocyte 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)
    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