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{{Infobox_gene}}
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'''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>
| update_page = yes
| require_manual_inspection = no
| update_protein_box = yes
| update_summary = yes
| update_citations = yes
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== Function ==
{{GNF_Protein_box
| image =
| image_source =
| PDB =
| Name = WNK lysine deficient protein kinase 4
| HGNCid = 14544
| Symbol = WNK4
| AltSymbols =; PHA2B; PRKWNK4
| OMIM = 601844
| ECnumber = 
| Homologene = 13020
| MGIid = 1917097
| Function = {{GNF_GO|id=GO:0000166 |text = nucleotide binding}} {{GNF_GO|id=GO:0004674 |text = protein serine/threonine kinase activity}} {{GNF_GO|id=GO:0005524 |text = ATP binding}} {{GNF_GO|id=GO:0016740 |text = transferase activity}}
| Component = {{GNF_GO|id=GO:0005923 |text = tight junction}}
| Process = {{GNF_GO|id=GO:0006468 |text = protein amino acid phosphorylation}} {{GNF_GO|id=GO:0006811 |text = ion transport}} {{GNF_GO|id=GO:0007243 |text = protein kinase cascade}} {{GNF_GO|id=GO:0050794 |text = regulation of cellular process}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 65266
    | Hs_Ensembl = ENSG00000126562
    | Hs_RefseqProtein = NP_115763
    | Hs_RefseqmRNA = NM_032387
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 17
    | Hs_GenLoc_start = 38186222
    | Hs_GenLoc_end = 38202587
    | Hs_Uniprot = Q96J92
    | Mm_EntrezGene = 69847
    | Mm_Ensembl = 
    | Mm_RefseqmRNA = NM_175638
    | Mm_RefseqProtein = NP_783569
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 
    | Mm_GenLoc_start = 
    | Mm_GenLoc_end = 
    | Mm_Uniprot = 
  }}
}}
'''WNK lysine deficient protein kinase 4''', also known as '''WNK4''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: WNK4 WNK lysine deficient protein kinase 4| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=65266| accessdate = }}</ref>


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
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>
{{PBB_Summary
| section_title =
| summary_text = The WNK4 gene encodes a serine-threonine kinase expressed in distal nephron.[supplied by OMIM]<ref name="entrez">{{cite web | title = Entrez Gene: WNK4 WNK lysine deficient protein kinase 4| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=65266| accessdate = }}</ref>
}}


==References==
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 reabsortion due to the increased salt load in the distal convluted 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>
{{reflist|2}}
 
==Further reading==
== References ==
{{reflist}}
 
== Further reading ==
{{refbegin | 2}}
{{refbegin | 2}}
{{PBB_Further_reading
*{{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 }}
| citations =
*{{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 | author=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 }}
*{{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 }}
*{{cite journal | author=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=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 | author=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= }}
*{{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 }}
*{{cite journal  | author=Wilson FH, Disse-Nicodème S, Choate KA, ''et al.'' |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=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 | author=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 }}
*{{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 }}
*{{cite journal  | author=Wilson FH, Kahle KT, Sabath E, ''et al.'' |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 }}
*{{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 }}
*{{cite journal  | author=Erlich PM, Cui J, Chazaro I, ''et al.'' |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 }}
*{{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 }}
*{{cite journal | author=Piechotta K, Garbarini N, England R, Delpire E |title=Characterization of the interaction of the stress kinase SPAK with the Na+-K+-2Cl- 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 }}
*{{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  | author=Ota T, Suzuki Y, Nishikawa T, ''et al.'' |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 }}
*{{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  | author=Kahle KT, Gimenez I, Hassan H, ''et al.'' |title=WNK4 regulates apical and basolateral Cl- 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 }}
*{{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 }}
*{{cite journal  | author=Yamauchi K, Rai T, Kobayashi K, ''et al.'' |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 }}
*{{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 }}
*{{cite journal  | author=Kamide K, Takiuchi S, Tanaka C, ''et al.'' |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 }}
*{{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  | author=Mayan H, Munter G, Shaharabany M, ''et al.'' |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 }}
*{{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 }}
*{{cite journal | author=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=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  | author=Cai H, Cebotaru V, Wang YH, ''et al.'' |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 }}
*{{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 }}
*{{cite journal | author=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  | author=Ring AM, Leng Q, Rinehart J, ''et al.'' |title=An SGK1 site in WNK4 regulates Na+ channel and K+ channel activity and has implications for aldosterone signaling and K+ 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 }}
}}
{{refend}}
{{refend}}


{{protein-stub}}
==External links==
{{WikiDoc Sources}}
* [https://www.ncbi.nlm.nih.gov/books/NBK65707/ GeneReviews/NCBI/NIH/UW entry on Pseudohypoaldosteronism Type II]
 
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Revision as of 22:45, 17 September 2017

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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RefSeq (protein)

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Location (UCSC)n/an/a
PubMed searchn/an/a
Wikidata
View/Edit Human

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.[1]

Function

The WNK4 gene encodes a serine-threonine kinase expressed in distal nephron.[1] Its primary role in renal physiology is as a molecular switch between the 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.[2]

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 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 reabsortion due to the increased salt load in the distal convluted tubule cells will ultimately increase circulating volume.[3]

References

  1. ↑ 1.0 1.1 "Entrez Gene: WNK4 WNK lysine deficient protein kinase 4".
  2. ↑ San-Cristobal P, de los Heros P, Ponce-Coria J, Moreno E, Gamba G (2008). "WNK kinases, renal ion transport and hypertension". Am. J. Nephrol. 28 (5): 860–70. doi:10.1159/000139639. PMC 2820349. PMID 18547946.
  3. ↑ 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 (March 2009). "Angiotensin II signaling increases activity of the renal Na-Cl cotransporter through a WNK4-SPAK-dependent pathway". Proc. Natl. Acad. Sci. U.S.A. 106 (11): 4384–9. doi:10.1073/pnas.0813238106. PMC 2647339. PMID 19240212.

Further reading

External links


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