ID WNK4_MOUSE Reviewed; 1222 AA. AC Q80UE6; A2A4J7; Q4VAC1; Q80XB5; Q80XN2; Q8R0N0; Q8R340; DT 02-FEB-2004, integrated into UniProtKB/Swiss-Prot. DT 01-JUN-2003, sequence version 1. DT 27-MAR-2024, entry version 170. DE RecName: Full=Serine/threonine-protein kinase WNK4 {ECO:0000305}; DE EC=2.7.11.1 {ECO:0000269|PubMed:21486947}; DE AltName: Full=Protein kinase lysine-deficient 4 {ECO:0000312|MGI:MGI:1917097}; DE AltName: Full=Protein kinase with no lysine 4 {ECO:0000303|PubMed:12515852}; GN Name=Wnk4 {ECO:0000303|PubMed:12515852, ECO:0000312|MGI:MGI:1917097}; GN Synonyms=Prkwnk4 {ECO:0000312|MGI:MGI:1917097}; OS Mus musculus (Mouse). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; OC Murinae; Mus; Mus. OX NCBI_TaxID=10090 {ECO:0000312|EMBL:AAO21955.1}; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], AND FUNCTION. RC STRAIN=C57BL/6J; TISSUE=Kidney; RX PubMed=12515852; DOI=10.1073/pnas.242735399; RA Wilson F.H., Kahle K.T., Sabath E., Lalioti M.D., Rapson A.K., Hoover R.S., RA Hebert S.C., Gamba G., Lifton R.P.; RT "Molecular pathogenesis of inherited hypertension with hyperkalemia: The RT Na-Cl cotransporter is inhibited by wild-type but not mutant WNK4."; RL Proc. Natl. Acad. Sci. U.S.A. 100:680-684(2003). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, AND MUTAGENESIS OF GLU-559; ASP-561 RP AND GLN-562. RC STRAIN=BALB/cJ; RX PubMed=12671053; DOI=10.1172/jci17443; RA Yang C.-L., Angell J., Mitchell R., Ellison D.H.; RT "WNK kinases regulate thiazide-sensitive Na-Cl cotransport."; RL J. Clin. Invest. 111:1039-1045(2003). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RC STRAIN=C57BL/6J; RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112; RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X., RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y., RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S., RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R., RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K., RA Eichler E.E., Ponting C.P.; RT "Lineage-specific biology revealed by a finished genome assembly of the RT mouse."; RL PLoS Biol. 7:E1000112-E1000112(2009). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC STRAIN=FVB/N; TISSUE=Kidney, and Mammary carcinoma; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [5] RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. RX PubMed=11498583; DOI=10.1126/science.1062844; RA Wilson F.H., Disse-Nicodeme S., Choate K.A., Ishikawa K., RA Nelson-Williams C., Desitter I., Gunel M., Milford D.V., Lipkin G.W., RA Achard J.-M., Feely M.P., Dussol B., Berland Y., Unwin R.J., Mayan H., RA Simon D.B., Farfel Z., Jeunemaitre X., Lifton R.P.; RT "Human hypertension caused by mutations in WNK kinases."; RL Science 293:1107-1112(2001). RN [6] RP FUNCTION, INTERACTION WITH KCNJ1, AND MUTAGENESIS OF ASP-318. RX PubMed=14608358; DOI=10.1038/ng1271; RA Kahle K.T., Wilson F.H., Leng Q., Lalioti M.D., O'Connell A.D., Dong K., RA Rapson A.K., MacGregor G.G., Giebisch G., Hebert S.C., Lifton R.P.; RT "WNK4 regulates the balance between renal NaCl reabsorption and K+ RT secretion."; RL Nat. Genet. 35:372-376(2003). RN [7] RP FUNCTION, AND MUTAGENESIS OF GLN-562. RX PubMed=16964266; DOI=10.1038/ng1877; RA Lalioti M.D., Zhang J., Volkman H.M., Kahle K.T., Hoffmann K.E., Toka H.R., RA Nelson-Williams C., Ellison D.H., Flavell R., Booth C.J., Lu Y., RA Geller D.S., Lifton R.P.; RT "Wnk4 controls blood pressure and potassium homeostasis via regulation of RT mass and activity of the distal convoluted tubule."; RL Nat. Genet. 38:1124-1132(2006). RN [8] RP FUNCTION, AND MUTAGENESIS OF LYS-183. RX PubMed=16403833; DOI=10.1152/ajprenal.00391.2005; RA Fu Y., Subramanya A., Rozansky D., Cohen D.M.; RT "WNK kinases influence TRPV4 channel function and localization."; RL Am. J. Physiol. 290:F1305-F1314(2006). RN [9] RP FUNCTION, AND MUTAGENESIS OF ASP-561. RX PubMed=17488636; DOI=10.1016/j.cmet.2007.03.009; RA Yang S.S., Morimoto T., Rai T., Chiga M., Sohara E., Ohno M., Uchida K., RA Lin S.H., Moriguchi T., Shibuya H., Kondo Y., Sasaki S., Uchida S.; RT "Molecular pathogenesis of pseudohypoaldosteronism type II: generation and RT analysis of a Wnk4(D561A/+) knockin mouse model."; RL Cell Metab. 5:331-344(2007). RN [10] RP FUNCTION, INTERACTION WITH WNK1 AND WNK3, AND PHOSPHORYLATION BY WNK1 AND RP WNK3. RX PubMed=17975670; DOI=10.1172/jci32033; RA Yang C.L., Zhu X., Ellison D.H.; RT "The thiazide-sensitive Na-Cl cotransporter is regulated by a WNK kinase RT signaling complex."; RL J. Clin. Invest. 117:3403-3411(2007). RN [11] RP FUNCTION, AND MUTAGENESIS OF LYS-183. RX PubMed=17673510; DOI=10.1113/jphysiol.2007.135855; RA Dorwart M.R., Shcheynikov N., Wang Y., Stippec S., Muallem S.; RT "SLC26A9 is a Cl(-) channel regulated by the WNK kinases."; RL J. Physiol. (Lond.) 584:333-345(2007). RN [12] RP FUNCTION, ACTIVE SITE, AND MUTAGENESIS OF ASP-318 AND GLN-562. RX PubMed=17360470; DOI=10.1073/pnas.0611727104; RA Ring A.M., Cheng S.X., Leng Q., Kahle K.T., Rinehart J., Lalioti M.D., RA Volkman H.M., Wilson F.H., Hebert S.C., Lifton R.P.; RT "WNK4 regulates activity of the epithelial Na+ channel in vitro and in RT vivo."; RL Proc. Natl. Acad. Sci. U.S.A. 104:4020-4024(2007). RN [13] RP FUNCTION, AND DISRUPTION PHENOTYPE. RX PubMed=19633012; DOI=10.1093/hmg/ddp344; RA Ohta A., Rai T., Yui N., Chiga M., Yang S.S., Lin S.H., Sohara E., RA Sasaki S., Uchida S.; RT "Targeted disruption of the Wnk4 gene decreases phosphorylation of Na-Cl RT cotransporter, increases Na excretion and lowers blood pressure."; RL Hum. Mol. Genet. 18:3978-3986(2009). RN [14] RP FUNCTION. RX PubMed=19240212; DOI=10.1073/pnas.0813238106; RA San-Cristobal P., Pacheco-Alvarez D., Richardson C., Ring A.M., Vazquez N., RA Rafiqi F.H., Chari D., Kahle K.T., Leng Q., Bobadilla N.A., Hebert S.C., RA Alessi D.R., Lifton R.P., Gamba G.; RT "Angiotensin II signaling increases activity of the renal Na-Cl RT cotransporter through a WNK4-SPAK-dependent pathway."; RL Proc. Natl. Acad. Sci. U.S.A. 106:4384-4389(2009). RN [15] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1196, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Testis; RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001; RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R., RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.; RT "A tissue-specific atlas of mouse protein phosphorylation and expression."; RL Cell 143:1174-1189(2010). RN [16] RP FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF ASP-561. RX PubMed=21486947; DOI=10.1242/jcs.084111; RA Chiga M., Rafiqi F.H., Alessi D.R., Sohara E., Ohta A., Rai T., Sasaki S., RA Uchida S.; RT "Phenotypes of pseudohypoaldosteronism type II caused by the WNK4 D561A RT missense mutation are dependent on the WNK-OSR1/SPAK kinase cascade."; RL J. Cell Sci. 124:1391-1395(2011). RN [17] RP FUNCTION, TISSUE SPECIFICITY, AND MUTAGENESIS OF ASP-318. RX PubMed=21317537; DOI=10.1172/jci43475; RA Yang D., Li Q., So I., Huang C.L., Ando H., Mizutani A., Seki G., RA Mikoshiba K., Thomas P.J., Muallem S.; RT "IRBIT governs epithelial secretion in mice by antagonizing the WNK/SPAK RT kinase pathway."; RL J. Clin. Invest. 121:956-965(2011). RN [18] RP MUTAGENESIS OF ASP-561. RX PubMed=23453970; DOI=10.1016/j.celrep.2013.02.024; RA Wakabayashi M., Mori T., Isobe K., Sohara E., Susa K., Araki Y., Chiga M., RA Kikuchi E., Nomura N., Mori Y., Matsuo H., Murata T., Nomura S., Asano T., RA Kawaguchi H., Nonoyama S., Rai T., Sasaki S., Uchida S.; RT "Impaired KLHL3-mediated ubiquitination of WNK4 causes human RT hypertension."; RL Cell Rep. 3:858-868(2013). RN [19] RP MUTAGENESIS OF GLN-562. RX PubMed=23576762; DOI=10.1073/pnas.1304592110; RA Shibata S., Zhang J., Puthumana J., Stone K.L., Lifton R.P.; RT "Kelch-like 3 and Cullin 3 regulate electrolyte homeostasis via RT ubiquitination and degradation of WNK4."; RL Proc. Natl. Acad. Sci. U.S.A. 110:7838-7843(2013). RN [20] RP ACTIVITY REGULATION. RX PubMed=33439774; DOI=10.1152/ajpcell.00456.2020; RA Pleinis J.M., Norrell L., Akella R., Humphreys J.M., He H., Sun Q., RA Zhang F., Sosa-Pagan J., Morrison D.E., Schellinger J.N., Jackson L.K., RA Goldsmith E.J., Rodan A.R.; RT "WNKs are potassium-sensitive kinases."; RL Am. J. Physiol. 320:C703-C721(2021). CC -!- FUNCTION: Serine/threonine-protein kinase component of the WNK4- CC SPAK/OSR1 kinase cascade, which acts as a key regulator of ion CC transport in the distal nephron and blood pressure (PubMed:12515852, CC PubMed:14608358, PubMed:16964266, PubMed:17488636, PubMed:17975670, CC PubMed:17360470, PubMed:19633012, PubMed:19240212, PubMed:21486947). CC The WNK4-SPAK/OSR1 kinase cascade is composed of WNK4, which mediates CC phosphorylation and activation of downstream kinases OXSR1/OSR1 and CC STK39/SPAK (PubMed:21486947). Following activation, OXSR1/OSR1 and CC STK39/SPAK catalyze phosphorylation of ion cotransporters, such as CC SLC12A1/NKCC2, SLC12A2/NKCC1, SLC12A3/NCC, SLC12A5/KCC2 or CC SLC12A6/KCC3, regulating their activity (PubMed:17488636, CC PubMed:19633012, PubMed:21486947). Acts as a molecular switch that CC regulates the balance between renal salt reabsorption and K(+) CC secretion by modulating the activities of renal transporters and CC channels, including the Na-Cl cotransporter SLC12A3/NCC and the K(+) CC channel, KCNJ1/ROMK (PubMed:14608358, PubMed:16964266, CC PubMed:17975670). Regulates NaCl reabsorption in the distal nephron by CC activating the thiazide-sensitive Na-Cl cotransporter SLC12A3/NCC in CC distal convoluted tubule cells of kidney: activates SLC12A3/NCC in a CC OXSR1/OSR1- and STK39/SPAK-dependent process (PubMed:14608358, CC PubMed:17488636, PubMed:17975670, PubMed:19633012, PubMed:21486947). CC Also acts as a scaffold protein independently of its protein kinase CC activity: negatively regulates cell membrane localization of various CC transporters and channels (CFTR, KCNJ1/ROMK, SLC4A4, SLC26A9 and TRPV4) CC by clathrin-dependent endocytosis (PubMed:14608358, PubMed:16403833, CC PubMed:17673510, PubMed:21317537). Also inhbits the activity of the CC epithelial Na(+) channel (ENaC) SCNN1A, SCNN1B, SCNN1D in a inase- CC independent mechanism (PubMed:17360470). May also phosphorylate NEDD4L CC (By similarity). {ECO:0000250|UniProtKB:Q96J92, CC ECO:0000269|PubMed:12515852, ECO:0000269|PubMed:14608358, CC ECO:0000269|PubMed:16403833, ECO:0000269|PubMed:16964266, CC ECO:0000269|PubMed:17360470, ECO:0000269|PubMed:17488636, CC ECO:0000269|PubMed:17673510, ECO:0000269|PubMed:17975670, CC ECO:0000269|PubMed:19240212, ECO:0000269|PubMed:19633012, CC ECO:0000269|PubMed:21317537, ECO:0000269|PubMed:21486947}. CC -!- CATALYTIC ACTIVITY: CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl- CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA- CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1; CC Evidence={ECO:0000250|UniProtKB:Q9H4A3}; CC -!- CATALYTIC ACTIVITY: CC Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L- CC threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, CC Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; CC EC=2.7.11.1; Evidence={ECO:0000269|PubMed:21486947}; CC -!- COFACTOR: CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; CC Evidence={ECO:0000250|UniProtKB:Q9H4A3}; CC -!- ACTIVITY REGULATION: Activation requires autophosphorylation of Ser-328 CC and Ser-332 (By similarity). Autophosphorylation and subsequent CC activation is inhibited by increases in intracellular ionic strength: CC Cl(-) potently inhibits WNK4 kinase activity via direct binding (By CC similarity). Also inhibited by K(+) ions (PubMed:33439774). CC {ECO:0000250|UniProtKB:Q9JIH7, ECO:0000269|PubMed:33439774}. CC -!- SUBUNIT: Interacts with the C-terminal region of KCNJ1 CC (PubMed:14608358). Interacts with WNK1 and WNK3 (PubMed:17975670). CC Interacts with KLHL3 (By similarity). {ECO:0000250|UniProtKB:Q96J92, CC ECO:0000269|PubMed:14608358, ECO:0000269|PubMed:17975670}. CC -!- INTERACTION: CC Q80UE6; P69744: Trpv5; NbExp=2; IntAct=EBI-295378, EBI-538447; CC Q80UE6; O00141: SGK1; Xeno; NbExp=2; IntAct=EBI-295378, EBI-1042854; CC Q80UE6; Q13507-3: TRPC3; Xeno; NbExp=2; IntAct=EBI-295378, EBI-15563545; CC -!- SUBCELLULAR LOCATION: Cell junction, tight junction CC {ECO:0000269|PubMed:11498583}. Note=Present exclusively in CC intercellular junctions in the distal convoluted tubule and in both the CC cytoplasm and intercellular junctions in the cortical collecting duct CC (PubMed:11498583). WNK4 is part of the tight junction complex CC (PubMed:11498583). {ECO:0000269|PubMed:11498583}. CC -!- TISSUE SPECIFICITY: Locates to the distal convoluted tubule, the CC medullary collecting duct and the cortical collecting duct of the CC kidney (PubMed:11498583). Expressed in pancreatic duct CC (PubMed:21317537). {ECO:0000269|PubMed:11498583, CC ECO:0000269|PubMed:21317537}. CC -!- DOMAIN: The RFXV motif mediates recognition with downstream kinases CC OXSR1/OSR1 and STK39/SPAK. {ECO:0000250|UniProtKB:Q96J92}. CC -!- PTM: Autophosphorylated at Ser-328 and Ser-332, promoting its CC activation (By similarity). Phosphorylated by WNK1 and WNK3 CC (PubMed:17975670). Phosphorylated at Ser-572 in a MAP3K15/ASK3- CC dependent process in response to osmotic stress or hypotonic low- CC chloride stimulation (By similarity). {ECO:0000250|UniProtKB:Q9JIH7, CC ECO:0000269|PubMed:17975670}. CC -!- PTM: Ubiquitinated by the BCR(KLHL3) complex, leading to its CC degradation. Also ubiquitinated by the BCR(KLHL2) complex. CC {ECO:0000250|UniProtKB:Q96J92}. CC -!- DISRUPTION PHENOTYPE: Embryonic lethality (PubMed:19633012). CC Hypomorphic mice do not display hypokalemia and metabolic alkalosis, CC but show low blood pressure and increased Na(+) and K(+) excretion CC under low-salt diet (PubMed:19633012). Phosphorylation of OXSR1/OSR1, CC STK39/SPAK and SLC12A3/NCC is significantly reduced in the hypomorphic CC mice (PubMed:19633012). {ECO:0000269|PubMed:19633012}. CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Ser/Thr protein CC kinase family. WNK subfamily. {ECO:0000255|PROSITE-ProRule:PRU00159}. CC -!- CAUTION: Was named WNK/'with no lysine(K)' because key residues for CC catalysis, including the lysine involved in ATP binding, are either not CC conserved or differ compared to the residues described in other kinase CC family proteins. {ECO:0000250|UniProtKB:Q9H4A3}. CC -!- SEQUENCE CAUTION: CC Sequence=AAH26679.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC Sequence=AAH43677.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC Sequence=AAO25619.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AY187027; AAO21955.1; -; mRNA. DR EMBL; AY184228; AAO25619.1; ALT_INIT; mRNA. DR EMBL; AL590969; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC026591; AAH26591.1; -; mRNA. DR EMBL; BC026679; AAH26679.1; ALT_INIT; mRNA. DR EMBL; BC043677; AAH43677.1; ALT_INIT; mRNA. DR EMBL; BC096453; AAH96453.1; -; mRNA. DR CCDS; CCDS25459.1; -. DR RefSeq; NP_783569.1; NM_175638.3. DR AlphaFoldDB; Q80UE6; -. DR SMR; Q80UE6; -. DR BioGRID; 213713; 6. DR DIP; DIP-33231N; -. DR ELM; Q80UE6; -. DR IntAct; Q80UE6; 6. DR MINT; Q80UE6; -. DR STRING; 10090.ENSMUSP00000099397; -. DR GlyGen; Q80UE6; 4 sites, 1 O-linked glycan (4 sites). DR iPTMnet; Q80UE6; -. DR PhosphoSitePlus; Q80UE6; -. DR MaxQB; Q80UE6; -. DR PaxDb; 10090-ENSMUSP00000099397; -. DR ProteomicsDB; 299696; -. DR Pumba; Q80UE6; -. DR Antibodypedia; 29411; 262 antibodies from 26 providers. DR DNASU; 69847; -. DR Ensembl; ENSMUST00000103108.8; ENSMUSP00000099397.2; ENSMUSG00000035112.18. DR GeneID; 69847; -. DR KEGG; mmu:69847; -. DR UCSC; uc007loe.2; mouse. DR AGR; MGI:1917097; -. DR CTD; 65266; -. DR MGI; MGI:1917097; Wnk4. DR VEuPathDB; HostDB:ENSMUSG00000035112; -. DR eggNOG; KOG0584; Eukaryota. DR GeneTree; ENSGT00940000159871; -. DR HOGENOM; CLU_000550_2_1_1; -. DR InParanoid; Q80UE6; -. DR OMA; XYLRRFR; -. DR OrthoDB; 5478852at2759; -. DR PhylomeDB; Q80UE6; -. DR TreeFam; TF315363; -. DR BioGRID-ORCS; 69847; 3 hits in 79 CRISPR screens. DR ChiTaRS; Wnk4; mouse. DR PRO; PR:Q80UE6; -. DR Proteomes; UP000000589; Chromosome 11. DR RNAct; Q80UE6; Protein. DR Bgee; ENSMUSG00000035112; Expressed in humerus cartilage element and 191 other cell types or tissues. DR ExpressionAtlas; Q80UE6; baseline and differential. DR GO; GO:0005923; C:bicellular tight junction; IDA:UniProtKB. DR GO; GO:0044297; C:cell body; IMP:MGI. DR GO; GO:0005737; C:cytoplasm; IDA:MGI. DR GO; GO:0005829; C:cytosol; ISO:MGI. DR GO; GO:0016020; C:membrane; ISO:MGI. DR GO; GO:0032991; C:protein-containing complex; IDA:MGI. DR GO; GO:0005524; F:ATP binding; ISS:UniProtKB. DR GO; GO:0031404; F:chloride ion binding; IMP:MGI. DR GO; GO:0008200; F:ion channel inhibitor activity; IDA:UniProtKB. DR GO; GO:0019870; F:potassium channel inhibitor activity; IBA:GO_Central. DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA. DR GO; GO:0004674; F:protein serine/threonine kinase activity; IMP:UniProtKB. DR GO; GO:0035932; P:aldosterone secretion; IMP:MGI. DR GO; GO:0055074; P:calcium ion homeostasis; IMP:MGI. DR GO; GO:0071466; P:cellular response to xenobiotic stimulus; IMP:MGI. DR GO; GO:0006821; P:chloride transport; IDA:MGI. DR GO; GO:0072156; P:distal tubule morphogenesis; ISS:UniProtKB. DR GO; GO:0070371; P:ERK1 and ERK2 cascade; IMP:MGI. DR GO; GO:0010467; P:gene expression; IMP:MGI. DR GO; GO:0006954; P:inflammatory response; IMP:MGI. DR GO; GO:0030644; P:intracellular chloride ion homeostasis; IMP:MGI. DR GO; GO:0035556; P:intracellular signal transduction; ISS:UniProtKB. DR GO; GO:0042116; P:macrophage activation; IMP:MGI. DR GO; GO:0050801; P:monoatomic ion homeostasis; IMP:MGI. DR GO; GO:0090188; P:negative regulation of pancreatic juice secretion; IMP:MGI. DR GO; GO:1903077; P:negative regulation of protein localization to plasma membrane; IDA:UniProtKB. DR GO; GO:0010766; P:negative regulation of sodium ion transport; ISS:UniProtKB. DR GO; GO:1903288; P:positive regulation of potassium ion import across plasma membrane; IBA:GO_Central. DR GO; GO:0071805; P:potassium ion transmembrane transport; IMP:MGI. DR GO; GO:0070528; P:protein kinase C signaling; IDA:MGI. DR GO; GO:0008104; P:protein localization; IDA:MGI. DR GO; GO:0006468; P:protein phosphorylation; ISS:UniProtKB. DR GO; GO:0008217; P:regulation of blood pressure; IMP:UniProtKB. DR GO; GO:1903764; P:regulation of potassium ion export across plasma membrane; IMP:UniProtKB. DR GO; GO:0070294; P:renal sodium ion absorption; IMP:UniProtKB. DR GO; GO:0003096; P:renal sodium ion transport; IDA:UniProtKB. DR GO; GO:0002021; P:response to dietary excess; IMP:MGI. DR GO; GO:0009410; P:response to xenobiotic stimulus; IGI:MGI. DR GO; GO:0007165; P:signal transduction; IMP:MGI. DR GO; GO:0035725; P:sodium ion transmembrane transport; IMP:MGI. DR CDD; cd14033; STKc_WNK4; 1. DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1. DR InterPro; IPR011009; Kinase-like_dom_sf. DR InterPro; IPR024678; Kinase_OSR1/WNK_CCT. DR InterPro; IPR000719; Prot_kinase_dom. DR InterPro; IPR008271; Ser/Thr_kinase_AS. DR PANTHER; PTHR13902; SERINE/THREONINE-PROTEIN KINASE WNK WITH NO LYSINE -RELATED; 1. DR PANTHER; PTHR13902:SF114; SERINE_THREONINE-PROTEIN KINASE WNK4; 1. DR Pfam; PF12202; OSR1_C; 1. DR Pfam; PF00069; Pkinase; 1. DR SMART; SM00220; S_TKc; 1. DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 1. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1. DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1. DR Genevisible; Q80UE6; MM. PE 1: Evidence at protein level; KW ATP-binding; Cell junction; Isopeptide bond; Kinase; Nucleotide-binding; KW Phosphoprotein; Reference proteome; Serine/threonine-protein kinase; KW Tight junction; Transferase; Ubl conjugation. FT CHAIN 1..1222 FT /note="Serine/threonine-protein kinase WNK4" FT /id="PRO_0000086825" FT DOMAIN 171..429 FT /note="Protein kinase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT REGION 1..165 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 525..562 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 554..564 FT /note="Interaction with KLHL3" FT /evidence="ECO:0000250|UniProtKB:Q96J92" FT REGION 626..659 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 747..809 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 877..896 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 927..976 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1000..1087 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1166..1222 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOTIF 996..999 FT /note="RFXV motif" FT /evidence="ECO:0000250|UniProtKB:Q96J92" FT COMPBIAS 44..60 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 61..78 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 79..99 FT /note="Pro residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 139..160 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 531..555 FT /note="Pro residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 779..800 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 931..945 FT /note="Pro residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 949..971 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1000..1039 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1047..1073 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1168..1183 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1194..1211 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 318 FT /note="Proton acceptor" FT /evidence="ECO:0000305|PubMed:17360470" FT BINDING 181 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000250|UniProtKB:Q9H4A3" FT BINDING 251..254 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000250|UniProtKB:Q9H4A3" FT BINDING 301 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000250|UniProtKB:Q9H4A3" FT MOD_RES 95 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q96J92" FT MOD_RES 328 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000250|UniProtKB:Q9JIH7" FT MOD_RES 332 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000250|UniProtKB:Q9JIH7" FT MOD_RES 572 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q96J92" FT MOD_RES 1014 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q7TPK6" FT MOD_RES 1196 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:21183079" FT CROSSLNK 154 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000250|UniProtKB:Q96J92" FT CROSSLNK 172 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000250|UniProtKB:Q96J92" FT CROSSLNK 183 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000250|UniProtKB:Q96J92" FT CROSSLNK 223 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000250|UniProtKB:Q96J92" FT CROSSLNK 238 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000250|UniProtKB:Q96J92" FT CROSSLNK 325 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000250|UniProtKB:Q96J92" FT CROSSLNK 384 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000250|UniProtKB:Q96J92" FT CROSSLNK 390 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000250|UniProtKB:Q96J92" FT CROSSLNK 447 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000250|UniProtKB:Q96J92" FT CROSSLNK 451 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000250|UniProtKB:Q96J92" FT CROSSLNK 990 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000250|UniProtKB:Q96J92" FT CROSSLNK 1123 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000250|UniProtKB:Q96J92" FT CROSSLNK 1136 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000250|UniProtKB:Q96J92" FT CROSSLNK 1137 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000250|UniProtKB:Q96J92" FT MUTAGEN 183 FT /note="K->M: Abolished serine/threonine-protein kinase FT activity without affecting ability to regulate localization FT of TRPV4 and SLC12A9." FT /evidence="ECO:0000269|PubMed:16403833, FT ECO:0000269|PubMed:17673510" FT MUTAGEN 318 FT /note="D->A: Loss of serine/threonine-protein kinase FT activity. No effect on inhibition of KCNJ1, SCNN1A, SCNN1B FT or SCNN1D." FT /evidence="ECO:0000269|PubMed:14608358, FT ECO:0000269|PubMed:17360470" FT MUTAGEN 318 FT /note="D->E: No effect on inhibition of SLC4A4." FT /evidence="ECO:0000269|PubMed:21317537" FT MUTAGEN 559 FT /note="E->K: No effect on inhibition of SLC12A3." FT /evidence="ECO:0000269|PubMed:12671053" FT MUTAGEN 561 FT /note="D->A: Increased protein level, probably due to FT defects in ubiquitination. Knockin mice display higher FT blood pressure, hyperkalemia, hypercalciuria and marked FT hyperplasia of the distal convoluted tubule cells of FT kidney. Increased phosphorylation of OXSR1/OSR1 and FT STK39/SPAK is observed, leading to phosphorylation and FT activation of SLC12A3/NCC." FT /evidence="ECO:0000269|PubMed:12671053, FT ECO:0000269|PubMed:17488636, ECO:0000269|PubMed:21486947, FT ECO:0000269|PubMed:23453970" FT MUTAGEN 562 FT /note="Q->E: Increased protein level, probably due to FT defects in ubiquitination. Knockin mice display higher FT blood pressure, hyperkalemia, hypercalciuria and marked FT hyperplasia of the distal convoluted tubule cells of FT kidney." FT /evidence="ECO:0000269|PubMed:12671053, FT ECO:0000269|PubMed:16964266, ECO:0000269|PubMed:17360470, FT ECO:0000269|PubMed:23576762" FT CONFLICT 179 FT /note="R -> K (in Ref. 2; AAO25619)" FT /evidence="ECO:0000305" FT CONFLICT 607 FT /note="S -> F (in Ref. 4; AAH26679)" FT /evidence="ECO:0000305" SQ SEQUENCE 1222 AA; 132410 MW; BE0A193E7D79DCFE CRC64; MLAPRNTETG VPMSQTEADL ALRPSPALTS TGPTRLGPPP RRVRRFSGKA EPRPRSSRPS RRSSVDLGLL SSWSQPASLL PEPPDPPDSA GPTRSPPSSS KEPPEGTWMG AAPVKAVDSA CPELTGSSGG PGSREPPRVP DAAARERRRE QEEKEDTETQ AVATSPDGRY LKFDIEIGRG SFKTVYRGLD TDTTVEVAWC ELQTRKLSRA ERQRFSEEVE MLKGLQHPNI VRFYDSWKSV LRGQVCIVLV TELMTSGTLK TYLRRFREMK PRVLQRWSRQ ILRGLHFLHS RVPPILHRDL KCDNVFITGP SGSVKIGDLG LATLKRASFA KSVIGTPEFM APEMYEEKYD EAVDVYAFGM CMLEMATSEY PYSECQNAAQ IYRKVTSGTK PNSFYKVKMP EVKEIIEGCI RTDKNERFTI QDLLAHAFFR EERGVHVELA EEDDGEKPGL KLWLRMEDAR RGGRPRDNQA IEFLFQLGRD AAEEVAQEMV ALGLVCEADY QPVARAVRER VAAIQRKREK LRKARELEVL PPDSGPPPAT VSLAPGPPSA FPPEPEEPEA DQHQSFLFRH ASYSSTTSDC ETDGYLSSSG FLDASDPALQ PPGGLPSSPA ESHLCLPSGF ALSIPRSGPG SDFSPGDSYA SDAASGLSDM GEGGQMRKNP VKTLRRRPRS RLRVTSVSDQ SDRVVECQLQ THNSKMVTFR FDLDGDSPEE IAAAMVYNEF ILPSERDGFL SRIREIIQRV ETLLKRDAGP PEAAEDALSP QEEPAALPAL PGPPNAEPQR SISPEQRSWA AFSTSPSSPG TPLSPGAPFS PGTPPVFPCP IFPITSPSCY PCPFSQVSSN PYPQAPSSLL PLSSSASQVP LPSSSLPISA PLPFSPSYPQ DPLSPTSLPV CPSPPSLPST TAAPLLSLAS AFSLAVMTVA QSLLSPSPGL LSQSPPAPPG PLPSLPLSLA SCDQESLSAQ TAETENEASR NPAQPLLGDA RLAPISEEGK PQLVGRFQVT SSKEPAEPPL QPASPTLSRS LKLPSPPLTS ESSDTEDSAA GGPETREALA ESDRAAEGLG VAVDDEKDEG KEPLLGGSSP ILSHPSPVWM NYSYSSLCLS SEESESSGED EEFWAELQNL RQKHLSEVEA LQTLQKKEIE DLYSRLGKQP PPGIVAPAAM LSCRQRRLSK GSFPTSRRNS LQRSDLPGPG IMRRNSLSGS STGSQEQRAS KGVTFAGDIG RM //