5o21

Structural highlights

Function

[WNK3_HUMAN] Serine/threonine kinase which plays an important role in the regulation of electrolyte homeostasis, cell signaling, survival and proliferation. Acts as an activator and inhibitor of sodium-coupled chloride cotransporters and potassium-coupled chloride cotransporters respectively (PubMed:16275913, PubMed:16275911, PubMed:16357011). Phosphorylates WNK4. Regulates the phosphorylation of SLC12A1 and SLC12A2. Increases Ca(2+) influx mediated by TRPV5 and TRPV6 by enhancing their membrane expression level via a kinase-dependent pathway (PubMed:18768590). Inhibits the activity of KCNJ1 by decreasing its expression at the cell membrane in a non-catalytic manner.^{[1] [2] [3] [4] [5] [6] [7]} Isoform 1, isoform 2, isoform 3 and isoform 4 stimulate the activity of SLC12A1, SLC12A2 and SLC12A3 and inhibit the activity of SLC12A4, SLC12A5, SLC12A6 and SLC12A7. According to PubMed:19470686, isoform 1 inhibits the activity of SLC12A3.^{[8] [9]}

References

1. ↑ Kahle KT, Rinehart J, de Los Heros P, Louvi A, Meade P, Vazquez N, Hebert SC, Gamba G, Gimenez I, Lifton RP. WNK3 modulates transport of Cl- in and out of cells: implications for control of cell volume and neuronal excitability. Proc Natl Acad Sci U S A. 2005 Nov 15;102(46):16783-8. Epub 2005 Nov 7. PMID:16275911 doi:http://dx.doi.org/10.1073/pnas.0508307102
2. ↑ Rinehart J, Kahle KT, de Los Heros P, Vazquez N, Meade P, Wilson FH, Hebert SC, Gimenez I, Gamba G, Lifton RP. WNK3 kinase is a positive regulator of NKCC2 and NCC, renal cation-Cl- cotransporters required for normal blood pressure homeostasis. Proc Natl Acad Sci U S A. 2005 Nov 15;102(46):16777-82. Epub 2005 Nov 7. PMID:16275913 doi:http://dx.doi.org/10.1073/pnas.0508303102
3. ↑ Leng Q, Kahle KT, Rinehart J, MacGregor GG, Wilson FH, Canessa CM, Lifton RP, Hebert SC. WNK3, a kinase related to genes mutated in hereditary hypertension with hyperkalaemia, regulates the K+ channel ROMK1 (Kir1.1). J Physiol. 2006 Mar 1;571(Pt 2):275-86. Epub 2005 Dec 15. PMID:16357011 doi:http://dx.doi.org/10.1113/jphysiol.2005.102202
4. ↑ Verissimo F, Silva E, Morris JD, Pepperkok R, Jordan P. Protein kinase WNK3 increases cell survival in a caspase-3-dependent pathway. Oncogene. 2006 Jul 13;25(30):4172-82. Epub 2006 Feb 27. PMID:16501604 doi:http://dx.doi.org/10.1038/sj.onc.1209449
5. ↑ Yang CL, Zhu X, Ellison DH. The thiazide-sensitive Na-Cl cotransporter is regulated by a WNK kinase signaling complex. J Clin Invest. 2007 Nov;117(11):3403-11. PMID:17975670 doi:10.1172/JCI32033
6. ↑ Zhang W, Na T, Peng JB. WNK3 positively regulates epithelial calcium channels TRPV5 and TRPV6 via a kinase-dependent pathway. Am J Physiol Renal Physiol. 2008 Nov;295(5):F1472-84. doi:, 10.1152/ajprenal.90229.2008. Epub 2008 Sep 3. PMID:18768590 doi:http://dx.doi.org/10.1152/ajprenal.90229.2008
7. ↑ Heise CJ, Xu BE, Deaton SL, Cha SK, Cheng CJ, Earnest S, Sengupta S, Juang YC, Stippec S, Xu Y, Zhao Y, Huang CL, Cobb MH. Serum and glucocorticoid-induced kinase (SGK) 1 and the epithelial sodium channel are regulated by multiple with no lysine (WNK) family members. J Biol Chem. 2010 Aug 13;285(33):25161-7. doi: 10.1074/jbc.M110.103432. Epub 2010, Jun 4. PMID:20525693 doi:10.1074/jbc.M110.103432
8. ↑ Glover M, Zuber AM, O'Shaughnessy KM. Renal and brain isoforms of WNK3 have opposite effects on NCCT expression. J Am Soc Nephrol. 2009 Jun;20(6):1314-22. doi: 10.1681/ASN.2008050542. Epub 2009 , May 21. PMID:19470686 doi:http://dx.doi.org/10.1681/ASN.2008050542
9. ↑ Cruz-Rangel S, Melo Z, Vazquez N, Meade P, Bobadilla NA, Pasantes-Morales H, Gamba G, Mercado A. Similar effects of all WNK3 variants on SLC12 cotransporters. Am J Physiol Cell Physiol. 2011 Sep;301(3):C601-8. doi:, 10.1152/ajpcell.00070.2011. Epub 2011 May 25. PMID:21613606 doi:http://dx.doi.org/10.1152/ajpcell.00070.2011