WNK2

Summary

WNK2 (WNK lysine deficient protein kinase 2, HGNC:14542) is a protein-coding gene on chromosome 9q22.31, encoding Serine/threonine-protein kinase WNK2 (Q9Y3S1). Serine/threonine-protein kinase component of the WNK2-SPAK/OSR1 kinase cascade, which plays an important role in the regulation of electrolyte homeostasis, cell signaling, survival, and proliferation.

The protein encoded by this gene is a cytoplasmic serine-threonine kinase that belongs to the protein kinase superfamily. The protein plays an important role in the regulation of electrolyte homeostasis, cell signaling survival, and proliferation. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 65268 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 3,401 total — 1 likely-pathogenic (top 1% of genes corpus-wide)
• GTEx eGene: eQTL in 23 tissues, sQTL in 4 (q < 0.05)
• Cancer driver (intOGen): activating (oncogene-like) across 3 cancer types (inferred from mutation patterns)
• Constraint (gnomAD): pLI 0.12 (intermediate), LOEUF 0.51 (moderately constrained)
• MANE Select transcript: NM_006648
• Notable: 3,401 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14542
Approved symbol	WNK2
Name	WNK lysine deficient protein kinase 2
Location	9q22.31
Locus type	gene with protein product
Status	Approved
Aliases	NY-CO-43, KIAA1760
Ensembl gene	ENSG00000165238
Ensembl biotype	protein_coding
OMIM	606249
Entrez	65268

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 13 protein_coding, 6 protein_coding_CDS_not_defined, 2 retained_intron

MANE Select: ENST00000427277

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 4, TSL 2: 2, TSL 3: 3, TSL 4: 2, TSL 5: 3

ENST00000427277, ENST00000297954, ENST00000395477, ENST00000411624, ENST00000432730, ENST00000448039, ENST00000453718, ENST00000460335, ENST00000462595, ENST00000464625, ENST00000467401, ENST00000471076, ENST00000478583, ENST00000479696, ENST00000693671, ENST00000913009, ENST00000913010, ENST00000913011, ENST00000913012, ENST00000913013, ENST00001138380

RefSeq mRNA: 2 — MANE Select: NM_006648 NM_001282394, NM_006648

CCDS: CCDS75858

Canonical transcript exons

ENST00000427277 — 30 exons

Exon	Start	End
ENSE00003470660	93306777	93306821
ENSE00003493905	93292491	93293173
ENSE00003514967	93229696	93229868
ENSE00003515238	93263566	93263734
ENSE00003523499	93268020	93268065
ENSE00003523817	93234808	93234965
ENSE00003536955	93238233	93238321
ENSE00003545658	93288788	93289620
ENSE00003547416	93256948	93257139
ENSE00003575167	93300051	93300149
ENSE00003579582	93261814	93262107
ENSE00003584089	93247543	93247834
ENSE00003585991	93267746	93267916
ENSE00003586453	93256299	93256454
ENSE00003590340	93263917	93264033
ENSE00003593679	93262670	93262719
ENSE00003610646	93268627	93268746
ENSE00003619254	93317520	93317631
ENSE00003641349	93252883	93253082
ENSE00003644359	93230888	93231108
ENSE00003647374	93184928	93185610
ENSE00003662082	93299070	93299261
ENSE00003670972	93297853	93298067
ENSE00003690555	93292308	93292396
ENSE00003692836	93239757	93239976
ENSE00003729308	93258931	93259614
ENSE00003740111	93289978	93290047
ENSE00003787333	93308328	93308584
ENSE00003929307	93320367	93320569
ENSE00003936757	93184139	93184385

Expression profiles

Bgee: expression breadth ubiquitous, 232 present calls, max score 97.91.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0330 / max 12.6286, expressed in 12 samples.

Highest expression (Bgee): apex of heart, uterine tube, atrium auricular region, cardiac atrium, hemisphere of cerebellum.

Genetic regulation across tissues (GTEx eQTL / sQTL)

WNK2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 23 tissues and its splicing (sQTL) in 4 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 27 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Skin Sun Exposed Lower leg	eqtl	8.7e-29	-0.42	9:93285170:T:C
Skin Not Sun Exposed Suprapubic	eqtl	1.0e-24	-0.46	9:93270437:G:A
Esophagus Muscularis	eqtl	2.8e-22	-0.24	9:93161958:C:T
Thyroid	eqtl	7.7e-21	+0.38	9:93325525:C:T
Esophagus Gastroesophageal Junction	eqtl	1.4e-10	-0.20	9:93161958:C:T
Nerve Tibial	eqtl	7.3e-09	-0.54	9:93273803:G:A
Pancreas	eqtl	7.5e-08	-0.36	9:93222472:A:G
Lung	eqtl	2.1e-07	+0.31	9:93228219:C:T
Esophagus Mucosa	eqtl	1.6e-06	+0.19	9:93265485:T:C
Brain Cerebellum	eqtl	1.5e-05	+0.20	9:93190656:G:A
Testis	eqtl	5.7e-05	+0.27	9:93405943:G:A
Colon Sigmoid	eqtl	2.5e-04	-0.14	9:93161958:C:T
Brain Spinal cord cervical c-1	eqtl	3.3e-04	-0.22	9:93285170:T:C
Esophagus Muscularis	sqtl	7.8e-04	-0.44	9:93285170:T:C
Spleen	eqtl	2.4e-03	+0.31	9:93259834:C:T
Heart Atrial Appendage	sqtl	7.2e-03	-0.46	9:93285170:T:C
Heart Atrial Appendage	eqtl	1.1e-02	+0.19	9:92670914:C:T
Brain Cerebellum	sqtl	1.5e-02	-0.72	9:93221328:T:C
Whole Blood	eqtl	1.5e-02	-0.22	9:93222472:A:G
Brain Cerebellar Hemisphere	eqtl	1.7e-02	+0.17	9:93149697:T:A

FANTOM5 promoters

3 alternative TSS:

Promoter ID	TPM avg	Samples expressed
97404	0.0136	8
97407	0.0124	4
97406	0.0070	4

Top tissues by expression

showing 100 of 251 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	97.91	gold quality
right uterine tube	UBERON:0001302	97.44	gold quality
right atrium auricular region	UBERON:0006631	97.35	gold quality
cardiac atrium	UBERON:0002081	96.87	gold quality
right hemisphere of cerebellum	UBERON:0014890	96.68	gold quality
body of pancreas	UBERON:0001150	96.41	gold quality
cerebellar hemisphere	UBERON:0002245	96.12	gold quality
cerebellar cortex	UBERON:0002129	96.01	gold quality
transverse colon	UBERON:0001157	95.73	gold quality
adenohypophysis	UBERON:0002196	95.70	gold quality
ganglionic eminence	UBERON:0004023	95.64	gold quality
cortical plate	UBERON:0005343	95.25	gold quality
heart left ventricle	UBERON:0002084	95.24	gold quality
muscle layer of sigmoid colon	UBERON:0035805	95.11	gold quality
mucosa of transverse colon	UBERON:0004991	94.94	gold quality
cardiac muscle of right atrium	UBERON:0003379	94.92	gold quality
cardiac ventricle	UBERON:0002082	94.81	gold quality
left ventricle myocardium	UBERON:0006566	94.81	silver quality
cerebellum	UBERON:0002037	94.79	gold quality
right frontal lobe	UBERON:0002810	94.59	gold quality
pituitary gland	UBERON:0000007	94.29	gold quality
hindlimb stylopod muscle	UBERON:0004252	93.79	gold quality
small intestine Peyer’s patch	UBERON:0003454	93.56	gold quality
lower esophagus muscularis layer	UBERON:0035833	93.07	gold quality
lower esophagus	UBERON:0013473	93.02	gold quality
gastrocnemius	UBERON:0001388	92.89	gold quality
Brodmann (1909) area 9	UBERON:0013540	92.70	gold quality
mucosa of stomach	UBERON:0001199	92.43	gold quality
parotid gland	UBERON:0001831	92.29	gold quality
anterior cingulate cortex	UBERON:0009835	92.17	gold quality
colon	UBERON:0001155	92.09	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	92.05	gold quality
heart	UBERON:0000948	92.04	gold quality
small intestine	UBERON:0002108	91.94	gold quality
rectum	UBERON:0001052	91.78	gold quality
muscle of leg	UBERON:0001383	91.74	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	91.73	gold quality
prefrontal cortex	UBERON:0000451	91.71	gold quality
saliva-secreting gland	UBERON:0001044	91.57	gold quality
large intestine	UBERON:0000059	91.56	gold quality
ventricular zone	UBERON:0003053	91.54	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	91.52	gold quality
minor salivary gland	UBERON:0001830	91.41	gold quality
intestine	UBERON:0000160	91.40	gold quality
neocortex	UBERON:0001950	91.27	gold quality
frontal cortex	UBERON:0001870	91.09	gold quality
myocardium	UBERON:0002349	90.94	silver quality
pancreas	UBERON:0001264	90.55	gold quality
primary visual cortex	UBERON:0002436	90.32	gold quality
body of stomach	UBERON:0001161	90.22	gold quality
amygdala	UBERON:0001876	90.10	gold quality
skin of leg	UBERON:0001511	89.98	gold quality
cerebral cortex	UBERON:0000956	89.97	gold quality
nucleus accumbens	UBERON:0001882	89.93	gold quality
skin of abdomen	UBERON:0001416	89.90	gold quality
brain	UBERON:0000955	89.72	gold quality
colonic epithelium	UBERON:0000397	89.70	gold quality
forebrain	UBERON:0001890	89.52	gold quality
hypothalamus	UBERON:0001898	89.49	gold quality
caudate nucleus	UBERON:0001873	89.13	gold quality
putamen	UBERON:0001874	88.50	gold quality
lateral nuclear group of thalamus	UBERON:0002736	88.26	gold quality
mouth mucosa	UBERON:0003729	88.13	gold quality
Brodmann (1909) area 23	UBERON:0013554	88.01	gold quality
Ammon’s horn	UBERON:0001954	87.60	gold quality
zone of skin	UBERON:0000014	87.47	gold quality
stomach	UBERON:0000945	87.47	gold quality
temporal lobe	UBERON:0001871	87.29	gold quality
middle temporal gyrus	UBERON:0002771	86.81	gold quality
prostate gland	UBERON:0002367	86.65	gold quality
superior frontal gyrus	UBERON:0002661	86.43	gold quality
muscle tissue	UBERON:0002385	85.83	gold quality
occipital lobe	UBERON:0002021	85.62	gold quality
skeletal muscle tissue	UBERON:0001134	85.24	gold quality
sural nerve	UBERON:0015488	84.90	gold quality
cerebellar vermis	UBERON:0004720	84.59	silver quality
substantia nigra	UBERON:0002038	84.01	gold quality
postcentral gyrus	UBERON:0002581	83.99	gold quality
entorhinal cortex	UBERON:0002728	83.83	gold quality
left uterine tube	UBERON:0001303	83.72	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	83.67	gold quality
nasal cavity mucosa	UBERON:0001826	82.92	gold quality
lower esophagus mucosa	UBERON:0035834	82.87	gold quality
parietal lobe	UBERON:0001872	82.75	gold quality
left testis	UBERON:0004533	82.71	gold quality
midbrain	UBERON:0001891	82.60	gold quality
heart right ventricle	UBERON:0002080	82.35	silver quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	82.34	gold quality
right testis	UBERON:0004534	82.30	gold quality
esophagus	UBERON:0001043	82.26	gold quality
fundus of stomach	UBERON:0001160	82.15	gold quality
duodenum	UBERON:0002114	81.93	gold quality
biceps brachii	UBERON:0001507	81.62	silver quality
pancreatic ductal cell	CL:0002079	81.33	silver quality
vastus lateralis	UBERON:0001379	81.31	silver quality
testis	UBERON:0000473	81.05	gold quality
epithelial cell of pancreas	CL:0000083	80.96	gold quality
islet of Langerhans	UBERON:0000006	80.87	gold quality
fallopian tube	UBERON:0003889	80.84	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	80.77	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.40
E-MTAB-5061	no	3.38
E-GEOD-137537	no	3.28

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 79 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Postcentral gyrus	tissue	133.8
Hippocampus	tissue	106.0	low
Locus coeruleus	tissue	74.1
Nucleus accumbens	tissue	63.5
Cerebral cortex	tissue	61.4	medium
Insular cortex	tissue	61.4
Somatosensory cortex	tissue	59.7
Motor cortex	tissue	57.7
Prefrontal cortex	tissue	57.5
Temporal cortex	tissue	56.8
Hippocampal formation	tissue	55.0
Entorhinal cortex	tissue	55.0
Basal ganglia	tissue	52.5	low
Choroid plexus	tissue	51.8
Occipital cortex	tissue	51.6
Retrosplenial and cingulate cortex	tissue	51.2
Retrosplenial cortex	tissue	48.0
Skeletal muscle	tissue	47.1	medium
Amygdala	tissue	46.8
Cerebellum	tissue	44.1	high
Putamen	tissue	42.2
Olfactory bulb	tissue	40.7
Ventral forebrain	tissue	40.6
Salivary gland	tissue	40.0	high
Pancreas	tissue	34.4	high
Thalamus	tissue	34.4
Frontal cortex	tissue	32.4
Septum	tissue	32.2
Heart muscle	tissue	31.2	low
Midbrain	tissue	31.0
Superior colliculi	tissue	29.3
Pons	tissue	29.2
Pituitary gland	tissue	26.5
Hypothalamus	tissue	22.5
Substantia nigra	tissue	21.4
Tongue	tissue	21.1
Caudate putamen	tissue	18.3
Retina	tissue	18.2
Spinal cord	tissue	17.9
Periaqueductal gray	tissue	17.6
Medulla oblongata	tissue	17.5
Duodenum	tissue	14.0	high
Small intestine	tissue	12.8	high
Colon	tissue	12.6	high
Fallopian tube	tissue	9.9	medium
Corpus callosum	tissue	9.3
Seminal vesicle	tissue	9.2	medium
Prostate	tissue	8.7	high
Rectum	tissue	7.8	high
Thymus	tissue	5.1
Skin 1	tissue	5.0	not detected
Epididymis	tissue	3.8	medium
Stomach 1	tissue	3.5	low
Esophagus	tissue	3.2	not detected
Testis	tissue	3.1	high
Breast	tissue	2.8	high
Vagina	tissue	2.7	not detected
Endometrium 1	tissue	2.6	medium
Smooth muscle	tissue	2.5	low
Appendix	tissue	2.4	high

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Precentral gyrus (154.1), Supplementary motor cortex (116.7), Posterior cingulate cortex (115.4), Hippocampus, CA3 (114.5), Entorhinal gyrus (111.0).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): TP53, ZNF160

miRNA regulators (miRDB)

Targeting WNK2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

7 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-140-5P	99.44	67.20	792
HSA-MIR-6738-3P	99.03	67.14	1326
HSA-MIR-5001-3P	98.91	67.28	1394
HSA-MIR-3611	98.76	68.76	1290
HSA-MIR-5699-5P	97.36	67.03	1014
HSA-MIR-1913	97.07	66.20	1417
HSA-MIR-3654	96.43	66.55	646

Functional genomics

gnomAD constraint: pLI 0.122, LOEUF 0.508, missense Z 0.802 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000427277 splits into 7 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
9:93,184,930–93,185,474	260 / 285.6	0.91	no
9:93,185,475–93,247,649	230 / 501.1	0.46	no
9:93,247,650–93,263,932	893 / 909.0	0.98	no
9:93,263,933–93,267,755	21 / 53.2	0.39	no
9:93,267,756–93,300,059	1098 / 1101.0	1.00	no
9:93,300,060–93,306,815	29 / 55.6	0.52	no
9:93,306,816–93,320,389	167 / 184.2	0.91	no

Literature-anchored findings (GeneRIF, showing 20)

• epigenetic silencing, occasional deletion and point mutation, and functional assessment suggest that aberrations of WNK2 may contribute to unregulated tumor cell growth (PMID:17578925)
• WNK2 is involved in the modulation of growth factor-induced cancer cell proliferation through the MEK1/ERK1/2 pathway. (PMID:17667937)
• WNK2 controls a RhoA-mediated cross-talk mechanism that regulates the efficiency with which MEK1 can activate ERK1/2 upon growth factor stimulation. (PMID:18593598)
• Epigenetic silencing of the kinase tumor suppressor WNK2 is tumor-type and tumor-grade specific. (PMID:19001526)
• a role for WNK2 in the regulation of CCCs in the mammalian brain, with implications for both cell volume regulation and/or GABAergic signaling. (PMID:21733846)
• results validate the WNK2 gene as a recurrent target for epigenetic silencing in glia-derived brain tumours and provide first mechanistic evidence for a tumour-suppressing role of WNK2 that is related to Rac1 signalling and tumour cell invasion and growth (PMID:23035050)
• Wnk kinases are positive regulators of canonical Wnt/beta-catenin signaling. (PMID:23797875)
• Downregulation of WNK2 by promoter hypermethylation occurs early in Pancreatic ductal adenocarcinoma pathogenesis and may support tumor cell growth via the ERK-MAPK pathway. (PMID:23912455)
• WNK2 promoter methylation and silencing in gliomas is associated with increased JNK activation and MMP2 expression and activity, thus explaining in part tumor cell invasion potential. (PMID:25596741)
• The data suggest that miR-370 acts as an oncogene by downregulating WNK2 in breast cancer. (PMID:31009242)
• Genomic sequencing identifies WNK2 as a driver in hepatocellular carcinoma and a risk factor for early recurrence. (PMID:31349001)
• Long non-coding RNA LINC00858 exerts a tumor-promoting role in colon cancer via HNF4alpha and WNK2 regulation. (PMID:31884577)
• WNK2 Inhibits Autophagic Flux in Human Glioblastoma Cell Line. (PMID:32093151)
• LINC00858 knockdown inhibits gastric cancer cell growth and induces apoptosis through reducing WNK2 promoter methylation. (PMID:32447640)
• Long non-coding RNA LINC00858 inhibits colon cancer cell apoptosis, autophagy, and senescence by activating WNK2 promoter methylation. (PMID:32768499)
• Circ_0001666 affects miR-620/WNK2 axis to inhibit breast cancer progression. (PMID:34061329)
• WNK Inhibition Increases Surface Liquid pH and Host Defense in Cystic Fibrosis Airway Epithelia. (PMID:35849656)
• Germline mutations in WNK2 could be associated with serrated polyposis syndrome. (PMID:36270769)
• Regional bias of tumor suppressor gene mutations of STARD8 and WNK2 in colon cancers. (PMID:38091885)
• PAX6-WNK2 Axis Governs Corneal Epithelial Homeostasis. (PMID:39453672)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	wnk2	ENSDARG00000104989
mus_musculus	Wnk2	ENSMUSG00000037989
rattus_norvegicus	Wnk2	ENSRNOG00000016684
drosophila_melanogaster	Wnk	FBGN0037098
caenorhabditis_elegans		WBGENE00006941

Paralogs (6): WNK1 (ENSG00000060237), NRBP1 (ENSG00000115216), WNK4 (ENSG00000126562), DSTYK (ENSG00000133059), NRBP2 (ENSG00000185189), WNK3 (ENSG00000196632)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1922857) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 2 distinct phenotype terms.

Mouse phenotype (MP)	Records
hyperactivity	1
increased vertical activity	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Macaca fascicularis	Q4R8X0	100.0%	Diamond
Oryza sativa Indica Group	A2YMV6	99.9%	Diamond
Oryza sativa Japonica Group	Q0D598	99.9%	Diamond
Pongo abelii	Q5RBH9	99.8%	Diamond
Plasmodium falciparum 3D7	C6KTB8	94.4%	Diamond
Drosophila pseudoobscura pseudoobscura	Q297L2	84.6%	Diamond
Sus scrofa	Q6R2V0	84.5%	Diamond
Arabidopsis thaliana	Q8S8Y8	80.1%	Diamond
Phycomyces blakesleeanus NRRL 1555(-)	Q01577	52.0%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
FAM120AOS	protein-coding	158293
FAM120A	protein-coding	23196
NINJ1	protein-coding	4814
CARD19	protein-coding	84270

Protein

Protein identifiers

Serine/threonine-protein kinase WNK2 — Q9Y3S1 (reviewed: Q9Y3S1)

Alternative names: Antigen NY-CO-43, Protein kinase lysine-deficient 2, Protein kinase with no lysine 2, Serologically defined colon cancer antigen 43

All UniProt accessions (6): Q9Y3S1, A6PVV2, E9PCD1, H0Y7J9, H0Y7R3, H0Y7T5

UniProt curated annotations — full annotation on UniProt →

Function. Serine/threonine-protein kinase component of the WNK2-SPAK/OSR1 kinase cascade, which plays an important role in the regulation of electrolyte homeostasis, cell signaling, survival, and proliferation. The WNK2-SPAK/OSR1 kinase cascade is composed of WNK2, which mediates phosphorylation and activation of downstream kinases OXSR1/OSR1 and STK39/SPAK. Following activation, OXSR1/OSR1 and STK39/SPAK catalyze phosphorylation of ion cotransporters, regulating their activity. Acts as an activator and inhibitor of sodium-coupled chloride cotransporters and potassium-coupled chloride cotransporters respectively. Activates SLC12A2, SCNN1A, SCNN1B, SCNN1D and SGK1 and inhibits SLC12A5. Negatively regulates the EGF-induced activation of the ERK/MAPK-pathway and the downstream cell cycle progression. Affects MAPK3/MAPK1 activity by modulating the activity of MAP2K1 and this modulation depends on phosphorylation of MAP2K1 by PAK1. WNK2 acts by interfering with the activity of PAK1 by controlling the balance of the activity of upstream regulators of PAK1 activity, RHOA and RAC1, which display reciprocal activity.

Subunit / interactions. Forms a complex with the phosphorylated form of STK39.

Subcellular location. Cytoplasm. Cell membrane.

Tissue specificity. Expressed in various cancer cell lines (at protein level). Predominantly expressed in heart, brain, skeletal muscle and colon.

Post-translational modifications. Autophosphorylated. Autophosphorylation at Ser-352 and Ser-356 promotes its activity.

Activity regulation. Activation requires autophosphorylation of Ser-356 and, to a lower extent, Ser-352.

Miscellaneous. Incomplete sequence.

Similarity. Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. WNK subfamily.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9Y3S1-1	1	yes
Q9Y3S1-2	2
Q9Y3S1-3	3
Q9Y3S1-4	4

RefSeq proteins (2): NP_001269323, NP_006639* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR024678	Kinase_OSR1/WNK_CCT	Domain
IPR050588	WNK_Ser-Thr_kinase	Family
IPR056865	CCTL2_WNK	Domain

Pfam: PF00069, PF12202, PF24889

Catalyzed reactions (Rhea)

• L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+) (RHEA:17989)
• L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+) (RHEA:46608)

UniProt features (76 total): compositionally biased region 20, modified residue 16, region of interest 15, splice variant 9, helix 4, binding site 3, strand 3, sequence variant 2, chain 1, domain 1, active site 1, turn 1

Structure

Experimental structures (PDB)

2 structures by resolution:

PDB	Title	Method	Resolution (Å)
6ELM	Crystal structure of the human WNK2 CCT1 domain	X-RAY DIFFRACTION	1.14
6FBK	Crystal structure of the human WNK2 CCT-like 1 domain in complex with a WNK1 RFXV peptide	X-RAY DIFFRACTION	1.74

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y3S1-F1	44.29	0.12

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Transferases, Kinases, Predicted intracellular proteins, Plasma proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol

Antibody reliability (HPA): IH enhanced · IF approved

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1)

Position	Role
342	proton acceptor

Ligand- & substrate-binding residues (3)

Position	Role
205	ATP
275–278	ATP
325	ATP

Post-translational modifications (16)

Type	Positions
Omega-n-methylarginine	19, 30
Phosphoserine	45, 352, 356, 560, 1150, 1262, 1588, 1685, 1736, 1817, 1818, 1862, 1889, 2067

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 3; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

3 pathways:

ID	Pathway	Evidence
R-HSA-2672351	Stimuli-sensing channels	curated
R-HSA-983712	Ion channel transport	—
R-HSA-382551	Transport of small molecules	—

MSigDB gene sets: 126 (showing top): GOBP_NEGATIVE_REGULATION_OF_ERK1_AND_ERK2_CASCADE, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, GCANCTGNY_MYOD_Q6, GOBP_POSITIVE_REGULATION_OF_TRANSPORTER_ACTIVITY, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, GOBP_POSITIVE_REGULATION_OF_SODIUM_ION_TRANSPORT, CAGCTG_AP4_Q5, GOBP_POSITIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, GOBP_NEGATIVE_REGULATION_OF_MAPK_CASCADE, CEBPB_01, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_REGULATION_OF_SODIUM_ION_TRANSPORT, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, MODULE_331, GOBP_POSITIVE_REGULATION_OF_MOLECULAR_FUNCTION

GO Biological Process (12): protein phosphorylation (GO:0006468), DNA damage response (GO:0006974), negative regulation of cell population proliferation (GO:0008285), intracellular signal transduction (GO:0035556), protein autophosphorylation (GO:0046777), monoatomic ion homeostasis (GO:0050801), negative regulation of ERK1 and ERK2 cascade (GO:0070373), positive regulation of canonical Wnt signaling pathway (GO:0090263), regulation of monoatomic cation transmembrane transport (GO:1904062), positive regulation of sodium ion transmembrane transporter activity (GO:2000651), homeostatic process (GO:0042592), negative regulation of intracellular signal transduction (GO:1902532)

GO Molecular Function (8): protein serine/threonine kinase activity (GO:0004674), ATP binding (GO:0005524), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (3): cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886)

Reactome top-level categories

2 top-level categories:

Category	Pathways
Ion channel transport	1
Transport of small molecules	1

GO top-level categories

42 GO namespaces:

Category	Terms
intracellular anatomical structure	2
protein kinase activity	2
cellular anatomical structure	2
phosphorylation	1
protein modification process	1
cellular response to stress	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
signal transduction	1
protein phosphorylation	1
chemical homeostasis	1
negative regulation of MAPK cascade	1
ERK1 and ERK2 cascade	1
regulation of ERK1 and ERK2 cascade	1
positive regulation of Wnt signaling pathway	1
canonical Wnt signaling pathway	1
regulation of canonical Wnt signaling pathway	1
regulation of monoatomic ion transmembrane transport	1
monoatomic cation transmembrane transport	1
sodium ion transmembrane transporter activity	1
positive regulation of ion transmembrane transporter activity	1
positive regulation of sodium ion transmembrane transport	1
regulation of sodium ion transmembrane transporter activity	1
biological_process	1
negative regulation of signal transduction	1
intracellular signal transduction	1
regulation of intracellular signal transduction	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
anion binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
cytoplasm	1
membrane	1
cell periphery	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 8 of 23 annotations. The rest are phylogenetic / computational / electronic (IEA).

8 experimentally-supported GO terms:

GO term	NS	Evidence
monoatomic ion homeostasis	BP	mutant phenotype
negative regulation of ERK1 and ERK2 cascade	BP	mutant phenotype
negative regulation of cell population proliferation	BP	mutant phenotype
positive regulation of canonical Wnt signaling pathway	BP	mutant phenotype
positive regulation of sodium ion transmembrane transporter activity	BP	mutant phenotype
protein autophosphorylation	BP	direct assay
protein phosphorylation	BP	direct assay
cytoplasm	CC	direct assay

Protein interactions and networks

STRING

showing 15 of 560 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
WNK2	FGD3	Q5JSP0	753
WNK2	SLC12A3	P55017	638
WNK2	SLC12A2	P55011	629
WNK2	KCNJ1	P48048	624
WNK2	SLC12A5	Q9H2X9	607
WNK2	SYT2	Q8N9I0	594
WNK2	FGD1	P98174	566
WNK2	SLC12A4	Q9UP95	565
WNK2	MBP	P02686	549
WNK2	NEDD4L	Q96PU5	533
WNK2	SLC12A1	Q13621	525
WNK2	SCNN1A	P37088	493
WNK2	ITSN1	Q15811	461
WNK2	CFTR	P13569	409
WNK2	OXSR1	O95747	393

IntAct

Human interaction partners of WNK2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

10 partners by confidence:

Partner	Interaction type	MIscore	Records
OXSR1	direct interaction	0.590	1
PKM	phosphorylation reaction	0.440	1
ABL1	physical association	0.400	1
FYN	physical association	0.400	1
SLC43A3	physical association	0.400	1
SMC1A	physical association	0.400	1
ESS2	physical association	0.370	1
ATXN1	physical association	0.000	1
UBE2I	physical association	0.000	1
WNK1	physical association	0.000	1

BioGRID (45 interactions; top human partners by supporting records): KLHL3 (Affinity Capture-MS; 3 records), TSC22D4 (Affinity Capture-MS; 3 records), WNK1 (Affinity Capture-MS; 3 records), OXSR1 (Affinity Capture-MS; 2 records), YWHAZ (Affinity Capture-MS; 2 records), AAK1 (Affinity Capture-MS), ACTC1 (Cross-Linking-MS (XL-MS)), ARHGAP24 (Affinity Capture-MS), ATXN1 (Two-hybrid), BCAR1 (Affinity Capture-MS), C1QBP (Cross-Linking-MS (XL-MS)), CLTA (Proximity Label-MS), CUL3 (Affinity Capture-MS), DGCR14 (Two-hybrid), GNB2 (Proximity Label-MS)

SIGNOR signaling

3 signaling interactions:

A	Effect	B	Mechanism
WNK2	“up-regulates activity”	WNK1	phosphorylation
KLHL2	“down-regulates quantity by destabilization”	WNK2	binding
“Cullin 3-RBX1-Skp1”	“down-regulates quantity by destabilization”	WNK2	polyubiquitination

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 3 cancer types — HCC, LMS, PLMESO.

intOGen’s role is a computational inference from cohort mutation patterns and may diverge from the gene’s curated/literature role; read it alongside the evidence above.

Genetic variants

Variant evidence for WNK2: 3,401 ClinVar records (1 pathogenic / likely pathogenic); 7 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

3,401 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	2042
Likely benign	1322
Benign	3

Top pathogenic / likely-pathogenic (1)

Showing all 1 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
520975	NM_006648.4(WNK2):c.4801dup (p.Asp1601fs)	Likely pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore WNK2’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 34 predictions of 3,062):

Position(s)	Effect	Δscore	Sites
9:93229694–93229695	acceptor_loss	1.0000	6
9:93229857	donor_gain	1.0000
9:93229869	donor_loss	1.0000	2
9:93234799–93234800	acceptor_gain	1.0000	2
9:93234806–93234807	acceptor_loss	1.0000	4
9:93234966–93234967	donor_loss	1.0000	5
9:93235474	donor_gain	1.0000
9:93238322–93238323	donor_loss	1.0000	5
9:93239977–93239978	donor_loss	1.0000	5
9:93267744–93267745	acceptor_loss	1.0000	3

AlphaMissense

595 missense substitutions predicted likely pathogenic (of 2,328 scored), across 155 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
H1941	8	0.976	0.998
F1785	8	0.964	0.998
D1920	8	0.959	0.993
D1922	8	0.955	0.986
D1927	8	0.924	0.983
D1845	8	0.892	0.942
S1919	8	0.885	0.997
S1918	8	0.872	0.996
D1792	8	0.831	0.953
E1944	7	0.942	0.980
E1926	7	0.918	0.969
E1955	7	0.896	0.970
E1933	7	0.885	0.953
N1921	7	0.867	0.979
Q1952	7	0.854	0.996
D1929	7	0.843	0.916
E1924	7	0.820	0.918
D1809	7	0.766	0.853
K1965	6	0.946	0.992
G1964	6	0.935	0.992

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

1 prognostic cancer types:

Cancer	Prognostic	p-value
Lung Squamous Cell Carcinoma (TCGA)	favorable	0.000121

Disease associations

OMIM: gene MIM:606249 | disease phenotypes:

GWAS associations

7 associations:

Study	Trait	p-value
GCST006924_2	Loneliness (MTAG)	1e-13
GCST010703_54	Brain morphology (MOSTest)	6e-11
GCST006923_10	Loneliness	7e-11
GCST006919_2	Ability to confide in someone	2e-9
GCST011983_15	Fasting glucose	1e-6
GCST008103_94	Bipolar disorder	4e-6
GCST008760_5	Perceived sweetness of sucrose	8e-6

EFO canonical traits (from GWAS)

3 canonical traits:

EFO ID	Trait name
EFO:0009592	social interaction measurement
EFO:0007865	loneliness measurement
EFO:0004346	neuroimaging measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5639 (SINGLE PROTEIN)

PharmGKB: 1 entry (CPIC guideline: no)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Wnk family

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
compound 25 [PMID: 17935989]	Inhibition	5.82	pKi

Binding affinities (BindingDB)

8 measured of 15 human assays (15 total across all organisms); most potent 8 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
1-[2-(4-methylphenyl)-5-tert-butyl-pyrazol-3-yl]-3-[4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]urea	KD	0.37 nM
4-[4-[(5-tert-butyl-2-quinolin-6-ylpyrazol-3-yl)carbamoylamino]-3-fluorophenoxy]-N-methylpyridine-2-carboxamide	IC50	5.5 nM
3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	IC50	5.6 nM	US-8822500: Tyrosine kinase inhibitors
Staurosporine, 8	IC50	6.5 nM
CHEMBL2171124	IC50	407 nM
(3R,4R)-3-methoxy-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	IC50	720 nM	US-8889696: Substituted pyrido[2,3-d]pyrimidin-7(8H)-ones and therapeutic uses thereof
7-chloro-3-oxo-8-[(thiazol-5-ylmethyl)-amino]-11,16-dioxa-2,4,19,21-tetraaza-tricyclo[15.3.1.0*5,10*]henicosa-1(21),5,7,9,17,19-hexaene-18-crbonitrile	KI	1540 nM
CHEMBL4848254	KD	10000 nM

ChEMBL bioactivities

7 potent at pChembl≥5 of 7 total, top 7 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.03	IC50	934	nM	STAUROSPORINE
5.84	IC50	1450	nM	STAUROSPORINE
5.84	IC50	1460	nM	STAUROSPORINE
5.55	IC50	2785	nM	CHEMBL3702566
5.41	IC50	3892	nM	CHEMBL2171124
5.09	IC50	8086	nM	CHEMBL3683258
5.00	Kd	1e+04	nM	CHEMBL4848254

PubChem BioAssay actives

6 with measured affinity, of 495 total; 4 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
[2-[(4-chlorophenyl)methoxy]phenyl]-[5-[2-(methylamino)-1,3-thiazol-4-yl]-2,3-dihydroindol-1-yl]methanone	1802280: WNK In Vitro Radiometric Assays from Article 10.1021/acschembio.6b00511: “Discovery and Characterization of Allosteric WNK Kinase Inhibitors.”	ic50	0.0500	uM
(2S,3R,4R,6R)-3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	2198459: Inhibition of human WNK2 using myelin basic protein as substrate preincubated for 20 mins followed by [gamma-33P]-ATP addition and measured after 120 mins by radiometric Hot-SpotSM Kinase assay	ic50	0.9340	uM
1-[5-(4-amino-7-methylpyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindol-1-yl]-2-[3-(trifluoromethyl)phenyl]ethanone	701932: Inhibition of WNK2	ic50	3.8920	uM
N,N-dimethyl-4-pyrazolo[1,5-b]pyridazin-3-ylpyrimidin-2-amine	1752109: Binding affinity to wild-type human partial length WNK2 (V47 to D482 residues) expressed in mammalian expression system measured after 1 hr by competitive binding assay	kd	10.0000	uM

CTD chemical–gene interactions

34 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases methylation, increases expression	2
sodium arsenite	decreases expression, increases expression	2
Resveratrol	affects cotreatment, decreases expression, increases expression	2
Benzo(a)pyrene	affects methylation, increases methylation	2
Diethylhexyl Phthalate	decreases expression, increases abundance, increases methylation, increases expression	2
Estradiol	affects cotreatment, decreases expression, increases expression	2
Nickel	decreases expression	2
FR900359	affects phosphorylation	1
dicrotophos	increases expression	1
beta-lapachone	decreases expression	1
mono-(2-ethylhexyl)phthalate	increases abundance, increases methylation	1
butyraldehyde	decreases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
pentanal	decreases expression	1
abrine	decreases expression	1
quinocetone	increases expression	1
Sunitinib	increases expression	1
Arsenic Trioxide	increases expression	1
Acetaminophen	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Caffeine	affects phosphorylation	1
Calcitriol	increases expression	1
Folic Acid	decreases expression	1
Gallic Acid	decreases expression	1
Lead	decreases expression	1
Methapyrilene	increases methylation	1
Plant Extracts	affects cotreatment, decreases expression	1
Smoke	decreases expression, increases abundance	1
Tobacco Smoke Pollution	decreases expression	1

ChEMBL screening assays

178 unique, capped per target: 178 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1043843	Binding	Residual activity of WNK2 at 1 uM by microplate scintillation counting	Substituted 2-arylbenzothiazoles as kinase inhibitors: hit-to-lead optimization. — *Bioorg Med Chem*

Cellosaurus cell lines

4 cell lines: 2 transformed cell line, 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B3LD	Abcam HEK293T WNK2 KO 1	Transformed cell line	Female
CVCL_B3LE	Abcam HEK293T WNK2 KO 2	Transformed cell line	Female
CVCL_TY09	HAP1 WNK2 (-) 1	Cancer cell line	Male
CVCL_TY10	HAP1 WNK2 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for WNK2 across ~30M SureChEMBL compounds — explore on Sugi Predict.