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WNK2 (WNK lysine deficient protein kinase 2)

Written2010-04Peter Jordan
Departamento de Genetica, Instituto Nacional de Saude Dr Ricardo Jorge, Avenida Padre Cruz, 1649-016 Lisboa, Portugal

(Note : for Links provided by Atlas : click)

Identity

Alias_namesSDCCAG43
PRKWNK2
serologically defined colon cancer antigen 43
Alias_symbol (synonym)NY-CO-43
KIAA1760
Other aliasKAIA302
P/OKcl.13
HGNC (Hugo) WNK2
LocusID (NCBI) 65268
Atlas_Id 41867
Location 9q22.31  [Link to chromosome band 9q22]
Location_base_pair Starts at 95947212 and ends at 96081655 bp from pter ( according to hg19-Feb_2009)  [Mapping WNK2.png]
Local_order The WNK2 gene is covered by BAC clones RP11-370F5, RP11-480F4 and RP11-165J3 and is flanked by the NINJ1 (telomeric) and C9orf129 (centromeric) genes.
Fusion genes
(updated 2016)
IFT74 (9p21.2) / WNK2 (9q22.31)KCNK10 (14q31.3) / WNK2 (9q22.31)KIAA0368 (9q31.3) / WNK2 (9q22.31)
WNK2 (9q22.31) / SECISBP2 (9q22.2)

DNA/RNA

 
  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.

Protein

 
  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).
Tissue
Histology/Type
cDNA
Protein
Mutation
Ref
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
Heterozygous somatic mutations in the WNK2 gene identified by large-scale tumor sequencing.

Implicated in

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

To be noted

Possible role in invasion due to the effect of WNK2 on Rho-GTPases. WNK2 controls (through a yet unknown mechanism) the activation of RhoA, which in turn determines the activation of Rac1 in a reciprocal manner. Experimental depletion of WNK2 leads to reduced RhoA and increased Rac1 activation.

Bibliography

Somatic mutations of the protein kinase gene family in human lung cancer.
Davies H, Hunter C, Smith R, Stephens P, Greenman C, Bignell G, Teague J, Butler A, Edkins S, Stevens C, Parker A, O'Meara S, Avis T, Barthorpe S, Brackenbury L, Buck G, Clements J, Cole J, Dicks E, Edwards K, Forbes S, Gorton M, Gray K, Halliday K, Harrison R, Hills K, Hinton J, Jones D, Kosmidou V, Laman R, Lugg R, Menzies A, Perry J, Petty R, Raine K, Shepherd R, Small A, Solomon H, Stephens Y, Tofts C, Varian J, Webb A, West S, Widaa S, Yates A, Brasseur F, Cooper CS, Flanagan AM, Green A, Knowles M, Leung SY, Looijenga LH, Malkowicz B, Pierotti MA, Teh BT, Yuen ST, Lakhani SR, Easton DF, Weber BL, Goldstraw P, Nicholson AG, Wooster R, Stratton MR, Futreal PA.
Cancer Res. 2005 Sep 1;65(17):7591-5.
PMID 16140923
 
Patterns of somatic mutation in human cancer genomes.
Greenman C, Stephens P, Smith R, Dalgliesh GL, Hunter C, Bignell G, Davies H, Teague J, Butler A, Stevens C, Edkins S, O'Meara S, Vastrik I, Schmidt EE, Avis T, Barthorpe S, Bhamra G, Buck G, Choudhury B, Clements J, Cole J, Dicks E, Forbes S, Gray K, Halliday K, Harrison R, Hills K, Hinton J, Jenkinson A, Jones D, Menzies A, Mironenko T, Perry J, Raine K, Richardson D, Shepherd R, Small A, Tofts C, Varian J, Webb T, West S, Widaa S, Yates A, Cahill DP, Louis DN, Goldstraw P, Nicholson AG, Brasseur F, Looijenga L, Weber BL, Chiew YE, DeFazio A, Greaves MF, Green AR, Campbell P, Birney E, Easton DF, Chenevix-Trench G, Tan MH, Khoo SK, Teh BT, Yuen ST, Leung SY, Wooster R, Futreal PA, Stratton MR.
Nature. 2007 Mar 8;446(7132):153-8.
PMID 17344846
 
Cloning, genomic organization, alternative splicing and expression analysis of the human gene WNK3 (PRKWNK3).
Holden S, Cox J, Raymond FL.
Gene. 2004 Jun 23;335:109-19.
PMID 15194194
 
Epigenome scans and cancer genome sequencing converge on WNK2, a kinase-independent suppressor of cell growth.
Hong C, Moorefield KS, Jun P, Aldape KD, Kharbanda S, Phillips HS, Costello JF.
Proc Natl Acad Sci U S A. 2007 Jun 26;104(26):10974-9. Epub 2007 Jun 19.
PMID 17578925
 
Molecular basis of T cell-mediated recognition of pancreatic cancer cells.
Ito M, Shichijo S, Tsuda N, Ochi M, Harashima N, Saito N, Itoh K.
Cancer Res. 2001 Mar 1;61(5):2038-46.
PMID 11280764
 
Epigenetic silencing of the kinase tumor suppressor WNK2 is tumor-type and tumor-grade specific.
Jun P, Hong C, Lal A, Wong JM, McDermott MW, Bollen AW, Plass C, Held WA, Smiraglia DJ, Costello JF.
Neuro Oncol. 2009 Aug;11(4):414-22. Epub 2008 Nov 11.
PMID 19001526
 
Emerging roles for WNK kinases in cancer.
Moniz S, Jordan P.
Cell Mol Life Sci. 2010 Apr;67(8):1265-76. Epub 2010 Jan 22. (REVIEW)
PMID 20094755
 
WNK2 modulates MEK1 activity through the Rho GTPase pathway.
Moniz S, Matos P, Jordan P.
Cell Signal. 2008 Oct;20(10):1762-8. Epub 2008 Jun 14.
PMID 18593598
 
Protein kinase WNK2 inhibits cell proliferation by negatively modulating the activation of MEK1/ERK1/2.
Moniz S, Verissimo F, Matos P, Brazao R, Silva E, Kotelevets L, Chastre E, Gespach C, Jordan P.
Oncogene. 2007 Sep 6;26(41):6071-81. Epub 2007 Jul 30.
PMID 17667937
 
An integrated genomic analysis of human glioblastoma multiforme.
Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL, Olivi A, McLendon R, Rasheed BA, Keir S, Nikolskaya T, Nikolsky Y, Busam DA, Tekleab H, Diaz LA Jr, Hartigan J, Smith DR, Strausberg RL, Marie SK, Shinjo SM, Yan H, Riggins GJ, Bigner DD, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW.
Science. 2008 Sep 26;321(5897):1807-12. Epub 2008 Sep 4.
PMID 18772396
 
Characterization of human colon cancer antigens recognized by autologous antibodies.
Scanlan MJ, Chen YT, Williamson B, Gure AO, Stockert E, Gordan JD, Tureci O, Sahin U, Pfreundschuh M, Old LJ.
Int J Cancer. 1998 May 29;76(5):652-8.
PMID 9610721
 
Human hypertension caused by mutations in WNK kinases.
Wilson FH, Disse-Nicodeme S, Choate KA, Ishikawa K, Nelson-Williams C, Desitter I, Gunel M, Milford DV, Lipkin GW, Achard JM, Feely MP, Dussol B, Berland Y, Unwin RJ, Mayan H, Simon DB, Farfel Z, Jeunemaitre X, Lifton RP.
Science. 2001 Aug 10;293(5532):1107-12.
PMID 11498583
 

Citation

This paper should be referenced as such :
Jordan, P
WNK2 (WNK lysine deficient protein kinase 2)
Atlas Genet Cytogenet Oncol Haematol. 2011;15(1):77-79.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/WNK2ID41867ch9q22.html


External links

Nomenclature
HGNC (Hugo)WNK2   14542
Cards
AtlasWNK2ID41867ch9q22
Entrez_Gene (NCBI)WNK2  65268  WNK lysine deficient protein kinase 2
AliasesNY-CO-43; P/OKcl.13; PRKWNK2; SDCCAG43
GeneCards (Weizmann)WNK2
Ensembl hg19 (Hinxton)ENSG00000165238 [Gene_View]  chr9:95947212-96081655 [Contig_View]  WNK2 [Vega]
Ensembl hg38 (Hinxton)ENSG00000165238 [Gene_View]  chr9:95947212-96081655 [Contig_View]  WNK2 [Vega]
ICGC DataPortalENSG00000165238
TCGA cBioPortalWNK2
AceView (NCBI)WNK2
Genatlas (Paris)WNK2
WikiGenes65268
SOURCE (Princeton)WNK2
Genetics Home Reference (NIH)WNK2
Genomic and cartography
GoldenPath hg19 (UCSC)WNK2  -     chr9:95947212-96081655 +  9q22.3   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)WNK2  -     9q22.3   [Description]    (hg38-Dec_2013)
EnsemblWNK2 - 9q22.3 [CytoView hg19]  WNK2 - 9q22.3 [CytoView hg38]
Mapping of homologs : NCBIWNK2 [Mapview hg19]  WNK2 [Mapview hg38]
OMIM606249   
Gene and transcription
Genbank (Entrez)AB044546 AB051547 AF039702 AJ242724 AK000694
RefSeq transcript (Entrez)NM_001282394 NM_006648
RefSeq genomic (Entrez)NC_000009 NC_018920 NT_008470 NW_004929366
Consensus coding sequences : CCDS (NCBI)WNK2
Cluster EST : UnigeneHs.654856 [ NCBI ]
CGAP (NCI)Hs.654856
Alternative Splicing GalleryENSG00000165238
Gene ExpressionWNK2 [ NCBI-GEO ]   WNK2 [ EBI - ARRAY_EXPRESS ]   WNK2 [ SEEK ]   WNK2 [ MEM ]
Gene Expression Viewer (FireBrowse)WNK2 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)65268
GTEX Portal (Tissue expression)WNK2
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ9Y3S1   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ9Y3S1  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ9Y3S1
Splice isoforms : SwissVarQ9Y3S1
Catalytic activity : Enzyme2.7.11.1 [ Enzyme-Expasy ]   2.7.11.12.7.11.1 [ IntEnz-EBI ]   2.7.11.1 [ BRENDA ]   2.7.11.1 [ KEGG ]   
PhosPhoSitePlusQ9Y3S1
Domaine pattern : Prosite (Expaxy)PROTEIN_KINASE_DOM (PS50011)    PROTEIN_KINASE_ST (PS00108)   
Domains : Interpro (EBI)Kinase-like_dom    Kinase_OSR1/WNK_CCT    Prot_kinase_dom    Ser/Thr_kinase_AS   
Domain families : Pfam (Sanger)OSR1_C (PF12202)    Pkinase (PF00069)   
Domain families : Pfam (NCBI)pfam12202    pfam00069   
Conserved Domain (NCBI)WNK2
DMDM Disease mutations65268
Blocks (Seattle)WNK2
SuperfamilyQ9Y3S1
Human Protein AtlasENSG00000165238
Peptide AtlasQ9Y3S1
HPRD06951
IPIIPI00398808   IPI00398809   IPI00398811   IPI00874163   IPI00855897   IPI01013686   IPI00384826   IPI01025221   IPI00976988   IPI01018754   IPI00796716   IPI01018815   
Protein Interaction databases
DIP (DOE-UCLA)Q9Y3S1
IntAct (EBI)Q9Y3S1
FunCoupENSG00000165238
BioGRIDWNK2
STRING (EMBL)WNK2
ZODIACWNK2
Ontologies - Pathways
QuickGOQ9Y3S1
Ontology : AmiGOprotein serine/threonine kinase activity  protein serine/threonine kinase activity  ATP binding  cytoplasm  cytosol  plasma membrane  protein phosphorylation  negative regulation of cell proliferation  intracellular signal transduction  protein autophosphorylation  negative regulation of ERK1 and ERK2 cascade  regulation of ion homeostasis  positive regulation of sodium ion transmembrane transporter activity  
Ontology : EGO-EBIprotein serine/threonine kinase activity  protein serine/threonine kinase activity  ATP binding  cytoplasm  cytosol  plasma membrane  protein phosphorylation  negative regulation of cell proliferation  intracellular signal transduction  protein autophosphorylation  negative regulation of ERK1 and ERK2 cascade  regulation of ion homeostasis  positive regulation of sodium ion transmembrane transporter activity  
REACTOMEQ9Y3S1 [protein]
REACTOME Pathways2672351 [pathway]   
NDEx NetworkWNK2
Atlas of Cancer Signalling NetworkWNK2
Wikipedia pathwaysWNK2
Orthology - Evolution
OrthoDB65268
GeneTree (enSembl)ENSG00000165238
Phylogenetic Trees/Animal Genes : TreeFamWNK2
HOVERGENQ9Y3S1
HOGENOMQ9Y3S1
Homologs : HomoloGeneWNK2
Homology/Alignments : Family Browser (UCSC)WNK2
Gene fusions - Rearrangements
Fusion : MitelmanIFT74/WNK2 [9p21.2/9q22.31]  [t(9;9)(p21;q22)]  
Fusion : MitelmanKIAA0368/WNK2 [9q31.3/9q22.31]  [t(9;9)(q22;q31)]  
Fusion : MitelmanWNK2/SECISBP2 [9q22.31/9q22.2]  [t(9;9)(q22;q22)]  
Fusion: TCGAIFT74 9p21.2 WNK2 9q22.31 LUSC
Fusion: TCGAKIAA0368 9q31.3 WNK2 9q22.31 BRCA
Fusion: TCGAWNK2 9q22.31 SECISBP2 9q22.2 LUSC
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerWNK2 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)WNK2
dbVarWNK2
ClinVarWNK2
1000_GenomesWNK2 
Exome Variant ServerWNK2
ExAC (Exome Aggregation Consortium)WNK2 (select the gene name)
Genetic variants : HAPMAP65268
Genomic Variants (DGV)WNK2 [DGVbeta]
DECIPHER (Syndromes)9:95947212-96081655  ENSG00000165238
CONAN: Copy Number AnalysisWNK2 
Mutations
ICGC Data PortalWNK2 
TCGA Data PortalWNK2 
Broad Tumor PortalWNK2
OASIS PortalWNK2 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICWNK2  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDWNK2
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch WNK2
DgiDB (Drug Gene Interaction Database)WNK2
DoCM (Curated mutations)WNK2 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)WNK2 (select a term)
intoGenWNK2
NCG5 (London)WNK2
Cancer3DWNK2(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM606249   
Orphanet
MedgenWNK2
Genetic Testing Registry WNK2
NextProtQ9Y3S1 [Medical]
TSGene65268
GENETestsWNK2
Huge Navigator WNK2 [HugePedia]
snp3D : Map Gene to Disease65268
BioCentury BCIQWNK2
ClinGenWNK2
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD65268
Chemical/Pharm GKB GenePA33783
Clinical trialWNK2
Miscellaneous
canSAR (ICR)WNK2 (select the gene name)
Probes
Litterature
PubMed30 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineWNK2
EVEXWNK2
GoPubMedWNK2
iHOPWNK2
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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