WNK2 (WNK lysine deficient protein kinase 2)

2010-04-01   Peter Jordan 

Departamento de Genetica, Instituto Nacional de Saude Dr Ricardo Jorge, Avenida Padre Cruz, 1649-016 Lisboa, Portugal

Identity

HGNC
LOCATION
9q22.31
LOCUSID
ALIAS
NY-CO-43,P/OKcl.13,PRKWNK2,SDCCAG43
FUSION GENES

DNA/RNA

Atlas Image
Human WNK2 gene structure. The gene spans 136 Kbp, contains 31 exons and localizes to chromosome 9q22.31. Exons (vertical boxes) and separating introns are shown in proportion to their sizes; however, intron scale differs from exon scale.

Description

The human WNK2 gene is composed of 31 exons spanning 136 Kbp on chromosome 9q22.31. The promoter region contains a 700 bp CpG island between 1103 bp and 396 bp upstream of the ATG translation start codon. A second CpG island spans exon 1 from 135 bp upstream of the ATG translation start codon until 638 bp downstream of the ATG and close to the end of exon 1.

Transcription

Two major alternative transcripts exist depending on the terminal exon chosen. One variant uses exons 1-30, has a coding sequence of 6894 bp and yields WNK2(1-2297) (related to clone KIAA1760, Acc. Nb. AB051547). The other variant skips exon 30 and includes exon 31, has a coding sequence of 6765 bp and yields WNK2(1-2254) (related to clone Kaia302; Acc. Nb. AK000694). Both terminal exons 30 and 31 carry their own 3-untranslated regions and polyadenylation signals. In addition, there is evidence for alternative splicing in other exons and in a tissue-specific manner.

Pseudogene

None known.

Proteins

Atlas Image
Diagram of the WNK2 protein in scale. The sequence contains a catalytic domain near the N-terminus and a coiled coil domain near the C-terminus. Except for three short homology regions shared with the three other human WNK kinases, no other functional domains are known. The two splicing variants WNK2(1-2297) and WNK2(1-2254) differ in the C-terminal protein sequence.

Description

Amino acids: 2297 or 2254. Molecular Weight: 243000 Daltons. The WNK2 protein encodes a cytoplasmic serine-threonine kinase that lacks a lysine in subdomain II required for ATP-binding in most protein kinases and instead uses an alternative lysine in subdomain I. WNK kinase form a separate family branch, most closely related to kinases MEKK, Raf and PAK.

Expression

WNK2 is preferentially expressed in heart, skeletal muscle and brain but also in small intestine, colon and liver. Loss of expression was reported in a large percentage of human gliomas (Hong et al., 2007) and grade II and III meningiomas (Jun et al., 2009) due to extensive methylation in the CpG island at the 5 end of the WNK2 gene. In contrast, promoter methylation was rare in other tumor types. This finding makes WNK2 a candidate tumor suppressor gene in brain tumors.

Localisation

The subcellular localization of GFP-tagged WNK2 in HeLa cells was predominantly cytoplasmic. Part of the endogenous WNK2 pool in HT29 colorectal cells localized to the plasma membrane and overexpression of a WNK2(1922-2156) that contains the coiled-coil domain was targeted to the plasma membrane.

Function

Human WNK2 modulates the activation level of ERK1 and ERK2. Experimental depletion of WNK2 or overexpression of a kinase-dead WNK2K207M mutant led to increased phospho-ERK1/2 levels when a basal ERK stimulation was present but not, for example, in serum-free culture conditions (Moniz et al., 2007). This increase in ERK1/2 activation promoted cell cycle progression through G1/S and sensitized cells to respond to lower concentrations of EGF. From these data one might predict that loss of WNK2 expression will promote cell cycle progression in tumor cells. Interestingly, WNK2 expression is silenced in a significant percentage of human gliomas (Hong et al., 2007) suggesting that this pathway may be used in some tumor types to promote cell proliferation. The molecular mechanism through which a reduction in WNK2 expression can increase ERK1/2 activation involves phosphorylation of MEK1 at serine 298, a modification that increases MEK1 affinity towards ERK1/2. Apparently, WNK2 affects PAK1 activation via Rac1 and PAK1 is the kinase responsible for MEK1 S298 phosphorylation (Moniz et al., 2008).

Homology

The catalytic domain of WNK2 is 90% identical to WNK1, 91% identical to WNK3 and 81% identical to WNK4. The remaining sequence of WNK2 has little homology to other WNK members except for three small WNK homology regions (Holden et al., 2004; Moniz et al., 2007). These include an acidic motif (residues 586-597) to which hereditary mutations in WNK4 cluster (Wilson et al., 2001), residues 1186-1261 without any recognizable motif, and residues 1918-1988 including a coiled-coil domain.

Mutations

Note

At present it is unclear whether the observed somatic mutations have a functional impact on the WNK2 protein or confer any selective advantage to tumors cells.

Germinal

No germinal mutations described.

Somatic

Somatic mutations in WNK2 have been found in the course of large scale tumor genome sequencing efforts (see Table below).
TissueHistology/TypecDNAProteinMutationRef
Colorectaladenocarcinomac.1964delCp.P655fs*2Frameshift deletionGreenman et al., 2007
Brainglioblastomac.3799G>Ap.A1267TMissenseParsons et al., 2008
Stomachadenocarcinomac.4269delCp.S1424fs*5Frameshift deletionGreenman et al., 2007
Lungneuroendocrine carcinomac.5009G>Ap.G1670EMissenseGreenman et al., 2007; Davies et al., 2005
Lungadenocarcinomac.6089G>Tp.S2030IMissenseGreenman et al., 2007; Davies et al., 2005
Ovaryserous carcinomac.1528G>Tp.V510L MissenseGreenman et al., 2007
Ovarymucinous carcinomac.6798delCp.T2267fs*31Frameshift deletionGreenman et al., 2007

Implicated in

Entity name
Brain tumors
Note
Promoter methylation leads to loss of expression.
Disease
Glioma and meningioma.
Prognosis
Unknown.
Entity name
Colon cancer
Note
WNK2 clone was isolated as a serologically defined colon cancer antigen 43; WNK2 is expressed in colon.

Bibliography

Pubmed IDLast YearTitleAuthors
161409232005Somatic mutations of the protein kinase gene family in human lung cancer.Davies H et al
173448462007Patterns of somatic mutation in human cancer genomes.Greenman C et al
151941942004Cloning, genomic organization, alternative splicing and expression analysis of the human gene WNK3 (PRKWNK3).Holden S et al
175789252007Epigenome scans and cancer genome sequencing converge on WNK2, a kinase-independent suppressor of cell growth.Hong C et al
112807642001Molecular basis of T cell-mediated recognition of pancreatic cancer cells.Ito M et al
190015262009Epigenetic silencing of the kinase tumor suppressor WNK2 is tumor-type and tumor-grade specific.Jun P et al
200947552010Emerging roles for WNK kinases in cancer.Moniz S et al
185935982008WNK2 modulates MEK1 activity through the Rho GTPase pathway.Moniz S et al
176679372007Protein kinase WNK2 inhibits cell proliferation by negatively modulating the activation of MEK1/ERK1/2.Moniz S et al
187723962008An integrated genomic analysis of human glioblastoma multiforme.Parsons DW et al
96107211998Characterization of human colon cancer antigens recognized by autologous antibodies.Scanlan MJ et al
114985832001Human hypertension caused by mutations in WNK kinases.Wilson FH et al

Other Information

Locus ID:

NCBI: 65268
MIM: 606249
HGNC: 14542
Ensembl: ENSG00000165238

Variants:

dbSNP: 65268
ClinVar: 65268
TCGA: ENSG00000165238
COSMIC: WNK2

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000165238ENST00000297954Q9Y3S1
ENSG00000165238ENST00000395477F8W9F9
ENSG00000165238ENST00000411624H0Y7R3
ENSG00000165238ENST00000427277E9PCD1
ENSG00000165238ENST00000432730H0Y7T5
ENSG00000165238ENST00000448039A6PVV2
ENSG00000165238ENST00000448251H0Y493
ENSG00000165238ENST00000453718H0Y7J9

Expression (GTEx)

0
5
10
15
20
25
30
35
40
45
50

Pathways

PathwaySourceExternal ID
Transmembrane transport of small moleculesREACTOMER-HSA-382551
Ion channel transportREACTOMER-HSA-983712
Stimuli-sensing channelsREACTOMER-HSA-2672351

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
203796142010Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.62
217338462011WNK2 kinase is a novel regulator of essential neuronal cation-chloride cotransporters.30
175789252007Epigenome scans and cancer genome sequencing converge on WNK2, a kinase-independent suppressor of cell growth.24
176679372007Protein kinase WNK2 inhibits cell proliferation by negatively modulating the activation of MEK1/ERK1/2.24
230350502013Loss of WNK2 expression by promoter gene methylation occurs in adult gliomas and triggers Rac1-mediated tumour cell invasiveness.20
190015262009Epigenetic silencing of the kinase tumor suppressor WNK2 is tumor-type and tumor-grade specific.17
237978752013Wnk kinases are positive regulators of canonical Wnt/β-catenin signalling.16
185935982008WNK2 modulates MEK1 activity through the Rho GTPase pathway.12
201983152010Association of genetic variants with hemorrhagic stroke in Japanese individuals.11
197248952009Association of gene polymorphisms with chronic kidney disease in Japanese individuals.7

Citation

Peter Jordan

WNK2 (WNK lysine deficient protein kinase 2)

Atlas Genet Cytogenet Oncol Haematol. 2010-04-01

Online version: http://atlasgeneticsoncology.org/gene/41867/wnk2