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.

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.

None known.

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.

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.

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.

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).

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.

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.

No germinal mutations described.

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
Colorectal	adenocarcinoma	c.1964delC	p.P655fs*2	Frameshift deletion	Greenman et al., 2007
Brain	glioblastoma	c.3799G>A	p.A1267T	Missense	Parsons et al., 2008
Stomach	adenocarcinoma	c.4269delC	p.S1424fs*5	Frameshift deletion	Greenman et al., 2007
Lung	neuroendocrine carcinoma	c.5009G>A	p.G1670E	Missense	Greenman et al., 2007; Davies et al., 2005
Lung	adenocarcinoma	c.6089G>T	p.S2030I	Missense	Greenman et al., 2007; Davies et al., 2005
Ovary	serous carcinoma	c.1528G>T	p.V510L	Missense	Greenman et al., 2007
Ovary	mucinous carcinoma	c.6798delC	p.T2267fs*31	Frameshift deletion	Greenman 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. Article Bibliography Pubmed ID Last Year Title Authors 16140923 2005 Somatic mutations of the protein kinase gene family in human lung cancer. Davies H et al 17344846 2007 Patterns of somatic mutation in human cancer genomes. Greenman C et al 15194194 2004 Cloning, genomic organization, alternative splicing and expression analysis of the human gene WNK3 (PRKWNK3). Holden S et al 17578925 2007 Epigenome scans and cancer genome sequencing converge on WNK2, a kinase-independent suppressor of cell growth. Hong C et al 11280764 2001 Molecular basis of T cell-mediated recognition of pancreatic cancer cells. Ito M et al 19001526 2009 Epigenetic silencing of the kinase tumor suppressor WNK2 is tumor-type and tumor-grade specific. Jun P et al 20094755 2010 Emerging roles for WNK kinases in cancer. Moniz S et al 18593598 2008 WNK2 modulates MEK1 activity through the Rho GTPase pathway. Moniz S et al 17667937 2007 Protein kinase WNK2 inhibits cell proliferation by negatively modulating the activation of MEK1/ERK1/2. Moniz S et al 18772396 2008 An integrated genomic analysis of human glioblastoma multiforme. Parsons DW et al 9610721 1998 Characterization of human colon cancer antigens recognized by autologous antibodies. Scanlan MJ et al 11498583 2001 Human 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 ID Transcript ID Uniprot ENSG00000165238 ENST00000297954 Q9Y3S1 ENSG00000165238 ENST00000395477 F8W9F9 ENSG00000165238 ENST00000411624 H0Y7R3 ENSG00000165238 ENST00000427277 E9PCD1 ENSG00000165238 ENST00000432730 H0Y7T5 ENSG00000165238 ENST00000448039 A6PVV2 ENSG00000165238 ENST00000448251 H0Y493 ENSG00000165238 ENST00000453718 H0Y7J9 Expression (GTEx) 0 5 10 15 20 25 30 35 40 45 50 Adipose - Subcutaneous Adipose - Visceral Adrenal Gland Artery - Aorta Artery - Tibial Bladder Brain - Amygdala Brain - Anterior cingulate cortex Brain - Caudate Brain - Cerebellar Hemisphere Brain - Cerebellum Brain - Cortex Brain - Frontal Cortex Brain - Hippocampus Brain - Hypothalamus Brain - Nucleus accumbens Brain - Putamen Brain - Spinal cord Brain - Substantia nigra Breast - Mammary Tissue Cells - Cultured fibroblasts Cells - EBV - transformed lymphocytes Cervix - Ectocervix Cervix - Endocervix Colon - Sigmoid Colon - Transverse Esophagus - Gastroesophageal Junction Esophagus - Mucosa Esophagus - Muscularis Fallopian Tube Heart - Atrial Appendage Heart - Left Ventricle Kidney - Cortex Kidney - Medulla Liver Lung Minor Salivary Gland Muscle - Skeletal Nerve - Tibial Ovary Pancreas Pituitary Prostate Skin - Not Sun Exposed Skin - Sun Exposed Small Intestine - Terminal Ileum Spleen Stomach Testis Thyroid Uterus Vagina Whole Blood Pathways Pathway Source External ID Transmembrane transport of small molecules REACTOME R-HSA-382551 Ion channel transport REACTOME R-HSA-983712 Stimuli-sensing channels REACTOME R-HSA-2672351 Protein levels (Protein atlas) Not detected Low Medium High cerebral cortex cerebellum hippocampus caudate thyroid gland parathyroid gland adrenal gland nasopharynx bronchus lung oral mucosa salivary gland esophagus stomach 1 stomach 2 duodenum small intestine colon rectum liver gallbladder pancreas kidney urinary bladder testis epididymis seminal vesicle prostate vagina ovary fallopian tube endometrium 1 endometrium 2 cervix, uterine placenta breast heart muscle smooth muscle skeletal muscle soft tissue 1 soft tissue 2 adipose tissue skin 2 appendix spleen lymph node tonsil bone marrow References Pubmed ID Year Title Citations 38091885 2024 Regional bias of tumor suppressor gene mutations of STARD8 and WNK2 in colon cancers. 0 38091885 2024 Regional bias of tumor suppressor gene mutations of STARD8 and WNK2 in colon cancers. 0 36270769 2023 Germline mutations in WNK2 could be associated with serrated polyposis syndrome. 2 36270769 2023 Germline mutations in WNK2 could be associated with serrated polyposis syndrome. 2 35849656 2022 WNK Inhibition Increases Surface Liquid pH and Host Defense in Cystic Fibrosis Airway Epithelia. 3 35849656 2022 WNK Inhibition Increases Surface Liquid pH and Host Defense in Cystic Fibrosis Airway Epithelia. 3 34061329 2021 Circ_0001666 affects miR-620/WNK2 axis to inhibit breast cancer progression. 5 34061329 2021 Circ_0001666 affects miR-620/WNK2 axis to inhibit breast cancer progression. 5 31884577 2020 Long non-coding RNA LINC00858 exerts a tumor-promoting role in colon cancer via HNF4α and WNK2 regulation. 17 32093151 2020 WNK2 Inhibits Autophagic Flux in Human Glioblastoma Cell Line. 4 32447640 2020 LINC00858 knockdown inhibits gastric cancer cell growth and induces apoptosis through reducing WNK2 promoter methylation. 3 32768499 2020 Long non-coding RNA LINC00858 inhibits colon cancer cell apoptosis, autophagy, and senescence by activating WNK2 promoter methylation. 7 31884577 2020 Long non-coding RNA LINC00858 exerts a tumor-promoting role in colon cancer via HNF4α and WNK2 regulation. 17 32093151 2020 WNK2 Inhibits Autophagic Flux in Human Glioblastoma Cell Line. 4 32447640 2020 LINC00858 knockdown inhibits gastric cancer cell growth and induces apoptosis through reducing WNK2 promoter methylation. 3 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-(wnk-lysine-deficient-protein-kinase-2) Generate PDF × Please, confirm that you want to generate a PDF file of this page. 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