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

Summary

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

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_000017.11 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

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Go to reference sequence details

Genomic Sequence:

Go to nucleotide: Graphics FASTA GenBank

Expression

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See details

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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GeneRIFs: Gene References Into Functions

What's a GeneRIF?

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.
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.
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.
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.
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.
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.
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.
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.
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.
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)

Interactions

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Products	Interactant	Other Gene	Complex	Source	Pubs	Description

General gene information

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Markers

D11S2921 (e-PCR)
- UniSTS:152074

RH45445 (e-PCR)
- UniSTS:59661

D17S1186 (e-PCR)
- UniSTS:149798

RH66580 (e-PCR)
- UniSTS:89400

L18426 (e-PCR)
- UniSTS:34648

D11S3732 (e-PCR)
- UniSTS:152962

RH47257 (e-PCR)
- UniSTS:44990

D7S2800 (e-PCR)
- UniSTS:60903

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

EC 2.7.11.1

NP_115763.2

EC 2.7.11.1

XP_016880451.1

EC 2.7.11.1

XP_016880455.1

EC 2.7.11.1

XP_047292510.1

EC 2.7.11.1

XP_047292512.1

EC 2.7.11.1

XP_047292513.1

EC 2.7.11.1

XP_047292514.1

EC 2.7.11.1

XP_047292515.1

EC 2.7.11.1

XP_047292516.1

EC 2.7.11.1

XP_047292517.1

EC 2.7.11.1

XP_047292518.1

EC 2.7.11.1

XP_047292519.1

EC 2.7.11.1

XP_054172926.1

EC 2.7.11.1

XP_054172927.1

EC 2.7.11.1

XP_054172928.1

EC 2.7.11.1

XP_054172929.1

EC 2.7.11.1

XP_054172930.1

EC 2.7.11.1

XP_054172931.1

EC 2.7.11.1

XP_054172932.1

EC 2.7.11.1

XP_054172933.1

EC 2.7.11.1

XP_054172934.1

EC 2.7.11.1

XP_054172935.1

EC 2.7.11.1

XP_054172936.1

EC 2.7.11.1

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

NG_016227.1 RefSeqGene

Range

4980..21436

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GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

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
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

NC_000017.11 Reference GRCh38.p14 Primary Assembly

Range

42780610..42797066

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GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

XM_017024962.2 → XP_016880451.1 serine/threonine-protein kinase WNK4 isoform X1
XM_047436559.1 → XP_047292515.1 serine/threonine-protein kinase WNK4 isoform X6
XM_047436554.1 → XP_047292510.1 serine/threonine-protein kinase WNK4 isoform X2
XM_047436558.1 → XP_047292514.1 serine/threonine-protein kinase WNK4 isoform X5
XM_047436560.1 → XP_047292516.1 serine/threonine-protein kinase WNK4 isoform X7
XM_047436556.1 → XP_047292512.1 serine/threonine-protein kinase WNK4 isoform X3
XM_047436561.1 → XP_047292517.1 serine/threonine-protein kinase WNK4 isoform X8
XM_047436563.1 → XP_047292519.1 serine/threonine-protein kinase WNK4 isoform X10
XM_047436557.1 → XP_047292513.1 serine/threonine-protein kinase WNK4 isoform X4
XM_047436562.1 → XP_047292518.1 serine/threonine-protein kinase WNK4 isoform X9
XM_017024966.2 → XP_016880455.1 serine/threonine-protein kinase WNK4 isoform X11

Alternate T2T-CHM13v2.0

Genomic

NC_060941.1 Alternate T2T-CHM13v2.0

Range

43637750..43654206

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GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

XM_054316951.1 → XP_054172926.1 serine/threonine-protein kinase WNK4 isoform X1
XM_054316956.1 → XP_054172931.1 serine/threonine-protein kinase WNK4 isoform X6
XM_054316952.1 → XP_054172927.1 serine/threonine-protein kinase WNK4 isoform X2
XM_054316955.1 → XP_054172930.1 serine/threonine-protein kinase WNK4 isoform X5
XM_054316957.1 → XP_054172932.1 serine/threonine-protein kinase WNK4 isoform X7
XM_054316953.1 → XP_054172928.1 serine/threonine-protein kinase WNK4 isoform X3
XM_054316958.1 → XP_054172933.1 serine/threonine-protein kinase WNK4 isoform X8
XM_054316960.1 → XP_054172935.1 serine/threonine-protein kinase WNK4 isoform X10
XM_054316954.1 → XP_054172929.1 serine/threonine-protein kinase WNK4 isoform X4
XM_054316959.1 → XP_054172934.1 serine/threonine-protein kinase WNK4 isoform X9
XM_054316961.1 → XP_054172936.1 serine/threonine-protein kinase WNK4 isoform X11