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WNK4 WNK lysine deficient protein kinase 4 [ Homo sapiens (human) ]

Gene ID: 65266, updated on 7-Apr-2024

Summary

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Official Symbol
WNK4provided by HGNC
Official Full Name
WNK lysine deficient protein kinase 4provided by HGNC
Primary source
HGNC:HGNC:14544
See related
Ensembl:ENSG00000126562 MIM:601844; AllianceGenome:HGNC:14544
Gene type
protein coding
RefSeq status
REVIEWED
Organism
Homo sapiens
Lineage
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as
PHA2B; PRKWNK4
Summary
This gene encodes a member of the WNK family of serine-threonine protein kinases. The kinase is part of the tight junction complex in kidney cells, and regulates the balance between NaCl reabsorption and K(+) secretion. The kinase regulates the activities of several types of ion channels, cotransporters, and exchangers involved in electrolyte flux in epithelial cells. Mutations in this gene result in pseudohypoaldosteronism type IIB.[provided by RefSeq, Sep 2009]
Expression
Biased expression in kidney (RPKM 12.8), prostate (RPKM 5.7) and 6 other tissues See more
Orthologs
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Genomic context

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Location:
17q21.2
Exon count:
18
Annotation release Status Assembly Chr Location
RS_2023_10 current GRCh38.p14 (GCF_000001405.40) 17 NC_000017.11 (42780610..42797066)
RS_2023_10 current T2T-CHM13v2.0 (GCF_009914755.1) 17 NC_060941.1 (43637750..43654206)
105.20220307 previous assembly GRCh37.p13 (GCF_000001405.25) 17 NC_000017.10 (40932628..40949084)

Chromosome 17 - NC_000017.11Genomic Context describing neighboring genes Neighboring gene RAMP2 antisense RNA 1 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 8547 Neighboring gene receptor activity modifying protein 2 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 12222 Neighboring gene H3K27ac hESC enhancer GRCh37_chr17:40925642-40926189 Neighboring gene Sharpr-MPRA regulatory region 12532 Neighboring gene vacuolar protein sorting 25 homolog Neighboring gene H3K4me1 hESC enhancer GRCh37_chr17:40932701-40933658 Neighboring gene CDK7 strongly-dependent group 2 enhancer GRCh37_chr17:40934948-40936147 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 12223 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 12224 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 12225 Neighboring gene cytochrome c oxidase assembly factor 3 Neighboring gene cyclin N-terminal domain containing 1 Neighboring gene beclin 1

Genomic regions, transcripts, and products

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Go to nucleotide: Graphics FASTA GenBank

Expression

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  • Project title: HPA RNA-seq normal tissues
  • Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
  • BioProject: PRJEB4337
  • Publication: PMID 24309898
  • Analysis date: Wed Apr 4 07:08:55 2018

Bibliography

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Related articles in PubMed

  1. Identification of a novel KLHL3-interacting motif in the C-terminal region of WNK4. Wang L, et al. Biochem Biophys Res Commun, 2023 Aug 30. PMID 37285722
  2. A familial case of pseudohypoaldosteronism type II (PHA2) with a novel mutation (D564N) in the acidic motif in WNK4. Sakoh T, et al. Mol Genet Genomic Med, 2019 Jun. PMID 31044551, Free PMC Article
  3. The regulation of Na+Cl- cotransporter by with-no-lysine kinase 4. Argaiz ER, et al. Curr Opin Nephrol Hypertens, 2016 Sep. PMID 27322883
  4. Novel Association of WNK4 Gene, Ala589Ser Polymorphism in Essential Hypertension, and Type 2 Diabetes Mellitus in Malaysia. Ghodsian N, et al. J Diabetes Res, 2016. PMID 27314050, Free PMC Article
  5. Comprehensive assessment of the association of WNK4 polymorphisms with hypertension: evidence from a meta-analysis. Guo XG, et al. Sci Rep, 2014 Sep 30. PMID 25266424, Free PMC Article

See all (87) citations in PubMed

GeneRIFs: Gene References Into Functions

What's a GeneRIF?
  1. KLHL3-dependent WNK4 degradation affected by potassium through the neddylation and autophagy pathway.
    Title: KLHL3-dependent WNK4 degradation affected by potassium through the neddylation and autophagy pathway.
  2. Identification of a novel KLHL3-interacting motif in the C-terminal region of WNK4.
    Title: Identification of a novel KLHL3-interacting motif in the C-terminal region of WNK4.
  3. D564N mutation in WNK4 is a novel genetic cause of PHA2 with a relatively mild phenotype.
    Title: A familial case of pseudohypoaldosteronism type II (PHA2) with a novel mutation (D564N) in the acidic motif in WNK4.
  4. Molecular dynamics simulations indicate the effects of these mutations on the interaction between the Kelch domain of kelch-like protein 3 (KLHL3) and the acidic motif (AM) of WNK lysine deficient protein kinase 4 protein (WNK4).
    Title: Unveiling the Distinct Mechanisms by which Disease-Causing Mutations in the Kelch Domain of KLHL3 Disrupt the Interaction with the Acidic Motif of WNK4 through Molecular Dynamics Simulation.
  5. This study has identified specific WNK4 that are involved in opening TRPV4, using a selective screen of short interfering ribonucleic acid (siRNA) SMARTpools, which individually targeted all human kinases, in human embryonic kidney 293 (HEK293) cells that stably express inducible TRPV4.
    Title: A Functional Kinase Short Interfering Ribonucleic Acid Screen Using Protease-Activated Receptor 2-Dependent Opening of Transient Receptor Potential Vanilloid-4.
  6. Kidney-specific WNK1 isoform is a potent activator of WNK4 and NCC-mediated sodium/chloride transport.
    Title: Kidney-specific WNK1 isoform (KS-WNK1) is a potent activator of WNK4 and NCC.
  7. tacrolimus increases levels of KLHL3(S433-P), resulting in increased levels of WNK4, phosphorylated SPAK, and Na-Cl cotransporter.These findings demonstrate that KLHL3(S433-P) is a calcineurin substrate and implicate increased KLHL3 phosphorylation in tacrolimus-induced pathologies.
    Title: Calcineurin dephosphorylates Kelch-like 3, reversing phosphorylation by angiotensin II and regulating renal electrolyte handling.
  8. 5 WNK4 sites (S47, S64, S1169, S1180, S1196) are phosphorylated downstream of AngII signaling in cultured cells and in vitro by PKC and PKA. Phosphorylation at S64 and S1196 promoted phosphorylation of the WNK4 kinase T-loop at S332 (required for kinase activation) and increased phosphorylation of SPAK. Volume depletion induced phosphorylation of these sites in vivo, predominantly in the distal convoluted tubule.
    Title: Phosphorylation by PKC and PKA regulate the kinase activity and downstream signaling of WNK4.
  9. Modulation of WNK4 activity by [Cl]i can account for its dual role on the NCC, and this has important physiological implications regarding the regulation of extracellular potassium concentration.
    Title: The regulation of Na+Cl- cotransporter by with-no-lysine kinase 4.
  10. This study provides substantial new insights into the role of phosphorylation of KLHL3 in regulating the interaction with WNK4
    Title: Phosphorylation of KLHL3 at serine 433 impairs its interaction with the acidic motif of WNK4: a molecular dynamics study.
Submit: New GeneRIF Correction See all GeneRIFs (59)

Phenotypes

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Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

Associated conditions

Description Tests
Pseudohypoaldosteronism type 2B
MedGen: C1840390 OMIM: 614491 GeneReviews: Pseudohypoaldosteronism Type II
Compare labs
Pseudohypoaldosteronism, type 2
MedGen: C1449844 GeneReviews: Pseudohypoaldosteronism Type II
not available

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

Genotypes

Pathways from PubChem

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Interactions

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Products Interactant Other Gene Complex Source Pubs Description

General gene information

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Markers

Homology

Gene Ontology Provided by GOA

Function Evidence Code Pubs
enables ATP binding ISS
Inferred from Sequence or Structural Similarity
more info
  
enables chloride ion binding IEA
Inferred from Electronic Annotation
more info
  
enables ion channel inhibitor activity ISS
Inferred from Sequence or Structural Similarity
more info
  
enables protein binding IPI
Inferred from Physical Interaction
more info
 PubMed 
enables protein kinase activity IBA
Inferred from Biological aspect of Ancestor
more info
  
enables protein serine kinase activity IEA
Inferred from Electronic Annotation
more info
  
enables protein serine/threonine kinase activity IDA
Inferred from Direct Assay
more info
 PubMed 
enables protein serine/threonine kinase activity ISS
Inferred from Sequence or Structural Similarity
more info
  
Process Evidence Code Pubs
involved_in ERK1 and ERK2 cascade IEA
Inferred from Electronic Annotation
more info
  
involved_in aldosterone secretion IEA
Inferred from Electronic Annotation
more info
  
involved_in calcium ion homeostasis IEA
Inferred from Electronic Annotation
more info
  
involved_in cellular response to xenobiotic stimulus IEA
Inferred from Electronic Annotation
more info
  
involved_in chloride transport IEA
Inferred from Electronic Annotation
more info
  
involved_in distal tubule morphogenesis IMP
Inferred from Mutant Phenotype
more info
 PubMed 
involved_in gene expression IEA
Inferred from Electronic Annotation
more info
  
involved_in inflammatory response IEA
Inferred from Electronic Annotation
more info
  
involved_in intracellular chloride ion homeostasis IEA
Inferred from Electronic Annotation
more info
  
involved_in intracellular signal transduction ISS
Inferred from Sequence or Structural Similarity
more info
  
involved_in macrophage activation IEA
Inferred from Electronic Annotation
more info
  
involved_in monoatomic ion homeostasis IMP
Inferred from Mutant Phenotype
more info
 PubMed 
involved_in negative regulation of pancreatic juice secretion IEA
Inferred from Electronic Annotation
more info
  
involved_in negative regulation of protein localization to plasma membrane ISS
Inferred from Sequence or Structural Similarity
more info
  
involved_in negative regulation of sodium ion transport ISS
Inferred from Sequence or Structural Similarity
more info
  
involved_in potassium ion transmembrane transport IEA
Inferred from Electronic Annotation
more info
  
involved_in protein kinase C signaling IEA
Inferred from Electronic Annotation
more info
  
involved_in protein localization IEA
Inferred from Electronic Annotation
more info
  
involved_in protein phosphorylation ISS
Inferred from Sequence or Structural Similarity
more info
  
involved_in regulation of blood pressure IEA
Inferred from Electronic Annotation
more info
  
involved_in regulation of potassium ion export across plasma membrane IEA
Inferred from Electronic Annotation
more info
  
involved_in renal sodium ion absorption IMP
Inferred from Mutant Phenotype
more info
 PubMed 
involved_in renal sodium ion absorption ISS
Inferred from Sequence or Structural Similarity
more info
 PubMed 
involved_in renal sodium ion transport ISS
Inferred from Sequence or Structural Similarity
more info
  
involved_in response to dietary excess IEA
Inferred from Electronic Annotation
more info
  
involved_in signal transduction IBA
Inferred from Biological aspect of Ancestor
more info
  
involved_in sodium ion transmembrane transport IEA
Inferred from Electronic Annotation
more info
  
Component Evidence Code Pubs
is_active_in bicellular tight junction ISS
Inferred from Sequence or Structural Similarity
more info
 PubMed 
located_in bicellular tight junction ISS
Inferred from Sequence or Structural Similarity
more info
  
located_in cell body IEA
Inferred from Electronic Annotation
more info
  
is_active_in cytoplasm IBA
Inferred from Biological aspect of Ancestor
more info
  
located_in cytosol ISS
Inferred from Sequence or Structural Similarity
more info
  
located_in membrane ISS
Inferred from Sequence or Structural Similarity
more info
  
part_of protein-containing complex IEA
Inferred from Electronic Annotation
more info
  

General protein information

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Preferred Names
serine/threonine-protein kinase WNK4
Names
protein kinase lysine-deficient 4
protein kinase with no lysine 4
NP_001308228.1
NP_115763.2
XP_016880451.1
XP_016880455.1
XP_047292510.1
XP_047292512.1
XP_047292513.1
XP_047292514.1
XP_047292515.1
XP_047292516.1
XP_047292517.1
XP_047292518.1
XP_047292519.1
XP_054172926.1
XP_054172927.1
XP_054172928.1
XP_054172929.1
XP_054172930.1
XP_054172931.1
XP_054172932.1
XP_054172933.1
XP_054172934.1
XP_054172935.1
XP_054172936.1

NCBI Reference Sequences (RefSeq)

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NEW Try the new Transcript table

RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

Genomic

  1. NG_016227.1 RefSeqGene

    Range
    4980..21436
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

  1. NM_001321299.2 → NP_001308228.1  serine/threonine-protein kinase WNK4 isoform 2

    Status: REVIEWED

    Source sequence(s)
    AC100793, BC144356, BM683764, CA388932
    Conserved Domains (1) summary
    pfam12202
    Location:117 → 153
    OSR1_C; Oxidative-stress-responsive kinase 1 C terminal

  2. NM_032387.5 → NP_115763.2  serine/threonine-protein kinase WNK4 isoform 1

    See identical proteins and their annotated locations for NP_115763.2

    Status: REVIEWED

    Source sequence(s)
    AC100793, BC136664, BM683764, CA388932
    Consensus CDS
    CCDS11439.1
    UniProtKB/Swiss-Prot
    B0LPI0, Q8N8X3, Q8N8Z2, Q96DT8, Q96J92, Q9BYS5
    Related
    ENSP00000246914.4, ENST00000246914.10
    Conserved Domains (3) summary
    smart00220
    Location:179 → 432
    S_TKc; Serine/Threonine protein kinases, catalytic domain
    cd14033
    Location:172 → 432
    STKc_WNK4; Catalytic domain of the Serine/Threonine protein kinase, With No Lysine (WNK) 4
    pfam12202
    Location:453 → 489
    OSR1_C; Oxidative-stress-responsive kinase 1 C terminal

RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2023_10

The following sections contain reference sequences that belong to a specific genome build. Explain

Reference GRCh38.p14 Primary Assembly

Genomic

  1. NC_000017.11 Reference GRCh38.p14 Primary Assembly

    Range
    42780610..42797066
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

  1. XM_017024962.2 → XP_016880451.1  serine/threonine-protein kinase WNK4 isoform X1

  2. XM_047436559.1 → XP_047292515.1  serine/threonine-protein kinase WNK4 isoform X6

  3. XM_047436554.1 → XP_047292510.1  serine/threonine-protein kinase WNK4 isoform X2

  4. XM_047436558.1 → XP_047292514.1  serine/threonine-protein kinase WNK4 isoform X5

  5. XM_047436560.1 → XP_047292516.1  serine/threonine-protein kinase WNK4 isoform X7

  6. XM_047436556.1 → XP_047292512.1  serine/threonine-protein kinase WNK4 isoform X3

  7. XM_047436561.1 → XP_047292517.1  serine/threonine-protein kinase WNK4 isoform X8

  8. XM_047436563.1 → XP_047292519.1  serine/threonine-protein kinase WNK4 isoform X10

  9. XM_047436557.1 → XP_047292513.1  serine/threonine-protein kinase WNK4 isoform X4

  10. XM_047436562.1 → XP_047292518.1  serine/threonine-protein kinase WNK4 isoform X9

  11. XM_017024966.2 → XP_016880455.1  serine/threonine-protein kinase WNK4 isoform X11

Alternate T2T-CHM13v2.0

Genomic

  1. NC_060941.1 Alternate T2T-CHM13v2.0

    Range
    43637750..43654206
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

  1. XM_054316951.1 → XP_054172926.1  serine/threonine-protein kinase WNK4 isoform X1

  2. XM_054316956.1 → XP_054172931.1  serine/threonine-protein kinase WNK4 isoform X6

  3. XM_054316952.1 → XP_054172927.1  serine/threonine-protein kinase WNK4 isoform X2

  4. XM_054316955.1 → XP_054172930.1  serine/threonine-protein kinase WNK4 isoform X5

  5. XM_054316957.1 → XP_054172932.1  serine/threonine-protein kinase WNK4 isoform X7

  6. XM_054316953.1 → XP_054172928.1  serine/threonine-protein kinase WNK4 isoform X3

  7. XM_054316958.1 → XP_054172933.1  serine/threonine-protein kinase WNK4 isoform X8

  8. XM_054316960.1 → XP_054172935.1  serine/threonine-protein kinase WNK4 isoform X10

  9. XM_054316954.1 → XP_054172929.1  serine/threonine-protein kinase WNK4 isoform X4

  10. XM_054316959.1 → XP_054172934.1  serine/threonine-protein kinase WNK4 isoform X9

  11. XM_054316961.1 → XP_054172936.1  serine/threonine-protein kinase WNK4 isoform X11

Nucleotide Protein
Heading Accession and Version
Protein Accession Links
GenPept Link UniProtKB Link
Q96J92.1 GenPept UniProtKB/Swiss-Prot:Q96J92

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