6fbk

Structural highlights

Disease

[WNK1_HUMAN] Hereditary sensory and autonomic neuropathy type 2;Pseudohypoaldosteronism type 2C. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry.

Function

[WNK2_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. Activates SLC12A2, SCNN1A, SCNN1B, SCNN1D and SGK1 and inhibits SLC12A5. Negatively regulates the EGF-induced activation of the ERK/MAPK-pathway and the downstream cell cycle progression. Affects MAPK3/MAPK1 activity by modulating the activity of MAP2K1 and this modulation depends on phosphorylation of MAP2K1 by PAK1. WNK2 acts by interfering with the activity of PAK1 by controlling the balance of the activity of upstream regulators of PAK1 activity, RHOA and RAC1, which display reciprocal activity.^{[1] [2] [3]} [WNK1_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. Activates SCNN1A, SCNN1B, SCNN1D and SGK1. Controls sodium and chloride ion transport by inhibiting the activity of WNK4, by either phosphorylating the kinase or via an interaction between WNK4 and the autoinhibitory domain of WNK1. WNK4 regulates the activity of the thiazide-sensitive Na-Cl cotransporter, SLC12A3, by phosphorylation. WNK1 may also play a role in actin cytoskeletal reorganization. Phosphorylates NEDD4L.^{[4] [5]}

References

1. ↑ Moniz S, Verissimo F, Matos P, Brazao R, Silva E, Kotelevets L, Chastre E, Gespach C, Jordan P. Protein kinase WNK2 inhibits cell proliferation by negatively modulating the activation of MEK1/ERK1/2. Oncogene. 2007 Sep 6;26(41):6071-81. doi: 10.1038/sj.onc.1210706. Epub 2007 Jul, 30. PMID:17667937 doi:http://dx.doi.org/10.1038/sj.onc.1210706
2. ↑ Moniz S, Matos P, Jordan P. WNK2 modulates MEK1 activity through the Rho GTPase pathway. Cell Signal. 2008 Oct;20(10):1762-8. doi: 10.1016/j.cellsig.2008.06.002. Epub, 2008 Jun 14. PMID:18593598 doi:http://dx.doi.org/10.1016/j.cellsig.2008.06.002
3. ↑ Rinehart J, Vazquez N, Kahle KT, Hodson CA, Ring AM, Gulcicek EE, Louvi A, Bobadilla NA, Gamba G, Lifton RP. WNK2 kinase is a novel regulator of essential neuronal cation-chloride cotransporters. J Biol Chem. 2011 Aug 26;286(34):30171-80. doi: 10.1074/jbc.M111.222893. Epub, 2011 Jul 6. PMID:21733846 doi:http://dx.doi.org/10.1074/jbc.M111.222893
4. ↑ Moore TM, Garg R, Johnson C, Coptcoat MJ, Ridley AJ, Morris JD. PSK, a novel STE20-like kinase derived from prostatic carcinoma that activates the c-Jun N-terminal kinase mitogen-activated protein kinase pathway and regulates actin cytoskeletal organization. J Biol Chem. 2000 Feb 11;275(6):4311-22. PMID:10660600
5. ↑ Lafreniere RG, MacDonald ML, Dube MP, MacFarlane J, O'Driscoll M, Brais B, Meilleur S, Brinkman RR, Dadivas O, Pape T, Platon C, Radomski C, Risler J, Thompson J, Guerra-Escobio AM, Davar G, Breakefield XO, Pimstone SN, Green R, Pryse-Phillips W, Goldberg YP, Younghusband HB, Hayden MR, Sherrington R, Rouleau GA, Samuels ME. Identification of a novel gene (HSN2) causing hereditary sensory and autonomic neuropathy type II through the Study of Canadian Genetic Isolates. Am J Hum Genet. 2004 May;74(5):1064-73. Epub 2004 Apr 1. PMID:15060842 doi:http://dx.doi.org/10.1086/420795