WNK4_HUMAN
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 03-AUG-2022, entry version 183.
DE RecName: Full=Serine/threonine-protein kinase WNK4 {ECO:0000305};
DE EC=2.7.11.1 {ECO:0000250|UniProtKB:Q9H4A3};
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: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 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 [9]
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 [10]
RP INTERACTION WITH KLHL3, AND CHARACTERIZATION OF VARIANTS PHA2B LYS-562 AND
RP 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 [11]
RP UBIQUITINATION, INTERACTION WITH KLHL3, AND CHARACTERIZATION OF VARIANT
RP 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 [12]
RP INTERACTION WITH KLHL3.
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 [13]
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 [14]
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, INTERACTION WITH KLHL3, AND CHARACTERIZATION OF VARIANTS PHA2B
RP 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 [15]
RP INTERACTION WITH KLHL3.
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 [16]
RP INTERACTION WITH KLHL3.
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 [17]
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 kinase which plays an important role in the
CC regulation of electrolyte homeostasis, cell signaling, survival and
CC proliferation. Acts as an activator and inhibitor of sodium-coupled
CC chloride cotransporters and potassium-coupled chloride cotransporters
CC respectively. Activates SCNN1A, SCNN1B, SCNN1D, SGK1, TRPV5 and TRPV6.
CC Regulates the activity of the thiazide-sensitive Na-Cl cotransporter,
CC SLC12A3, by phosphorylation which appears to prevent membrane
CC trafficking of SLC12A3. Also inhibits the renal K(+) channel, KCNJ1,
CC via a kinase-independent mechanism by which it induces clearance of the
CC protein from the cell surface by clathrin-dependent endocytosis. WNK4
CC appears to act as a molecular switch that can vary the balance between
CC NaCl reabsorption and K(+) secretion to maintain integrated
CC homeostasis. Phosphorylates NEDD4L. Acts as a scaffold to inhibit
CC SLC4A4 as well as CFTR activities and surface expression, recruits
CC STK39 which mediates the inhibition (By similarity).
CC {ECO:0000250|UniProtKB:Q80UE6, ECO:0000269|PubMed:20525693}.
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:0000250|UniProtKB:Q9H4A3};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000250|UniProtKB:Q9H4A3};
CC -!- ACTIVITY REGULATION: Activation requires autophosphorylation of Ser-
CC 335. Phosphorylation of Ser-331 also promotes increased activity (By
CC similarity). {ECO:0000250|UniProtKB:Q9JIH7}.
CC -!- SUBUNIT: Interacts with the C-terminal region of KCNJ1 (By similarity).
CC Interacts with WNK1 and WNK3 (By similarity). Interacts with KLHL3
CC (PubMed:23387299, PubMed:23453970, PubMed:23576762, PubMed:23665031,
CC PubMed:26435498, PubMed:27727489). {ECO:0000250|UniProtKB:Q80UE6,
CC ECO:0000269|PubMed:23387299, ECO:0000269|PubMed:23453970,
CC ECO:0000269|PubMed:23576762, ECO:0000269|PubMed:23665031,
CC ECO:0000269|PubMed:26435498, ECO:0000269|PubMed:27727489}.
CC -!- INTERACTION:
CC Q96J92; O95747: OXSR1; NbExp=12; IntAct=EBI-766352, EBI-620853;
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 WNK4 is part of the tight junction complex.
CC {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 -!- PTM: Phosphorylated by WNK1 and WNK3. {ECO:0000250|UniProtKB:Q80UE6}.
CC -!- PTM: Ubiquitinated by the BCR(KLHL3) complex, leading to its
CC degradation and increased expression of KCNJ1 at the cell surface.
CC Ubiquitinated by the BCR(KLHL2) complex. {ECO:0000269|PubMed:23453970,
CC ECO:0000269|PubMed:23576762, ECO:0000269|PubMed:23838290}.
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}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC 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; 11.
DR CORUM; Q96J92; -.
DR ELM; Q96J92; -.
DR IntAct; Q96J92; 9.
DR MINT; Q96J92; -.
DR STRING; 9606.ENSP00000246914; -.
DR ChEMBL; CHEMBL1795196; -.
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; Q96J92; -.
DR PeptideAtlas; Q96J92; -.
DR PRIDE; Q96J92; -.
DR ProteomicsDB; 76909; -. [Q96J92-1]
DR ProteomicsDB; 76910; -. [Q96J92-2]
DR ProteomicsDB; 76911; -. [Q96J92-3]
DR Antibodypedia; 29411; 243 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 CTD; 65266; -.
DR DisGeNET; 65266; -.
DR GeneCards; WNK4; -.
DR GeneReviews; WNK4; -.
DR HGNC; HGNC:14544; WNK4.
DR HPA; ENSG00000126562; Tissue enhanced (esophagus, 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; 27514at2759; -.
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; 22 hits in 1115 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 116 other tissues.
DR ExpressionAtlas; Q96J92; baseline and differential.
DR Genevisible; Q96J92; HS.
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:0019869; F:chloride channel inhibitor activity; IDA:UniProtKB.
DR GO; GO:0031404; F:chloride ion binding; IEA:Ensembl.
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; ISS:UniProtKB.
DR GO; GO:0032147; P:activation of protein kinase activity; IEA:Ensembl.
DR GO; GO:0035932; P:aldosterone secretion; IEA:Ensembl.
DR GO; GO:0055074; P:calcium ion homeostasis; IEA:Ensembl.
DR GO; GO:0030003; P:cellular cation homeostasis; ISS:UniProtKB.
DR GO; GO:0030644; P:cellular chloride 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:0035556; P:intracellular signal transduction; ISS:UniProtKB.
DR GO; GO:0050801; P:ion homeostasis; IMP:UniProtKB.
DR GO; GO:0006811; P:ion transport; ISS:UniProtKB.
DR GO; GO:0042116; P:macrophage activation; IEA:Ensembl.
DR GO; GO:0090188; P:negative regulation of pancreatic juice secretion; IEA:Ensembl.
DR GO; GO:0006469; P:negative regulation of protein kinase activity; IEA:Ensembl.
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:2000651; P:positive regulation of sodium ion transmembrane transporter activity; IBA:GO_Central.
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:0070294; P:renal sodium ion absorption; IMP:UniProtKB.
DR GO; GO:0002021; P:response to dietary excess; IEA:Ensembl.
DR GO; GO:0035725; P:sodium ion transmembrane transport; IEA:Ensembl.
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 Pfam; PF12202; OSR1_C; 1.
DR Pfam; PF00069; Pkinase; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
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 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 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 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"
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 /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 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
