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{{Infobox_gene}}
{{Infobox_gene}}
The protein '''with-no-lysine [K] kinase 4''' ('''WNK4''') is a member of a [[serine-threonine kinase]] family that comprises of four members. The family was so named because unlike other serine/threonine kinases, WNKs are characterized by the lack of lysine in the subdomain II of the catalytic domain<ref name=":0">{{Cite journal|last=Xu, B., English, J. M., Wilsbacher, J. L., Stippec, S., Goldsmith, E. J., Cobb, M. H.,|first=|date=|year=2000|title=WNK1, a novel mammalian serine/threonine protein kinase lacking the catalytic lysine in subdomain II.|url=|journal=J. Biol. Chem.|volume=275|issue=22|pages=16795-16801.|doi=10.1074/jbc.275.22.16795|pmid=10828064|via=}}</ref>. Instead, a lysine in the β2 strand of subdomain I of the catalytic domain is responsible for the kinase activity<ref name=":0" />.
'''Serine/threonine-protein kinase WNK4''' also known as '''WNK lysine deficient protein kinase 4''' or '''WNK4''', is an [[enzyme]] that in humans is encoded by the ''WNK4'' [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: WNK4 WNK lysine deficient protein kinase 4| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=65266| accessdate = }}</ref> Missense mutations cause a genetic form of pseudohypoaldosteronism type 2, also called [[Gordon syndrome]].

The ''WNK4'' gene is located on chromosome 17q21-q22. It produces a 1,243-amino acid protein encoded by a 3,732-nucleotide [[open reading frame]] within a 4 kb cDNA transcript<ref name=":1">{{Cite journal|last=Wilson, F.H., Disse-Nicodème, S., Choate, K. A., Ishikawa, K., Nelson-Williams, C., Desitter, I., Gunel, M., Milford, D. V., Lipkin, G. W., Achard, J. M., Feely, M. P., Dussol, B., Berland, Y., Unwin, R. J., Mayan, H., Simon, D. B., Farfel, Z., Jeunemaitre, X., Lifton, R. P.,|first=|date=|title=Human hypertension caused by mutations in WNK kinases.|url=|journal=Science|publication-date=2001|volume=293|issue=5532|pages=1107-1112|doi=10.1126/science.1062844|pmid=11498583|via=}}</ref>. WNK4 protein is highly expressed in the [[distal convoluted tubule]] (DCT) and the [[Collecting duct system|cortical collecting duct]] (CDD) of the [[kidney]]<ref name=":1" />. WNK4 is also present in the brain, lungs, liver, heart, and colon of various mammalian species<ref>{{Cite journal|last=Kahle, K.T., Gimenez, I., Hassan, H., Wilson, F. H., Wong, R. D., Forbush, B., Aronson, P. S., Lifton, R. P.,|first=|date=|year=2004|title=WNK4 regulates apical and basolateral Cl– flux in extrarenal epithelia.|url=|journal=Proc. Natl. Acad. Sci. USA|volume=101|issue=7|pages=2064-2069|doi=10.1073/pnas.0308434100|pmid=14769928|via=}}</ref><ref>{{Cite journal|last=Veríssimo, F., Jordan, P.,|first=|date=|year=2001|title=WNK kinases, a novel protein kinase subfamily in multi-cellular organisms.|url=|journal=Oncogene|volume=20|issue=39|pages=5562-5569.|doi=10.1038/sj.onc.1204726|pmid=11571656|via=}}</ref>.

Gene mutations in WNN4 has been found in patients with [[Pseudohypoaldosteronism|pseudohypoaldosteronism type II]] (PHAII)<ref name=":1" />, also known as familial hyperkalemic hypertension (FHHt)<ref>{{Cite journal|last=Arnold, J.E. and J.K. Healy,|first=|date=|year=1969|title=Hyperkalemia, hypertension and systemic acidosis without renal failure associated with a tubular defect in potassium excretion.|url=|journal=Am. J. Med.|volume=47|issue=3|pages=461-472|doi=10.1016/0002-9343(69)90230-7|pmid=5808659|via=}}</ref> or Gordon’s syndrome <ref>{{Cite journal|last=Gordon, R.D., Geddes, R. A., Pawsey, C. G., O'Halloran, M. W.,|first=|date=|year=1970|title=Hypertension and severe hyperkalaemia associated with suppression of renin and aldosterone and completely reversed by dietary sodium restriction.|url=|journal=Australas Ann. Med.|volume=19|issue=4|pages=287-294.|doi=10.1111/imj.1970.19.4.287|pmid=5490655|via=}}</ref>. PHAII is an [[autosomal dominant]] hereditary disease characterized by [[hyperkalemia]], [[hypertension]], and [[metabolic acidosis]]. WNK4 plays a critical role in the regulation of various transporters and channels in the kidney. PHAII-causing mutations in WNK4 results in the dysregulation of renal sodium and potassium transporters and channels, leading to defects in sodium and potassium retention by the kidney, and in turn, elevated [[blood pressure]] and potassium level ([[hyperkalemia]]).   

== Structure ==
The [[Protein tertiary structure|tertiary structure]] of WNK4 has not been elucidated to date. Nevertheless, several individual [[Protein domain|domain]] structures of the protein are identified. These include a [[Protein kinase domain|kinase domain]] near the [[amino terminus]] followed by an autoinhibitory domain, an acidic motif, two [[Coiled coil|coiled-coil]] domains, and a [[Calmodulin binding domain|calmodulin-binding domain]] in the [[C-terminus|C-terminal]] segment ('''Fig. 1'''). The structures for the kinase and autoinhibitory domains of [[WNK1]] have been identified. The high level of structural similarity between WNK4 and [[WNK1]] has allowed the investigators to deduce key structural details of WNK4 based on insights gained from corresponding regions within [[WNK1]]. The kinase domain of WNK4 has an 83% [[Sequence alignment|sequence identity]] with that of [[WNK1]]. The overall fold of the kinase domain of [[WNK1]] resembles those of other protein kinases that have a typical dual-domain architecture<ref name=":2">{{Cite journal|last=Min, X., Lee, B. H., Cobb, M. H., Goldsmith, E. J.,|first=|date=|year=2004|title=Crystal structure of the kinase domain of WNK1, a kinase that causes a hereditary form of hypertension|url=|journal=Structure|volume=12|issue=7|pages=1303-1311|doi=10.1016/j.str.2004.04.014|pmid=15242606|via=}}</ref>. The C-terminal domain of WNK4 bears a high degree of similarity to other kinases within the family. On the other hand, the N-terminal domain is unique in having a six-stranded instead of a five-stranded [[Beta sheet|β sheet]] to form a complete [[Beta barrel|β barrel]]<ref name=":2" />.
[[File:Figure 1. Domain structure of WNK4 and the positions of the initially identified PHAII-causing mutations. .jpg|left|thumb|245x245px|'''Fig. 1'''. '''Domain structure of WNK4 and the positions of the initially identified PHAII-causing mutations.''' The amino-acid (aa) positions of the domains are provided in parentheses. Some important PHAII mutations are localized in the acidic motif and calmodulin-binding domain, respectively. ]]
A chloride ion binding site has been identified in the region <sup>320</sup>DLG<sup>323</sup> of the kinase domain in WNK4<ref>{{Cite journal|last=Piala, A.T., Moon, T. M., Akella, R., He, H., Cobb, M. H., Goldsmith, E. J.|first=|date=|year=2014|title=Chloride sensing by WNK1 involves inhibition of autophosphorylation.|url=|journal=Sci. Signal.|volume=7|issue=324|pages=ra41|doi=10.1126/scisignal.2005050|pmid=24803536|via=}}</ref>. The binding of chloride binding in this region inhibits the activation of WNK4. The autoinhibitory domain is a homolog of the RFXV-binding PASK/FRAY homology 2 (PF2) domain<ref>{{Cite journal|last=Xu, B., Min, X., Stippec, S., Lee, B. H., Goldsmith, E. J., Cobb, M. H.|first=|date=|year=2002|title=Regulation of WNK1 by an autoinhibitory domain and autophosphorylation.|url=|journal=J. Biol. Chem.|volume=277|issue=50|pages=48456-48462.|doi=10.1074/jbc.M207917200|pmid=12374799|via=}}</ref>. Structural studies have revealed that the autoinhibitory domain consists of three β-strands and two [[Alpha helix|α-helice]]<nowiki/>s<ref name=":3">{{Cite journal|last=Moon, T.M., Correa, F., Kinch, L. N., Piala, A. T., Gardner, K. H., Goldsmith, E. J.|first=|date=|year=2013|title=Solution structure of the WNK1 autoinhibitory domain, a WNK-specific PF2 domain.|url=|journal=J. Mol. Biol.|volume=425|issue=8|pages=1245-1252|doi=10.1016/j.jmb.2013.01.031|pmid=23376100|via=}}</ref>. Notably, the RFXV‐binding groove is formed by the β3-αA interface of WNK proteins where RFXV peptide ligand interacts directly with residues Phe524, Asp531, and Glu539 of WNK1<ref name=":3" />. The interaction between the RFXV motif and the autoinhibitory domain makes it possible for the C-terminal region of WNK4 to be in close proximity of the kinases domain and subsequently regulate its activity.





== Function ==
== Function ==
[[File:Kinase Wiki.jpg|thumb|255x255px|'''Fig. 2.''' '''The WNK4-SPAK/OSR1-NCC phosphorylation cascade.''' WNK4 phosphorylates and activates SPAK/OSR1, which in turn phosphorylate and activates NCC. In this manner, WNK4 regulates sodium reabsorption in the distal convoluted tubule and downstream potassium secretion through its positive effects on NCC.  ]]
As a typical [[kinase]], the WNK4 accomplishes [[Protein phosphorylation|phosphorylation]] of its cognate substrate proteins by adding a phosphate moieties in an [[ATP]]-dependent manner.  This [[Molecular modification|structural modification]] usually results in functional alterations of downstream substrates. Some currently known substrates of WNK4 includes kinases STE20-serine-proline alanine-rich kinase (SPAK) and oxidative stress response 1 kinase (OSR1), which in turn can phosphorylate and activate the thiazide-sensitive [[Sodium chloride cotransporter|sodium-chloride cotransporter (NCC)]]<ref>{{Cite journal|last=Vitari, A.C., Deak, M., Morrice, N. A., Alessi, D. R.|first=|date=|year=2005|title=The WNK1 and WNK4 protein kinases that are mutated in Gordon’s hypertension syndrome phosphorylate and activate SPAK and OSR1 protein kinases.|url=|journal=Biochem. J.|volume=391|issue=Pt 1|pages=17-24|doi=10.1042/BJ20051180|pmid=16083423|via=}}</ref> <ref>{{Cite journal|last=Moriguchi, T., Urushiyama, S., Hisamoto, N., Iemura, S., Uchida, S., Natsume, T., Matsumoto, K., Shibuya, H.|first=|date=|year=2005|title=WNK1 regulates phosphorylation of cation-chloride-coupled cotransporters via the STE20-related kinases, SPAK and OSR1.|url=|journal=J. Biol. Chem.|volume=280|issue=52|pages=42685-42693|doi=10.1074/jbc.M510042200|pmid=16263722|via=}}</ref> ('''Fig. 2'''). Similarly, WNK4 activates [[Na-K-Cl cotransporter|NKCC1]] and deactivate [[Electroneutral cation-Cl|KCC]]2 through a SPAK-dependent mechanism<ref>{{Cite journal|last=Gagnon, K.B., England, R., Delpire, E.|first=|date=|year=2006|title=Volume sensitivity of cation-Cl- cotransporters is modulated by the interaction of two kinases: Ste20-related proline-alanine-rich kinase and WNK4|url=|journal=Am. J. Physiol. Cell Physiol.|volume=290|issue=1|pages=C134-C142|doi=10.1152/ajpcell.00037.2005|pmid=15930150|via=}}</ref>. The kinase activity of WNK4 has been demonstrated ''[[in vitro]]'' using the WNK4 kinase domain purified from ''[[E. coli]]'' <ref name=":4">{{Cite journal|last=Na, T., Wu, G., Peng, J. B.|first=|date=|year=2012|title=Disease-causing mutations in the acidic motif of WNK4 impair the sensitivity of WNK4 kinase to calcium ions|url=|journal=Biochem. Biophys. Res. Commun.|volume=419|issue=2|pages=293-298.|doi=10.1016/j.bbrc.2012.02.013|pmid=22342722|via=}}</ref>. This phosphorylation cascade is critical in regulating sodium and potassium [[homeostasis]] dysregulation of which is tied to the pathogenesis of PHAII.

In addition to NCC, WNK4 also regulates multiple ions channels and cotransporters in the kidney through various mechanisms. These include [[Epithelial sodium channel|epithelial Na<sup>+</sup> channel (ENaC)]], [[ROMK|renal outer medullary potassium channel (ROMK)]], [[TRPV4|transient receptor potential vanilloid member 4]] and [[TRPV5|5]] (TRPV4/5, calcium channels), Na-K-2Cl cotransporter 1 and 2 ([[Na-K-Cl cotransporter|NKCC1]]/2), [[Electroneutral cation-Cl|K<sup>+</sup>-Cl<sup>−</sup> cotransporter]] type 2 (KCC2), and other channels/transporters. WNK4 inhibits functions of ENaC, ROMK, and TRPV4 by reducing the total and cell surface expression of these channels<ref>{{Cite journal|last=Yu, L., Cai, H., Yue, Q., Alli,A. A., Wang, D., Al-Khalili, O., Bao, H. F., Eaton, D. C.|first=|date=|year=2013|title=WNK4 inhibition of ENaC is independent of Nedd4-2-mediated ENaC ubiquitination|url=|journal=Am. J. Physiol. Renal Physiol.|volume=305|issue=1|pages=F31-F41|doi=10.1152/ajprenal.00652.2012|pmid=23594824|via=}}</ref><ref name=":5">{{Cite journal|last=Ring, A.M., Leng, Q., Rinehart, J., Wilson, F. H., Kahle, K. T., Hebert, S. C., Lifton, R. P.|first=|date=|year=2007|title=An SGK1 site in WNK4 regulates Na+ channel and K+ channel activity and has implications for aldosterone signaling and K+ homeostasis.|url=|journal=Proc. Natl. Acad. Sci. USA|volume=104|issue=10|pages=4025-4029|doi=10.1073/pnas.0611728104|pmid=17360471|via=}}</ref><ref>{{Cite journal|last=Fu, Y., Subramanya, A., Rozansky, D., Cohen, D. M.|first=|date=|year=2006|title=WNK kinases influence TRPV4 channel function and localization|url=|journal=Am. J. Physiol. Renal Physiol.|volume=290|issue=6|pages=F1305-F1314.|doi=10.1152/ajprenal.00391.2005|pmid=16403833|via=}}</ref>. WNK4 enhances [[TRPV5]] by increasing its forward trafficking to the [[plasma membrane]] in a kinase-dependent manner <ref>{{Cite journal|last=Jiang, Y., Ferguson, W. B., Peng, J. B.|first=|date=|year=2007|title=WNK4 enhances TRPV5-mediated calcium transport: potential role in hypercalciuria of familial hyperkalemic hypertension caused by gene mutation of WNK4|url=|journal=Am. J. Physiol. Renal Physiol.|volume=292|issue=2|pages=F545-F554|doi=10.1152/ajprenal.00187.2006|pmid=17018846|via=}}</ref>. The inhibitory effect of WNK4 on [[ROMK]] is reversed by [[SGK1|serum and glucocorticoid kinase 1 (SGK1)]] or by a corresponding phosphomimetic S1169D mutation on WNK4<ref name=":5" />. The N-terminal segment of WNK4 containing the kinase domain and acidic motif is required WNK-mediated inhibition of ROMK expression<ref>{{Cite journal|last=Murthy, M., Cope, G., O'Shaughnessy, K. M.|first=|date=|year=2008|title=The acidic motif of WNK4 is crucial for its interaction with the K channel ROMK.|url=|journal=Biochem. Biophys. Res. Commun.|volume=375|issue=4|pages=651-654.|doi=10.1016/j.bbrc.2008.08.076|pmid=18755144|via=}}</ref>. The second coiled-coil domain of WNK4 mediates the downregulation of TRPV4. WNK4 and [[CAB39|calcium-binding protein 39 (Cab39)]] act together to activate transporters NKCC1 or NKCC2<ref>{{Cite journal|last=Ponce-Coria, J., Markadieu, N., Austin, T. M., Flammang, L., Rios, K., Welling, P. A., Delpire, E.|first=|date=|year=2014|title=A novel Ste20-related proline/alanine-rich kinase (SPAK)-independent pathway involving calcium-binding protein 39 (Cab39) and serine threonine kinase with no lysine member 4 (WNK4) in the activation of Na-K-Cl cotransporters.|url=|journal=J. Biol. Chem.|volume=289|issue=25|pages=17680-17688.|doi=10.1074/jbc.M113.540518|pmid=24811174|via=}}</ref>.

== Role in PHAII ==

=== PHAII mutations in WNK4 and the dysregulation of kinase activity ===
In 2001, four [[Missense mutation|missense mutations]] in the WNK4 gene were identified in patients with PHAII '''(Fig. 1''') <ref name=":1" />. Three of these mutations (E562K, D564A, and Q565E) are charge-changing substitutions in the acidic motif of WNK4, which are conserved among all members of the WNK family in human and rodent species. The fourth substitution (R1185C) is located in the [[Calmodulin binding domain|calmodulin-binding domain]] near the second [[Coiled coil|coiled-coil]] domain. Few other PHAII mutations in WNK4 have also been reported. Examples of these mutations include E560G<ref>{{Cite journal|last=Brooks, A.M., Owens, M., Sayer, J. A., Salzmann, M., Ellard, S., Vaidya, B.|first=|date=|year=2012|title=Pseudohypoaldosteronism type 2 presenting with hypertension and hyperkalaemia due to a novel mutation in the WNK4 gene.|url=|journal=QJM|volume=105|issue=8|pages=791-794|doi=10.1093/qjmed/hcr119|pmid=21764813|via=}}</ref>, P561L<ref>{{Cite journal|last=Gong, H., Tang, Z., Yang, Y., Sun, L., Zhang, W., Wang, W., Cui, B., Ning, G.|first=|date=|year=2008|title=A patient with pseudohypoaldosteronism type II caused by a novel mutation in WNK4 gene.|url=|journal=Endocrine|volume=33|issue=3|pages=230-234|doi=10.1007/s12020-008-9084-8|pmid=19016006|via=}}</ref>,  and D564H<ref>{{Cite journal|last=Golbang, A.P., Murthy, M., Hamad, A., Liu, C. H., Cope, G., van't Hoff, W., Cuthbert, A., O'Shaughnessy, K. M.|first=|date=|year=2005|title=A new kindred with pseudohypoaldosteronism type II and a novel mutation (564D>H) in the acidic motif of the WNK4 gene.|url=|journal=Hypertension|volume=46|issue=2|pages=295-300|doi=10.1161/01.HYP.0000174326.96918.d6|pmid=15998707|via=}}</ref>, all of which are located close to the acidic motif; and the K1169E <ref>{{Cite journal|last=Zhang, C., Wang, Z., Xie, J., Yan, F., Wang, W., Feng, X., Zhang, W., Chen, N.|first=|date=|year=2011|title=Identification of a novel WNK4 mutation in Chinese patients with pseudohypoaldosteronism type II|url=|journal=Nephron Physiol.|volume=118|issue=3|pages=53-61|doi=10.1159/000321879|pmid=21196779|via=}}</ref> which is located between the [[Coiled coil|coiled-coil]] 2 and the [[Calmodulin binding domain|calmodulin-binding domain]].
[[File:WNK4 PHAII.jpg|thumb|365x365px|'''Fig. 3. Proposed mechanisms by which PHAII-causing mutations in WNK4, KLHL3, and Cullin 3 lead to increased kinase activity of WNK4.''' ''Left panel'', under physiological condition, angiotensin II elicits an increase in intracellular Ca<sup>2+</sup>.  Ca<sup>2+</sup> ions interact with the acidic motif of WNK4 and increase the kinase activity. Ca<sup>2+</sup>/calmodulin (CaM) also binds to the C-terminal CaM-binding domain and relieves the inhibition of the kinase activity of WNK4. WNK4 protein is degraded by the KLHL3-Cullin 3 ubiquitin E3 ligase. ''Right panel'', under PHAII condition, PHAII mutations in the acidic motif mimic the Ca<sup>2+</sup> binding state and lead to an increase in kinase activity.  The R1185C mutation relieves the inhibitory effect of the C-terminal domain on the kinase activity of WNK4. Mutations in KLHL3 or Cullin 3 impair the degradation of WNK4 protein, leading to an increase in total kinase activity. ]]
The PHAII mutations appear to disrupt mechanisms underlying Ca<sup>2+</sup>-sensitivity of WNK4 kinase. Two mechanisms are important in this regard. Firstly, The PHAII-causing mutations in the acidic motif make the kinase domain insensitive to Ca<sup>2+</sup> concentration. The acidic motif of WNK4 potentially acts as a Ca<sup>2+</sup> sensor and WNK4 kinase activity rises when Ca<sup>2+</sup> concentration is elevated. This has been demonstrated using isolated WNK4 kinase domain truncated to contain the acidic motif<ref name=":4" />. The kinase activity is elevated when a PHAII-causing mutation is present in the acidic motif, similar to what is observed in a Ca<sup>2+</sup>-binding state ('''Fig. 3'''). Secondly, the WNK4 C-terminal region containing the calmodulin-binding domain and multiple SGK1 phosphorylation sites inhibits WNK4 activity at resting state<ref name=":6">{{Cite journal|last=Na, T., Wu, G., Zhang, W., Dong, W. J., Peng, J. B.|first=|date=|year=2013|title=Disease-causing R1185C mutation of WNK4 disrupts a regulatory mechanism involving calmodulin binding and SGK1 phosphorylation sites.|url=|journal=Am. J. Physiol. Renal Physiol.|volume=304|issue=1|pages=F8-F18|doi=10.1152/ajprenal.00284.2012|pmid=23054253|via=}}</ref>. However, when Ca<sup>2+</sup> levels are elevated, Ca<sup>2+</sup>/calmodulin complex binds to the C-terminal region, derepressing WNK4 kinase activity. Additionally, the RFXV motif is believed to interact with the autoinhibitory domain and subsequently triggers a conformational change that brings the C-terminal and kinase domain close for the inhibitory effect to take place. [[Angiotensin|Angiotensin II]] increases the SPAK phosphorylation and activates NCC through a WNK-dependent mechanism<ref>{{Cite journal|last=San-Cristobal, P., Pacheco-Alvarez, D., Richardson, C., et al.,|first=|date=|year=2009|title=Angiotensin II signaling increases activity of the renal Na-Cl cotransporter through a WNK4-SPAK-dependent pathway.|url=|journal=Proc. Natl. Acad. Sci. USA|volume=106|issue=11|pages=4384-4389.|doi=10.1073/pnas.0813238106|pmid=19240212|via=}}</ref>. The activation of SPAK and NCC by angiotensin II is abrogated by WNK4 knockdown<ref>{{Cite journal|last=Castañeda-Bueno, M., Cervantes-Pérez, L. G., Vázquez, N., et al.,|first=|date=|year=2012|title=Activation of the renal Na+:Cl- cotransporter by angiotensin II is a WNK4-dependent process.|url=|journal=Proc. Natl. Acad. Sci. USA|volume=109|issue=20|pages=7929-7934.|doi=10.1073/pnas.1200947109|pmid=22550170|via=}}</ref>. Activation of [[angiotensin II receptor]] AT1 couples to [[Gq alpha subunit|Gq/11]] to activate [[phospholipase C]] and to increase the intracellular Ca<sup>2+</sup> concentration. An increase in Ca<sup>2+</sup> concentration then elevates WNK4 activity through mechanisms described above ('''Fig. 3''', left panel). The PHAII-causing mutations in the acidic motif and the R1185C mutation in the [[Calmodulin binding domain|calmodulin-binding domain]] constitutively activate the WNK4 kinase domain allowing it to function despite the absence of angiotensin II ('''Fig. 3''', right panel).   

[[Angiotensin]] II stimulates the secretion of [[aldosterone]], which induces [[SGK1]].  SGK1 influences both the WNK-SPAK-NCC <ref>{{Cite journal|last=Chiga, M., Rai, T., Yang, S. S., Ohta, A., Takizawa, T., Sasaki, S., Uchida, S.|first=|date=|year=2008|title=Dietary salt regulates the phosphorylation of OSR1/SPAK kinases and the sodium chloride cotransporter through aldosterone.|url=|journal=Kidney Int.|volume=74|issue=11|pages=1403-1409|doi=10.1038/ki.2008.451|pmid=18800028|via=}}</ref> and SGK1-ENaC signaling cascades <ref>{{Cite journal|last=Rozansky, D.J., Cornwall, T., Subramanya, A. R., et al.,|first=|date=|year=2009|title=Aldosterone mediates activation of the thiazide-sensitive Na-Cl cotransporter through an SGK1 and WNK4 signaling pathway.|url=|journal=J. Clin. Invest.|volume=119|issue=9|pages=2601-2612|doi=10.1172/JCI38323|pmid=19690383|via=}}</ref>. There are multiple SGK1 phosphorylation sites in the C-terminal region of WNK4 located within or close to the [[Calmodulin binding domain|calmodulin-binding domain]]. SGK1-mediated phosphorylation of these sites is thought to disrupt the effect of the C-terminal inhibitory domain and concomitantly increase WNK4 kinase activity<ref name=":6" />. The alteration of SGK1 phosphorylation by the R1185C mutation is another indication that the mutation disrupts the C-terminal inhibitory mechanism in WNK4 ('''Fig. 3''', right panel).  

=== '''PHAII mutations in KLHL3 and Cullin 3 and dysregulation regulation of WNK4 protein abundance''' ===
Besides ''WNK1'' and ''WNK4'', mutations in two other genes, ''CUL3'' (encoding [[CUL3|Cullin 3]]) and ''KLHL3'' (encoding [[Kelch-like protein 3|Kelch Like Family Member 3]]) have been found in patients with PHAII<ref>{{Cite journal|last=Boyden, L.M., Choi, M., Choate, K. A., et al.,|first=|date=|year=2012|title=Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities.|url=|journal=Nature|volume=482|issue=7383|pages=98-102|doi=10.1038/nature10814|pmid=22266938|via=}}</ref><ref>{{Cite journal|last=Louis-Dit-Picard, H., Barc, J., Trujillano, D., et al.,|first=|date=|year=2012|title=KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron.|url=|journal=Nat. Genet.|volume=44|issue=4|pages=456-460|doi=10.1038/ng.2218|pmid=22406640|via=}}</ref>. These two proteins are part of the [[Ubiquitin ligase|ubiquitin E3 ligase]] complex involved in the ubiquitin-mediated degradation of [[WNK1]] and WNK4. The PHAII-causing mutations in [[Kelch-like protein 3|KLHL3]] and [[CUL3|cullin 3]] prevent interactions of these proteins with each other and with WNK1/4. The mutations on these proteins impair the degradation of WNK1/4. This in turn increases the protein abundance of WNK1/4 and concomitantly enhances total kinase activity<ref>{{Cite journal|last=Wakabayashi, M., Mori, T., Isobe. K., et al.,|first=|date=|year=2013|title=Impaired KLHL3-mediated ubiquitination of WNK4 causes human hypertension.|url=|journal=Cell Rep.|volume=3|issue=3|pages=858-868|doi=10.1016/j.celrep.2013.02.024|pmid=23453970|via=}}</ref>. The increased WNK4 kinase activity leads to the [[hyperactivation]] of NCC through WNK4-SPAK and/or the OSR1-NCC cascades ultimately resulting in the retention of sodium and potassium by the kidney.


=== '''The pathophysiological consequence of elevated WNK4 activity''' ===
The WNK4 gene encodes a [[serine-threonine kinase]] expressed in [[distal convoluted tubule|distal nephron]].<ref name="entrez"/> Its primary role in renal physiology is as a molecular switch between the [[Angiotensin#Angiotensin II|angiotensin II]]–[[aldosterone]] mediated volume retention and the aldosterone mediated potassium wasting. This is achieved by regulating the [[sodium-chloride symporter]] (NCC), that is uniquely expressed in the distal nephron and is sensitive to [[thiazide]] type diuretics.<ref name="pmid18547946">{{cite journal |vauthors=San-Cristobal P, de los Heros P, Ponce-Coria J, Moreno E, Gamba G | title = WNK kinases, renal ion transport and hypertension | journal = Am. J. Nephrol. | volume = 28 | issue = 5 | pages = 860–70 | year = 2008 | pmid = 18547946 | doi = 10.1159/000139639 | url = | issn = | pmc = 2820349 }}</ref>
[[File:Na K.jpg|thumb|'''Fig. 4. The physiological consequence of elevated NCC activity due to the increased WNK4 kinase activity in PHAII.'''  Shown are the renal tubule segments containing the distal convoluted tubule and the aldosterone-sensitive connecting tubule and collecting duct under normal and PHAII conditions due to mutations in WNK4, KLHL3, or cullin 3. The net effects of these mutations are to elevate WNK4 kinase activity in the distal convoluted tubule. This leads to the increased reabsorption of Na<sup>+</sup> in the distal convoluted tubule and thereby less Na<sup>+</sup> reabsorption and K<sup>+</sup> secretion. The consequence is the retention of Na<sup>+</sup> and K<sup>+</sup>, leading to high blood pressure and hyperkalemia over time. ]]
The primary effect of elevated WNK4 kinase activity is the increase of NCC-mediated sodium reabsorption in the [[distal convoluted tubule]] of the kidney. The increase in sodium reabsorption in this segment of the [[nephron]] reduces the sodium load in the [[Collecting duct system|collecting duct]], where sodium reabsorption by the [[Epithelial sodium channel|ENaC]] provides the driving force for potassium secretion through [[ROMK]] ('''Fig.''' 4).  The sodium reabsorption by hyperactive [[Sodium chloride cotransporter|NCC]] overrides the loss of reabsorption by [[Epithelial sodium channel|ENaC]], and the net effect is moderate sodium retention. Over time, this potentially contributes to the elevated blood pressure observed in PHAII patients. The reduction of secretion of potassium by the [[ROMK]] contributes to the development of [[hyperkalemia]]. The direct effects of elevated WNK4 activity on other channels and transporters, such as ENaC, ROMK, and Ca<sup>2+</sup>-activated  maxi K<sup>+</sup> channels, may also contribute to the pathogenesis of PHAII; however, the primary features of PHAII could be explained by the gain-of-function of NCC.


Under basal conditions (low circulating Ang II and low Aldosterone), WNK4 will inhibit NCC function. It has been proposed that in the event of [[hyperkalemia]] and an increased secretion of aldosterone (which will upregulate both ENac and ROMK), this inhibition of NCC, will allow an increase in the arrival of sodium to the distal nephron (rich in [[Epithelial sodium channel|ENaC]] and [[ROMK]]) which will allow the exchange of sodium for potassium ions, thereby reducing plasma potassium levels, without increasing [[sodium chloride]] retention (which is always accompanied by volume expansion). Furthermore, it has been proposed that in the presence of AngII the WNK4 mediated NCC inhibition will be suppressed thereby increasing sodium-chloride reabsorption in the distal convoluted tubule. This along with the concomitant increase in passive water reabsorption due to the increased salt load in the distal convoluted tubule cells will ultimately increase circulating volume.<ref name="pmid19240212">{{cite journal |vauthors=San-Cristobal P, Pacheco-Alvarez D, Richardson C, Ring AM, Vazquez N, Rafiqi FH, Chari D, Kahle KT, Leng Q, Bobadilla NA, Hebert SC, Alessi DR, Lifton RP, Gamba G | title = Angiotensin II signaling increases activity of the renal Na-Cl cotransporter through a WNK4-SPAK-dependent pathway | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 106 | issue = 11 | pages = 4384–9 |date=March 2009 | pmid = 19240212 | pmc = 2647339 | doi = 10.1073/pnas.0813238106 | url = | issn = }}</ref>


== References ==
== References ==
{{reflist}}
{{reflist}}


== Further reading ==
{{refbegin | 2}}
*{{cite journal |vauthors=Subramanya AR, Yang CL, McCormick JA, Ellison DH |title=WNK kinases regulate sodium chloride and potassium transport by the aldosterone-sensitive distal nephron. |journal=Kidney Int. |volume=70 |issue= 4 |pages= 630–4 |year= 2006 |pmid= 16820787 |doi= 10.1038/sj.ki.5001634 |doi-access= free }}
*{{cite journal |vauthors=Peng JB, Warnock DG |title=WNK4-mediated regulation of renal ion transport proteins. |journal=Am. J. Physiol. Renal Physiol. |volume=293 |issue= 4 |pages= F961–73 |year= 2007 |pmid= 17634397 |doi= 10.1152/ajprenal.00192.2007 }}
*{{cite journal |vauthors=Bonaldo MF, Lennon G, Soares MB |title=Normalization and subtraction: two approaches to facilitate gene discovery. |journal=Genome Res. |volume=6 |issue= 9 |pages= 791–806 |year= 1997 |pmid= 8889548 |doi=10.1101/gr.6.9.791 |doi-access=free }}
*{{cite journal |vauthors=Wilson FH, Disse-Nicodème S, Choate KA, etal |title=Human hypertension caused by mutations in WNK kinases. |journal=Science |volume=293 |issue= 5532 |pages= 1107–12 |year= 2001 |pmid= 11498583 |doi= 10.1126/science.1062844 }}
*{{cite journal |vauthors=Veríssimo F, Jordan P |title=WNK kinases, a novel protein kinase subfamily in multi-cellular organisms. |journal=Oncogene |volume=20 |issue= 39 |pages= 5562–9 |year= 2001 |pmid= 11571656 |doi= 10.1038/sj.onc.1204726 |doi-access= free }}
*{{cite journal |vauthors=Wilson FH, Kahle KT, Sabath E, etal |title=Molecular pathogenesis of inherited hypertension with hyperkalemia: the Na-Cl cotransporter is inhibited by wild-type but not mutant WNK4. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=100 |issue= 2 |pages= 680–4 |year= 2003 |pmid= 12515852 |doi= 10.1073/pnas.242735399 | pmc=141056 }}
*{{cite journal |vauthors=Erlich PM, Cui J, Chazaro I, etal |title=Genetic variants of WNK4 in whites and African Americans with hypertension. |journal=Hypertension |volume=41 |issue= 6 |pages= 1191–5 |year= 2003 |pmid= 12719438 |doi= 10.1161/01.HYP.0000070025.30572.91 |citeseerx= 10.1.1.550.357 }}
*{{cite journal |vauthors=Piechotta K, Garbarini N, England R, Delpire E |title=Characterization of the interaction of the stress kinase SPAK with the Na<sup>+</sup>-K<sup>+</sup>-2Cl<sup>−</sup> cotransporter in the nervous system: evidence for a scaffolding role of the kinase. |journal=J. Biol. Chem. |volume=278 |issue= 52 |pages= 52848–56 |year= 2004 |pmid= 14563843 |doi= 10.1074/jbc.M309436200 |doi-access= free }}
*{{cite journal |vauthors=Ota T, Suzuki Y, Nishikawa T, etal |title=Complete sequencing and characterization of 21,243 full-length human cDNAs. |journal=Nat. Genet. |volume=36 |issue= 1 |pages= 40–5 |year= 2004 |pmid= 14702039 |doi= 10.1038/ng1285 |doi-access= free }}
*{{cite journal |vauthors=Kahle KT, Gimenez I, Hassan H, etal |title=WNK4 regulates apical and basolateral Cl<sup>−</sup> flux in extrarenal epithelia. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=101 |issue= 7 |pages= 2064–9 |year= 2004 |pmid= 14769928 |doi= 10.1073/pnas.0308434100 | pmc=357052 }}
*{{cite journal |vauthors=Yamauchi K, Rai T, Kobayashi K, etal |title=Disease-causing mutant WNK4 increases paracellular chloride permeability and phosphorylates claudins. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=101 |issue= 13 |pages= 4690–4 |year= 2004 |pmid= 15070779 |doi= 10.1073/pnas.0306924101 | pmc=384808 }}
*{{cite journal |vauthors=Kamide K, Takiuchi S, Tanaka C, etal |title=Three novel missense mutations of WNK4, a kinase mutated in inherited hypertension, in Japanese hypertensives: implication of clinical phenotypes. |journal=Am. J. Hypertens. |volume=17 |issue= 5 Pt 1 |pages= 446–9 |year= 2004 |pmid= 15110905 |doi= 10.1016/j.amjhyper.2003.12.020 |doi-access= free }}
*{{cite journal |vauthors=Mayan H, Munter G, Shaharabany M, etal |title=Hypercalciuria in familial hyperkalemia and hypertension accompanies hyperkalemia and precedes hypertension: description of a large family with the Q565E WNK4 mutation. |journal=J. Clin. Endocrinol. Metab. |volume=89 |issue= 8 |pages= 4025–30 |year= 2004 |pmid= 15292344 |doi= 10.1210/jc.2004-0037 |doi-access= free }}
*{{cite journal |vauthors=Fu Y, Subramanya A, Rozansky D, Cohen DM |title=WNK kinases influence TRPV4 channel function and localization. |journal=Am. J. Physiol. Renal Physiol. |volume=290 |issue= 6 |pages= F1305–14 |year= 2006 |pmid= 16403833 |doi= 10.1152/ajprenal.00391.2005 }}
*{{cite journal |vauthors=Cai H, Cebotaru V, Wang YH, etal |title=WNK4 kinase regulates surface expression of the human sodium chloride cotransporter in mammalian cells. |journal=Kidney Int. |volume=69 |issue= 12 |pages= 2162–70 |year= 2006 |pmid= 16688122 |doi= 10.1038/sj.ki.5000333 |doi-access= free }}
*{{cite journal |vauthors=Jiang Y, Ferguson WB, Peng JB |title=WNK4 enhances TRPV5-mediated calcium transport: potential role in hypercalciuria of familial hyperkalemic hypertension caused by gene mutation of WNK4. |journal=Am. J. Physiol. Renal Physiol. |volume=292 |issue= 2 |pages= F545–54 |year= 2007 |pmid= 17018846 |doi= 10.1152/ajprenal.00187.2006 }}
*{{cite journal |vauthors=Ring AM, Leng Q, Rinehart J, etal |title=An SGK1 site in WNK4 regulates Na<sup>+</sup> channel and K<sup>+</sup> channel activity and has implications for aldosterone signaling and K<sup>+</sup> homeostasis. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=104 |issue= 10 |pages= 4025–9 |year= 2007 |pmid= 17360471 |doi= 10.1073/pnas.0611728104 | pmc=1803763 }}
{{refend}}


==External links==
== External links ==
*[https://www.proteinatlas.org/ENSG00000126562-WNK4 HumanProteinAtlas/WNK4]
* [https://www.ncbi.nlm.nih.gov/books/NBK65707/ GeneReviews/NCBI/NIH/UW entry on Pseudohypoaldosteronism Type II]
*[https://www.genecards.org/cgi-bin/carddisp.pl?gene=WNK4 GeneCard/WNK4]
*[https://www.uniprot.org/uniprot/Q96J92 UniProt/WNK4]
*[https://www.omim.org/entry/601844 OMIM/WNK4] <br />


{{Serine/threonine-specific protein kinases}}
{{Serine/threonine-specific protein kinases}}

Revision as of 21:32, 15 June 2020

WNK4
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesWNK4, PHA2B, PRKWNK lysine deficient protein kinase 4
External IDsOMIM: 601844; MGI: 1917097; HomoloGene: 13020; GeneCards: WNK4; OMA:WNK4 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

65266

69847

Ensembl

ENSG00000126562

ENSMUSG00000035112

UniProt

Q96J92

Q80UE6

RefSeq (mRNA)

NM_032387
NM_001321299

NM_175638

RefSeq (protein)

NP_001308228
NP_115763

NP_783569

Location (UCSC)Chr 17: 42.78 – 42.8 MbChr 11: 101.15 – 101.17 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

The protein with-no-lysine [K] kinase 4 (WNK4) is a member of a serine-threonine kinase family that comprises of four members. The family was so named because unlike other serine/threonine kinases, WNKs are characterized by the lack of lysine in the subdomain II of the catalytic domain[5]. Instead, a lysine in the β2 strand of subdomain I of the catalytic domain is responsible for the kinase activity[5].

The WNK4 gene is located on chromosome 17q21-q22. It produces a 1,243-amino acid protein encoded by a 3,732-nucleotide open reading frame within a 4 kb cDNA transcript[6]. WNK4 protein is highly expressed in the distal convoluted tubule (DCT) and the cortical collecting duct (CDD) of the kidney[6]. WNK4 is also present in the brain, lungs, liver, heart, and colon of various mammalian species[7][8].

Gene mutations in WNN4 has been found in patients with pseudohypoaldosteronism type II (PHAII)[6], also known as familial hyperkalemic hypertension (FHHt)[9] or Gordon’s syndrome [10]. PHAII is an autosomal dominant hereditary disease characterized by hyperkalemia, hypertension, and metabolic acidosis. WNK4 plays a critical role in the regulation of various transporters and channels in the kidney. PHAII-causing mutations in WNK4 results in the dysregulation of renal sodium and potassium transporters and channels, leading to defects in sodium and potassium retention by the kidney, and in turn, elevated blood pressure and potassium level (hyperkalemia).   

Structure

The tertiary structure of WNK4 has not been elucidated to date. Nevertheless, several individual domain structures of the protein are identified. These include a kinase domain near the amino terminus followed by an autoinhibitory domain, an acidic motif, two coiled-coil domains, and a calmodulin-binding domain in the C-terminal segment (Fig. 1). The structures for the kinase and autoinhibitory domains of WNK1 have been identified. The high level of structural similarity between WNK4 and WNK1 has allowed the investigators to deduce key structural details of WNK4 based on insights gained from corresponding regions within WNK1. The kinase domain of WNK4 has an 83% sequence identity with that of WNK1. The overall fold of the kinase domain of WNK1 resembles those of other protein kinases that have a typical dual-domain architecture[11]. The C-terminal domain of WNK4 bears a high degree of similarity to other kinases within the family. On the other hand, the N-terminal domain is unique in having a six-stranded instead of a five-stranded β sheet to form a complete β barrel[11].

Fig. 1. Domain structure of WNK4 and the positions of the initially identified PHAII-causing mutations. The amino-acid (aa) positions of the domains are provided in parentheses. Some important PHAII mutations are localized in the acidic motif and calmodulin-binding domain, respectively.

A chloride ion binding site has been identified in the region 320DLG323 of the kinase domain in WNK4[12]. The binding of chloride binding in this region inhibits the activation of WNK4. The autoinhibitory domain is a homolog of the RFXV-binding PASK/FRAY homology 2 (PF2) domain[13]. Structural studies have revealed that the autoinhibitory domain consists of three β-strands and two α-helices[14]. Notably, the RFXV‐binding groove is formed by the β3-αA interface of WNK proteins where RFXV peptide ligand interacts directly with residues Phe524, Asp531, and Glu539 of WNK1[14]. The interaction between the RFXV motif and the autoinhibitory domain makes it possible for the C-terminal region of WNK4 to be in close proximity of the kinases domain and subsequently regulate its activity.



Function

Fig. 2. The WNK4-SPAK/OSR1-NCC phosphorylation cascade. WNK4 phosphorylates and activates SPAK/OSR1, which in turn phosphorylate and activates NCC. In this manner, WNK4 regulates sodium reabsorption in the distal convoluted tubule and downstream potassium secretion through its positive effects on NCC.  

As a typical kinase, the WNK4 accomplishes phosphorylation of its cognate substrate proteins by adding a phosphate moieties in an ATP-dependent manner.  This structural modification usually results in functional alterations of downstream substrates. Some currently known substrates of WNK4 includes kinases STE20-serine-proline alanine-rich kinase (SPAK) and oxidative stress response 1 kinase (OSR1), which in turn can phosphorylate and activate the thiazide-sensitive sodium-chloride cotransporter (NCC)[15] [16] (Fig. 2). Similarly, WNK4 activates NKCC1 and deactivate KCC2 through a SPAK-dependent mechanism[17]. The kinase activity of WNK4 has been demonstrated in vitro using the WNK4 kinase domain purified from E. coli [18]. This phosphorylation cascade is critical in regulating sodium and potassium homeostasis dysregulation of which is tied to the pathogenesis of PHAII.

In addition to NCC, WNK4 also regulates multiple ions channels and cotransporters in the kidney through various mechanisms. These include epithelial Na+ channel (ENaC), renal outer medullary potassium channel (ROMK), transient receptor potential vanilloid member 4 and 5 (TRPV4/5, calcium channels), Na-K-2Cl cotransporter 1 and 2 (NKCC1/2), K+-Cl− cotransporter type 2 (KCC2), and other channels/transporters. WNK4 inhibits functions of ENaC, ROMK, and TRPV4 by reducing the total and cell surface expression of these channels[19][20][21]. WNK4 enhances TRPV5 by increasing its forward trafficking to the plasma membrane in a kinase-dependent manner [22]. The inhibitory effect of WNK4 on ROMK is reversed by serum and glucocorticoid kinase 1 (SGK1) or by a corresponding phosphomimetic S1169D mutation on WNK4[20]. The N-terminal segment of WNK4 containing the kinase domain and acidic motif is required WNK-mediated inhibition of ROMK expression[23]. The second coiled-coil domain of WNK4 mediates the downregulation of TRPV4. WNK4 and calcium-binding protein 39 (Cab39) act together to activate transporters NKCC1 or NKCC2[24].

Role in PHAII

PHAII mutations in WNK4 and the dysregulation of kinase activity

In 2001, four missense mutations in the WNK4 gene were identified in patients with PHAII (Fig. 1) [6]. Three of these mutations (E562K, D564A, and Q565E) are charge-changing substitutions in the acidic motif of WNK4, which are conserved among all members of the WNK family in human and rodent species. The fourth substitution (R1185C) is located in the calmodulin-binding domain near the second coiled-coil domain. Few other PHAII mutations in WNK4 have also been reported. Examples of these mutations include E560G[25], P561L[26],  and D564H[27], all of which are located close to the acidic motif; and the K1169E [28] which is located between the coiled-coil 2 and the calmodulin-binding domain.

Fig. 3. Proposed mechanisms by which PHAII-causing mutations in WNK4, KLHL3, and Cullin 3 lead to increased kinase activity of WNK4. Left panel, under physiological condition, angiotensin II elicits an increase in intracellular Ca2+.  Ca2+ ions interact with the acidic motif of WNK4 and increase the kinase activity. Ca2+/calmodulin (CaM) also binds to the C-terminal CaM-binding domain and relieves the inhibition of the kinase activity of WNK4. WNK4 protein is degraded by the KLHL3-Cullin 3 ubiquitin E3 ligase. Right panel, under PHAII condition, PHAII mutations in the acidic motif mimic the Ca2+ binding state and lead to an increase in kinase activity.  The R1185C mutation relieves the inhibitory effect of the C-terminal domain on the kinase activity of WNK4. Mutations in KLHL3 or Cullin 3 impair the degradation of WNK4 protein, leading to an increase in total kinase activity.

The PHAII mutations appear to disrupt mechanisms underlying Ca2+-sensitivity of WNK4 kinase. Two mechanisms are important in this regard. Firstly, The PHAII-causing mutations in the acidic motif make the kinase domain insensitive to Ca2+ concentration. The acidic motif of WNK4 potentially acts as a Ca2+ sensor and WNK4 kinase activity rises when Ca2+ concentration is elevated. This has been demonstrated using isolated WNK4 kinase domain truncated to contain the acidic motif[18]. The kinase activity is elevated when a PHAII-causing mutation is present in the acidic motif, similar to what is observed in a Ca2+-binding state (Fig. 3). Secondly, the WNK4 C-terminal region containing the calmodulin-binding domain and multiple SGK1 phosphorylation sites inhibits WNK4 activity at resting state[29]. However, when Ca2+ levels are elevated, Ca2+/calmodulin complex binds to the C-terminal region, derepressing WNK4 kinase activity. Additionally, the RFXV motif is believed to interact with the autoinhibitory domain and subsequently triggers a conformational change that brings the C-terminal and kinase domain close for the inhibitory effect to take place. Angiotensin II increases the SPAK phosphorylation and activates NCC through a WNK-dependent mechanism[30]. The activation of SPAK and NCC by angiotensin II is abrogated by WNK4 knockdown[31]. Activation of angiotensin II receptor AT1 couples to Gq/11 to activate phospholipase C and to increase the intracellular Ca2+ concentration. An increase in Ca2+ concentration then elevates WNK4 activity through mechanisms described above (Fig. 3, left panel). The PHAII-causing mutations in the acidic motif and the R1185C mutation in the calmodulin-binding domain constitutively activate the WNK4 kinase domain allowing it to function despite the absence of angiotensin II (Fig. 3, right panel).   

Angiotensin II stimulates the secretion of aldosterone, which induces SGK1.  SGK1 influences both the WNK-SPAK-NCC [32] and SGK1-ENaC signaling cascades [33]. There are multiple SGK1 phosphorylation sites in the C-terminal region of WNK4 located within or close to the calmodulin-binding domain. SGK1-mediated phosphorylation of these sites is thought to disrupt the effect of the C-terminal inhibitory domain and concomitantly increase WNK4 kinase activity[29]. The alteration of SGK1 phosphorylation by the R1185C mutation is another indication that the mutation disrupts the C-terminal inhibitory mechanism in WNK4 (Fig. 3, right panel).  

PHAII mutations in KLHL3 and Cullin 3 and dysregulation regulation of WNK4 protein abundance

Besides WNK1 and WNK4, mutations in two other genes, CUL3 (encoding Cullin 3) and KLHL3 (encoding Kelch Like Family Member 3) have been found in patients with PHAII[34][35]. These two proteins are part of the ubiquitin E3 ligase complex involved in the ubiquitin-mediated degradation of WNK1 and WNK4. The PHAII-causing mutations in KLHL3 and cullin 3 prevent interactions of these proteins with each other and with WNK1/4. The mutations on these proteins impair the degradation of WNK1/4. This in turn increases the protein abundance of WNK1/4 and concomitantly enhances total kinase activity[36]. The increased WNK4 kinase activity leads to the hyperactivation of NCC through WNK4-SPAK and/or the OSR1-NCC cascades ultimately resulting in the retention of sodium and potassium by the kidney.

The pathophysiological consequence of elevated WNK4 activity

Fig. 4. The physiological consequence of elevated NCC activity due to the increased WNK4 kinase activity in PHAII.  Shown are the renal tubule segments containing the distal convoluted tubule and the aldosterone-sensitive connecting tubule and collecting duct under normal and PHAII conditions due to mutations in WNK4, KLHL3, or cullin 3. The net effects of these mutations are to elevate WNK4 kinase activity in the distal convoluted tubule. This leads to the increased reabsorption of Na+ in the distal convoluted tubule and thereby less Na+ reabsorption and K+ secretion. The consequence is the retention of Na+ and K+, leading to high blood pressure and hyperkalemia over time.

The primary effect of elevated WNK4 kinase activity is the increase of NCC-mediated sodium reabsorption in the distal convoluted tubule of the kidney. The increase in sodium reabsorption in this segment of the nephron reduces the sodium load in the collecting duct, where sodium reabsorption by the ENaC provides the driving force for potassium secretion through ROMK (Fig. 4).  The sodium reabsorption by hyperactive NCC overrides the loss of reabsorption by ENaC, and the net effect is moderate sodium retention. Over time, this potentially contributes to the elevated blood pressure observed in PHAII patients. The reduction of secretion of potassium by the ROMK contributes to the development of hyperkalemia. The direct effects of elevated WNK4 activity on other channels and transporters, such as ENaC, ROMK, and Ca2+-activated  maxi K+ channels, may also contribute to the pathogenesis of PHAII; however, the primary features of PHAII could be explained by the gain-of-function of NCC.


References

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