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

    Gene ID: 65266, updated on 2-Nov-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
    mouse all
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    Genomic context

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    See WNK4 in Genome Data Viewer
    Location:
    17q21.2
    Exon count:
    18
    Annotation release Status Assembly Chr Location
    RS_2024_08 current GRCh38.p14 (GCF_000001405.40) 17 NC_000017.11 (42780610..42797066)
    RS_2024_08 current T2T-CHM13v2.0 (GCF_009914755.1) 17 NC_060941.1 (43637750..43654206)
    RS_2024_09 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 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. Downregulation of WNK4 expression facilitates the proliferation of gastric cancer cells via activation of the STAT3 signaling pathway. Li M, et al. Neoplasma, 2024 Jun. PMID 38764295
    2. Association of Ala589Ser polymorphism of WNK4 gene with essential hypertension in a high-risk Chinese population. Sun ZJ, et al. J Physiol Sci, 2009 Mar. PMID 19340547, Free PMC Article
    3. [Study on the association between genetic polymorphism on WNK4 genes and essential hypertension among Kazakhs ethnic population, in Xinjiang]. Cao FF, et al. Zhonghua Liu Xing Bing Xue Za Zhi, 2010 Apr. PMID 20513278
    4. WNK4 polymorphisms and essential hypertension in the Uyghur population. Lu M, et al. Clin Exp Hypertens, 2009 Apr. PMID 19330605
    5. A patient with pseudohypoaldosteronism type II caused by a novel mutation in WNK4 gene. Gong H, et al. Endocrine, 2008 Jun. PMID 19016006

    See all (96) citations in PubMed

    GeneRIFs: Gene References Into Functions

    What's a GeneRIF?
    1. Downregulation of WNK4 expression facilitates the proliferation of gastric cancer cells via activation of the STAT3 signaling pathway.
      Title: Downregulation of WNK4 expression facilitates the proliferation of gastric cancer cells via activation of the STAT3 signaling pathway.
    2. 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.
    3. 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.
    4. 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.
    5. 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.
    6. 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.
    7. 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.
    8. 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.
    9. 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.
    10. 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.
    Submit: New GeneRIF Correction See all GeneRIFs (60)

    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

    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 histone H2AS1 kinase activity 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 chromatin remodeling 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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    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_2024_08

    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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