ID WNK4_HUMAN Reviewed; 1243 AA. AC Q96J92; B0LPI0; Q8N8X3; Q8N8Z2; Q96DT8; Q9BYS5; DT 02-FEB-2004, integrated into UniProtKB/Swiss-Prot. DT 01-DEC-2001, sequence version 1. DT 27-MAR-2024, entry version 192. DE RecName: Full=Serine/threonine-protein kinase WNK4 {ECO:0000305}; DE EC=2.7.11.1 {ECO:0000269|PubMed:16832045}; DE AltName: Full=Protein kinase lysine-deficient 4 {ECO:0000312|HGNC:HGNC:14544}; DE AltName: Full=Protein kinase with no lysine 4 {ECO:0000303|PubMed:11571656}; GN Name=WNK4 {ECO:0000303|PubMed:11571656, ECO:0000312|HGNC:HGNC:14544}; GN Synonyms=PRKWNK4 {ECO:0000312|HGNC:HGNC:14544}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606 {ECO:0000312|EMBL:AAK91995.1}; RN [1] {ECO:0000305} RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), DISEASE, AND VARIANTS PHA2B RP LYS-562; ALA-564; GLU-565 AND CYS-1185. RC TISSUE=Kidney {ECO:0000312|EMBL:AAK91995.1}; 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 [2] {ECO:0000305} RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RC TISSUE=Kidney {ECO:0000312|EMBL:CAC48387.1}; RA Chistiakov D.A.; RL Thesis (2001), College de France / Paris, France. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), AND NUCLEOTIDE SEQUENCE RP [LARGE SCALE MRNA] OF 504-1165 (ISOFORM 3). RC TISSUE=Kidney; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [4] {ECO:0000305} RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RG NHLBI resequencing and genotyping service (RS&G); RL Submitted (DEC-2007) to the EMBL/GenBank/DDBJ databases. RN [5] {ECO:0000305} RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. 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 [7] {ECO:0000305} RP NUCLEOTIDE SEQUENCE [MRNA] OF 207-418 (ISOFORMS 1/3), TISSUE SPECIFICITY, RP AND CHROMOSOMAL LOCATION. RC TISSUE=Colon {ECO:0000312|EMBL:CAC32991.1}; RX PubMed=11571656; DOI=10.1038/sj.onc.1204726; RA Verissimo F., Jordan P.; RT "WNK kinases, a novel protein kinase subfamily in multi-cellular RT organisms."; RL Oncogene 20:5562-5569(2001). RN [8] RP DOMAIN, AND MUTAGENESIS OF ARG-1016; PHE-1017 AND VAL-1019. RX PubMed=16669787; DOI=10.1042/bj20060220; RA Vitari A.C., Thastrup J., Rafiqi F.H., Deak M., Morrice N.A., RA Karlsson H.K., Alessi D.R.; RT "Functional interactions of the SPAK/OSR1 kinases with their upstream RT activator WNK1 and downstream substrate NKCC1."; RL Biochem. J. 397:223-231(2006). RN [9] RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=16832045; DOI=10.1073/pnas.0604607103; RA Anselmo A.N., Earnest S., Chen W., Juang Y.C., Kim S.C., Zhao Y., RA Cobb M.H.; RT "WNK1 and OSR1 regulate the Na+, K+, 2Cl- cotransporter in HeLa cells."; RL Proc. Natl. Acad. Sci. U.S.A. 103:10883-10888(2006). RN [10] RP FUNCTION. RX PubMed=20525693; DOI=10.1074/jbc.m110.103432; RA Heise C.J., Xu B.E., Deaton S.L., Cha S.K., Cheng C.J., Earnest S., RA Sengupta S., Juang Y.C., Stippec S., Xu Y., Zhao Y., Huang C.L., Cobb M.H.; RT "Serum and glucocorticoid-induced kinase (SGK) 1 and the epithelial sodium RT channel are regulated by multiple with no lysine (WNK) family members."; RL J. Biol. Chem. 285:25161-25167(2010). RN [11] RP FUNCTION. RX PubMed=22989884; DOI=10.1074/jbc.m112.398750; RA Sengupta S., Tu S.W., Wedin K., Earnest S., Stippec S., Luby-Phelps K., RA Cobb M.H.; RT "Interactions with WNK (with no lysine) family members regulate oxidative RT stress response 1 and ion co-transporter activity."; RL J. Biol. Chem. 287:37868-37879(2012). RN [12] RP UBIQUITINATION BY KLHL2. RX PubMed=23838290; DOI=10.1016/j.bbrc.2013.06.104; RA Takahashi D., Mori T., Wakabayashi M., Mori Y., Susa K., Zeniya M., RA Sohara E., Rai T., Sasaki S., Uchida S.; RT "KLHL2 interacts with and ubiquitinates WNK kinases."; RL Biochem. Biophys. Res. Commun. 437:457-462(2013). RN [13] RP UBIQUITINATION, AND CHARACTERIZATION OF VARIANTS PHA2B LYS-562 AND GLU-565. RX PubMed=23387299; DOI=10.1042/bj20121903; RA Ohta A., Schumacher F.R., Mehellou Y., Johnson C., Knebel A., RA Macartney T.J., Wood N.T., Alessi D.R., Kurz T.; RT "The CUL3-KLHL3 E3 ligase complex mutated in Gordon's hypertension syndrome RT interacts with and ubiquitylates WNK isoforms: disease-causing mutations in RT KLHL3 and WNK4 disrupt interaction."; RL Biochem. J. 451:111-122(2013). RN [14] RP UBIQUITINATION, AND CHARACTERIZATION OF VARIANT PHA2B ALA-564. 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 [15] RP UBIQUITINATION. RX PubMed=23665031; DOI=10.1016/j.febslet.2013.04.032; RA Wu G., Peng J.B.; RT "Disease-causing mutations in KLHL3 impair its effect on WNK4 RT degradation."; RL FEBS Lett. 587:1717-1722(2013). RN [16] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-97, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [17] RP UBIQUITINATION AT LYS-157; LYS-175; LYS-186; LYS-226; LYS-241; LYS-328; RP LYS-387; LYS-393; LYS-450; LYS-454; LYS-1010; LYS-1144; LYS-1157 AND RP LYS-1158, AND CHARACTERIZATION OF VARIANTS PHA2B LYS-562 AND GLU-565. 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 [18] RP UBIQUITINATION. RX PubMed=26435498; DOI=10.1016/j.bbrc.2015.09.184; RA Yoshizaki Y., Mori Y., Tsuzaki Y., Mori T., Nomura N., Wakabayashi M., RA Takahashi D., Zeniya M., Kikuchi E., Araki Y., Ando F., Isobe K., RA Nishida H., Ohta A., Susa K., Inoue Y., Chiga M., Rai T., Sasaki S., RA Uchida S., Sohara E.; RT "Impaired degradation of WNK by Akt and PKA phosphorylation of KLHL3."; RL Biochem. Biophys. Res. Commun. 467:229-234(2015). RN [19] RP PHOSPHORYLATION AT SER-575, AND MUTAGENESIS OF SER-575. RX PubMed=26732173; DOI=10.1038/srep18710; RA Maruyama J., Kobayashi Y., Umeda T., Vandewalle A., Takeda K., Ichijo H., RA Naguro I.; RT "Osmotic stress induces the phosphorylation of WNK4 Ser575 via the p38MAPK- RT MK pathway."; RL Sci. Rep. 6:18710-18710(2016). RN [20] RP UBIQUITINATION. RX PubMed=27727489; DOI=10.1002/pro.3063; RA Wang L., Peng J.B.; RT "Phosphorylation of KLHL3 at serine 433 impairs its interaction with the RT acidic motif of WNK4: a molecular dynamics study."; RL Protein Sci. 26:163-173(2017). RN [21] {ECO:0007744|PDB:2V3S} RP X-RAY CRYSTALLOGRAPHY (1.70 ANGSTROMS) OF 1015-1020 IN COMPLEX WITH OXSR1, RP AND DOMAIN. RX PubMed=17721439; DOI=10.1038/sj.embor.7401048; RA Villa F., Goebel J., Rafiqi F.H., Deak M., Thastrup J., Alessi D.R., RA van Aalten D.M.; RT "Structural insights into the recognition of substrates and activators by RT the OSR1 kinase."; RL EMBO Rep. 8:839-845(2007). RN [22] {ECO:0007744|PDB:4CH9, ECO:0007744|PDB:4CHB} RP X-RAY CRYSTALLOGRAPHY (1.56 ANGSTROMS) OF 557-567 IN COMPLEX WITH KLHL2 AND RP KLHL3, UBIQUITINATION, AND CHARACTERIZATION OF VARIANTS PHA2B ALA-564 AND RP GLU-565. RX PubMed=24641320; DOI=10.1042/bj20140153; RA Schumacher F.R., Sorrell F.J., Alessi D.R., Bullock A.N., Kurz T.; RT "Structural and biochemical characterization of the KLHL3-WNK kinase RT interaction important in blood pressure regulation."; RL Biochem. J. 460:237-246(2014). RN [23] RP VARIANTS [LARGE SCALE ANALYSIS] ASP-434; LEU-813; SER-992 AND PRO-1013. RX PubMed=17344846; DOI=10.1038/nature05610; RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., RA Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., RA Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G., RA Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., RA Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., RA Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., RA Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., RA Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., RA Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., RA Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., RA Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., RA Futreal P.A., Stratton M.R.; RT "Patterns of somatic mutation in human cancer genomes."; RL Nature 446:153-158(2007). 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 (By similarity). The CC 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:16832045). 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:16832045, CC PubMed:22989884). Acts as a molecular switch that regulates the balance CC between renal salt reabsorption and K(+) secretion by modulating the CC activities of renal transporters and channels, including the Na-Cl CC cotransporter SLC12A3/NCC and the K(+) channel, KCNJ1/ROMK (By CC similarity). 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 (By similarity). Also acts CC as a scaffold protein independently of its protein kinase activity: CC negatively regulates cell membrane localization of various transporters CC and channels (CFTR, KCNJ1/ROMK, SLC4A4, SLC26A9 and TRPV4) by clathrin- CC dependent endocytosis (By similarity). Also inhbits the activity of the CC epithelial Na(+) channel (ENaC) SCNN1A, SCNN1B, SCNN1D in a inase- CC independent mechanism (By similarity). May also phosphorylate NEDD4L CC (PubMed:20525693). {ECO:0000250|UniProtKB:Q80UE6, CC ECO:0000269|PubMed:16832045, ECO:0000269|PubMed:20525693, CC ECO:0000269|PubMed:22989884}. 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:16832045}; CC -!- COFACTOR: CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; CC Evidence={ECO:0000250|UniProtKB:Q9H4A3}; CC -!- ACTIVITY REGULATION: Activation requires autophosphorylation of Ser-331 CC and Ser-335 (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 (By similarity). CC {ECO:0000250|UniProtKB:Q80UE6, ECO:0000250|UniProtKB:Q9JIH7}. CC -!- SUBUNIT: Interacts with the C-terminal region of KCNJ1. CC {ECO:0000250|UniProtKB:Q80UE6}. CC -!- INTERACTION: CC Q96J92; O95747: OXSR1; NbExp=12; IntAct=EBI-766352, EBI-620853; CC Q96J92; P62258: YWHAE; NbExp=2; IntAct=EBI-766352, EBI-356498; CC -!- SUBCELLULAR LOCATION: Cell junction, tight junction CC {ECO:0000250|UniProtKB:Q80UE6}. 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 (By similarity). WNK4 is part of the tight junction complex (By CC similarity). {ECO:0000250|UniProtKB:Q80UE6}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1 {ECO:0000269|PubMed:11498583, ECO:0000305}; CC IsoId=Q96J92-1; Sequence=Displayed; CC Name=2 {ECO:0000305}; CC IsoId=Q96J92-2; Sequence=VSP_050648, VSP_050649, VSP_050650, CC VSP_050651; CC Name=3 {ECO:0000305}; CC IsoId=Q96J92-3; Sequence=VSP_050652, VSP_050653; CC -!- TISSUE SPECIFICITY: Expressed in kidney, colon and skin. CC {ECO:0000269|PubMed:11571656}. CC -!- DOMAIN: The RFXV motif mediates recognition with downstream kinases CC OXSR1/OSR1 and STK39/SPAK. {ECO:0000269|PubMed:16669787, CC ECO:0000269|PubMed:24641320}. CC -!- PTM: Autophosphorylated at Ser-331 and Ser-335, promoting its CC activation (By similarity). Phosphorylated by WNK1 and WNK3 (By CC similarity). Phosphorylated at Ser-575 in a MAP3K15/ASK3-dependent CC process in response to osmotic stress or hypotonic low-chloride CC stimulation (PubMed:26732173). {ECO:0000250|UniProtKB:Q80UE6, CC ECO:0000250|UniProtKB:Q9JIH7, ECO:0000269|PubMed:26732173}. CC -!- PTM: Ubiquitinated by the BCR(KLHL3) complex, leading to its CC degradation (PubMed:23387299, PubMed:23453970, PubMed:23665031, CC PubMed:23576762, PubMed:26435498, PubMed:27727489, PubMed:24641320). CC Also ubiquitinated by the BCR(KLHL2) complex (PubMed:23838290, CC PubMed:24641320). {ECO:0000269|PubMed:23387299, CC ECO:0000269|PubMed:23453970, ECO:0000269|PubMed:23576762, CC ECO:0000269|PubMed:23665031, ECO:0000269|PubMed:23838290, CC ECO:0000269|PubMed:24641320, ECO:0000269|PubMed:26435498, CC ECO:0000269|PubMed:27727489}. CC -!- DISEASE: Pseudohypoaldosteronism 2B (PHA2B) [MIM:614491]: An autosomal CC dominant disorder characterized by hypertension, hyperkalemia, CC hyperchloremia, mild hyperchloremic metabolic acidosis, and correction CC of physiologic abnormalities by thiazide diuretics. CC {ECO:0000269|PubMed:11498583, ECO:0000269|PubMed:23387299, CC ECO:0000269|PubMed:23453970, ECO:0000269|PubMed:23576762, CC ECO:0000269|PubMed:24641320}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- MISCELLANEOUS: [Isoform 3]: Incomplete sequence. {ECO:0000305}. 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=BAC04669.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC Sequence=CAC48387.1; Type=Frameshift; 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; AF390018; AAK91995.1; -; mRNA. DR EMBL; AJ316534; CAC48387.1; ALT_FRAME; mRNA. DR EMBL; AK096003; BAC04669.1; ALT_INIT; mRNA. DR EMBL; AK096052; BAC04688.1; -; mRNA. DR EMBL; EU332870; ABY87559.1; -; Genomic_DNA. DR EMBL; CH471152; EAW60881.1; -; Genomic_DNA. DR EMBL; CH471152; EAW60882.1; -; Genomic_DNA. DR EMBL; BC136664; AAI36665.1; -; mRNA. DR EMBL; AJ309861; CAC32991.1; -; mRNA. DR CCDS; CCDS11439.1; -. [Q96J92-1] DR RefSeq; NP_115763.2; NM_032387.4. [Q96J92-1] DR PDB; 2V3S; X-ray; 1.70 A; C/D=1015-1020. DR PDB; 4CH9; X-ray; 1.84 A; C/D=557-567. DR PDB; 4CHB; X-ray; 1.56 A; C/D=557-567. DR PDBsum; 2V3S; -. DR PDBsum; 4CH9; -. DR PDBsum; 4CHB; -. DR AlphaFoldDB; Q96J92; -. DR SMR; Q96J92; -. DR BioGRID; 122421; 16. DR CORUM; Q96J92; -. DR ELM; Q96J92; -. DR IntAct; Q96J92; 9. DR MINT; Q96J92; -. DR STRING; 9606.ENSP00000246914; -. DR BindingDB; Q96J92; -. DR ChEMBL; CHEMBL1795196; -. DR TCDB; 8.A.23.1.50; the basigin (basigin) family. DR GlyGen; Q96J92; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; Q96J92; -. DR PhosphoSitePlus; Q96J92; -. DR BioMuta; WNK4; -. DR DMDM; 41688789; -. DR EPD; Q96J92; -. DR jPOST; Q96J92; -. DR MassIVE; Q96J92; -. DR MaxQB; Q96J92; -. DR PaxDb; 9606-ENSP00000246914; -. DR PeptideAtlas; Q96J92; -. DR ProteomicsDB; 76909; -. [Q96J92-1] DR ProteomicsDB; 76910; -. [Q96J92-2] DR ProteomicsDB; 76911; -. [Q96J92-3] DR Pumba; Q96J92; -. DR Antibodypedia; 29411; 262 antibodies from 26 providers. DR DNASU; 65266; -. DR Ensembl; ENST00000246914.10; ENSP00000246914.4; ENSG00000126562.17. [Q96J92-1] DR GeneID; 65266; -. DR KEGG; hsa:65266; -. DR MANE-Select; ENST00000246914.10; ENSP00000246914.4; NM_032387.5; NP_115763.2. DR UCSC; uc002ibj.4; human. [Q96J92-1] DR AGR; HGNC:14544; -. DR CTD; 65266; -. DR DisGeNET; 65266; -. DR GeneCards; WNK4; -. DR GeneReviews; WNK4; -. DR HGNC; HGNC:14544; WNK4. DR HPA; ENSG00000126562; Tissue enhanced (intestine, kidney, prostate). DR MalaCards; WNK4; -. DR MIM; 601844; gene. DR MIM; 614491; phenotype. DR neXtProt; NX_Q96J92; -. DR OpenTargets; ENSG00000126562; -. DR Orphanet; 88939; Pseudohypoaldosteronism type 2B. DR PharmGKB; PA134875400; -. DR VEuPathDB; HostDB:ENSG00000126562; -. DR eggNOG; KOG0584; Eukaryota. DR GeneTree; ENSGT00940000159871; -. DR HOGENOM; CLU_000550_2_1_1; -. DR InParanoid; Q96J92; -. DR OMA; HHPASMF; -. DR OrthoDB; 5478852at2759; -. DR PhylomeDB; Q96J92; -. DR TreeFam; TF315363; -. DR PathwayCommons; Q96J92; -. DR Reactome; R-HSA-2672351; Stimuli-sensing channels. DR SignaLink; Q96J92; -. DR SIGNOR; Q96J92; -. DR BioGRID-ORCS; 65266; 25 hits in 1194 CRISPR screens. DR ChiTaRS; WNK4; human. DR EvolutionaryTrace; Q96J92; -. DR GeneWiki; WNK4; -. DR GenomeRNAi; 65266; -. DR Pharos; Q96J92; Tbio. DR PRO; PR:Q96J92; -. DR Proteomes; UP000005640; Chromosome 17. DR RNAct; Q96J92; Protein. DR Bgee; ENSG00000126562; Expressed in kidney epithelium and 118 other cell types or tissues. DR ExpressionAtlas; Q96J92; baseline and differential. DR GO; GO:0005923; C:bicellular tight junction; ISS:UniProtKB. DR GO; GO:0044297; C:cell body; IEA:Ensembl. DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central. DR GO; GO:0005829; C:cytosol; ISS:ParkinsonsUK-UCL. DR GO; GO:0016020; C:membrane; ISS:ParkinsonsUK-UCL. DR GO; GO:0032991; C:protein-containing complex; IEA:Ensembl. DR GO; GO:0005524; F:ATP binding; ISS:UniProtKB. DR GO; GO:0031404; F:chloride ion binding; IEA:Ensembl. DR GO; GO:0008200; F:ion channel inhibitor activity; ISS:UniProtKB. DR GO; GO:0004672; F:protein kinase 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; IDA:UniProt. DR GO; GO:0035932; P:aldosterone secretion; IEA:Ensembl. DR GO; GO:0055074; P:calcium ion homeostasis; IEA:Ensembl. DR GO; GO:0071466; P:cellular response to xenobiotic stimulus; IEA:Ensembl. DR GO; GO:0006821; P:chloride transport; IEA:Ensembl. DR GO; GO:0072156; P:distal tubule morphogenesis; IMP:UniProtKB. DR GO; GO:0070371; P:ERK1 and ERK2 cascade; IEA:Ensembl. DR GO; GO:0010467; P:gene expression; IEA:Ensembl. DR GO; GO:0006954; P:inflammatory response; IEA:Ensembl. DR GO; GO:0030644; P:intracellular chloride ion homeostasis; IEA:Ensembl. DR GO; GO:0035556; P:intracellular signal transduction; ISS:UniProtKB. DR GO; GO:0042116; P:macrophage activation; IEA:Ensembl. DR GO; GO:0050801; P:monoatomic ion homeostasis; IMP:UniProtKB. DR GO; GO:0090188; P:negative regulation of pancreatic juice secretion; IEA:Ensembl. DR GO; GO:1903077; P:negative regulation of protein localization to plasma membrane; ISS:UniProtKB. DR GO; GO:0010766; P:negative regulation of sodium ion transport; ISS:UniProtKB. DR GO; GO:0071805; P:potassium ion transmembrane transport; IEA:Ensembl. DR GO; GO:0070528; P:protein kinase C signaling; IEA:Ensembl. DR GO; GO:0008104; P:protein localization; IEA:Ensembl. DR GO; GO:0006468; P:protein phosphorylation; ISS:UniProtKB. DR GO; GO:0008217; P:regulation of blood pressure; IEA:Ensembl. DR GO; GO:1903764; P:regulation of potassium ion export across plasma membrane; IEA:Ensembl. DR GO; GO:0070294; P:renal sodium ion absorption; IMP:UniProtKB. DR GO; GO:0003096; P:renal sodium ion transport; ISS:UniProtKB. DR GO; GO:0002021; P:response to dietary excess; IEA:Ensembl. DR GO; GO:0007165; P:signal transduction; IBA:GO_Central. DR GO; GO:0035725; P:sodium ion transmembrane transport; IEA:Ensembl. 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; Q96J92; HS. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; ATP-binding; Cell junction; KW Disease variant; Isopeptide bond; Kinase; Nucleotide-binding; KW Phosphoprotein; Reference proteome; Serine/threonine-protein kinase; KW Tight junction; Transferase; Ubl conjugation. FT CHAIN 1..1243 FT /note="Serine/threonine-protein kinase WNK4" FT /id="PRO_0000086824" FT DOMAIN 174..432 FT /note="Protein kinase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT REGION 1..142 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 526..564 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 557..567 FT /note="Interaction with KLHL3" FT /evidence="ECO:0000269|PubMed:24641320" FT REGION 630..683 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 751..871 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 943..1110 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1166..1243 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOTIF 1016..1019 FT /note="RFXV motif" FT /evidence="ECO:0000269|PubMed:16669787, FT ECO:0000269|PubMed:24641320" FT COMPBIAS 1..16 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 44..60 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 77..105 FT /note="Pro residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 533..558 FT /note="Pro residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 782..811 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 812..842 FT /note="Pro residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 949..974 FT /note="Pro residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1038..1060 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1068..1093 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1186..1204 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1215..1232 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 321 FT /note="Proton acceptor" FT /evidence="ECO:0000250|UniProtKB:Q9JIH7" FT BINDING 184 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000250|UniProtKB:Q9H4A3" FT BINDING 254..257 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000250|UniProtKB:Q9H4A3" FT BINDING 304 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000250|UniProtKB:Q9H4A3" FT MOD_RES 97 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 331 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000250|UniProtKB:Q9JIH7" FT MOD_RES 335 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000250|UniProtKB:Q9JIH7" FT MOD_RES 575 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:26732173" FT MOD_RES 1035 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q7TPK6" FT MOD_RES 1217 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q80UE6" FT CROSSLNK 157 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:23576762" FT CROSSLNK 175 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:23576762" FT CROSSLNK 186 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:23576762" FT CROSSLNK 226 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:23576762" FT CROSSLNK 241 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:23576762" FT CROSSLNK 328 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:23576762" FT CROSSLNK 387 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:23576762" FT CROSSLNK 393 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:23576762" FT CROSSLNK 450 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:23576762" FT CROSSLNK 454 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:23576762" FT CROSSLNK 1010 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:23576762" FT CROSSLNK 1144 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:23576762" FT CROSSLNK 1157 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:23576762" FT CROSSLNK 1158 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:23576762" FT VAR_SEQ 1..228 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_050648" FT VAR_SEQ 229..264 FT /note="QHPNIVRFYDSWKSVLRGQVCIVLVTELMTSGTLKT -> MRRRQQGAAGGN FT FPVGGSFPEDVSPHQDSGYAPSPR (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_050649" FT VAR_SEQ 828..1210 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_050650" FT VAR_SEQ 1145..1165 FT /note="HLSEVETLQTLQKKEIEDLYS -> PFHALRASSGTCQRWKHYRHY (in FT isoform 3)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_050652" FT VAR_SEQ 1166..1243 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_050653" FT VAR_SEQ 1233..1243 FT /note="GVTFAGDVGRM -> EAGQRPGKLWLRATVQLRVWGLELRRKEMMGRNPKLG FT AAPNP (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_050651" FT VARIANT 434 FT /note="E -> D (in an ovarian mucinous carcinoma sample; FT somatic mutation)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_041330" FT VARIANT 562 FT /note="E -> K (in PHA2B; impaired interaction with KLHL3; FT dbSNP:rs137853093)" FT /evidence="ECO:0000269|PubMed:11498583, FT ECO:0000269|PubMed:23387299, ECO:0000269|PubMed:23576762" FT /id="VAR_017588" FT VARIANT 564 FT /note="D -> A (in PHA2B; impaired interaction with KLHL3; FT dbSNP:rs137853094)" FT /evidence="ECO:0000269|PubMed:11498583, FT ECO:0000269|PubMed:23453970, ECO:0000269|PubMed:24641320" FT /id="VAR_017589" FT VARIANT 565 FT /note="Q -> E (in PHA2B; impaired interaction with KLHL3; FT dbSNP:rs137853092)" FT /evidence="ECO:0000269|PubMed:11498583, FT ECO:0000269|PubMed:23387299, ECO:0000269|PubMed:23576762, FT ECO:0000269|PubMed:24641320" FT /id="VAR_017590" FT VARIANT 601 FT /note="A -> S (in dbSNP:rs55781437)" FT /id="VAR_061748" FT VARIANT 677 FT /note="R -> W (in dbSNP:rs9896991)" FT /id="VAR_051685" FT VARIANT 813 FT /note="P -> L" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_041331" FT VARIANT 961 FT /note="P -> S (in dbSNP:rs2290041)" FT /id="VAR_051686" FT VARIANT 992 FT /note="P -> S (in a metastatic melanoma sample; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_041332" FT VARIANT 1013 FT /note="L -> P" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_041333" FT VARIANT 1185 FT /note="R -> C (in PHA2B; dbSNP:rs137853095)" FT /evidence="ECO:0000269|PubMed:11498583" FT /id="VAR_017591" FT MUTAGEN 575 FT /note="S->A: Abolished MAP3K15/ASK3-dependent FT phosphorylation." FT /evidence="ECO:0000269|PubMed:26732173" FT MUTAGEN 575 FT /note="S->E,D: Mimics phosphorylation without affecting FT WNK4 kinase activity." FT /evidence="ECO:0000269|PubMed:26732173" FT MUTAGEN 1016 FT /note="R->A: Abolished interaction with OXSR1/OSR1." FT /evidence="ECO:0000269|PubMed:16669787" FT MUTAGEN 1017 FT /note="F->A: Abolished interaction with OXSR1/OSR1." FT /evidence="ECO:0000269|PubMed:16669787" FT MUTAGEN 1019 FT /note="V->A: Abolished interaction with OXSR1/OSR1." FT /evidence="ECO:0000269|PubMed:16669787" FT CONFLICT 525 FT /note="R -> C (in Ref. 3; BAC04688)" FT /evidence="ECO:0000305" FT HELIX 562..564 FT /evidence="ECO:0007829|PDB:4CHB" SQ SEQUENCE 1243 AA; 134739 MW; BAC35F0098BA3391 CRC64; MLASPATETT VLMSQTEADL ALRPPPPLGT AGQPRLGPPP RRARRFSGKA EPRPRSSRLS RRSSVDLGLL SSWSLPASPA PDPPDPPDSA GPGPARSPPP SSKEPPEGTW TEGAPVKAAE DSARPELPDS AVGPGSREPL RVPEAVALER RREQEEKEDM ETQAVATSPD GRYLKFDIEI GRGSFKTVYR GLDTDTTVEV AWCELQTRKL SRAERQRFSE EVEMLKGLQH PNIVRFYDSW KSVLRGQVCI VLVTELMTSG TLKTYLRRFR EMKPRVLQRW SRQILRGLHF LHSRVPPILH RDLKCDNVFI TGPTGSVKIG DLGLATLKRA SFAKSVIGTP EFMAPEMYEE KYDEAVDVYA FGMCMLEMAT SEYPYSECQN AAQIYRKVTS GRKPNSFHKV KIPEVKEIIE GCIRTDKNER FTIQDLLAHA FFREERGVHV ELAEEDDGEK PGLKLWLRME DARRGGRPRD NQAIEFLFQL GRDAAEEVAQ EMVALGLVCE ADYQPVARAV RERVAAIQRK REKLRKAREL EALPPEPGPP PATVPMAPGP PSVFPPEPEE PEADQHQPFL FRHASYSSTT SDCETDGYLS SSGFLDASDP ALQPPGGVPS SLAESHLCLP SAFALSIPRS GPGSDFSPGD SYASDAASGL SDVGEGMGQM RRPPGRNLRR RPRSRLRVTS VSDQNDRVVE CQLQTHNSKM VTFRFDLDGD SPEEIAAAMV YNEFILPSER DGFLRRIREI IQRVETLLKR DTGPMEAAED TLSPQEEPAP LPALPVPLPD PSNEELQSST SLEHRSWTAF STSSSSPGTP LSPGNPFSPG TPISPGPIFP ITSPPCHPSP SPFSPISSQV SSNPSPHPTS SPLPFSSSTP EFPVPLSQCP WSSLPTTSPP TFSPTCSQVT LSSPFFPPCP STSSFPSTTA APLLSLASAF SLAVMTVAQS LLSPSPGLLS QSPPAPPSPL PSLPLPPPVA PGGQESPSPH TAEVESEASP PPARPLPGEA RLAPISEEGK PQLVGRFQVT SSKEPAEPLP LQPTSPTLSG SPKPSTPQLT SESSDTEDSA GGGPETREAL AESDRAAEGL GAGVEEEGDD GKEPQVGGSP QPLSHPSPVW MNYSYSSLCL SSEESESSGE DEEFWAELQS LRQKHLSEVE TLQTLQKKEI EDLYSRLGKQ PPPGIVAPAA MLSSRQRRLS KGSFPTSRRN SLQRSEPPGP GIMRRNSLSG SSTGSQEQRA SKGVTFAGDV GRM //