The DOI matches its Crossref record; 28 of the 28 references it cites were found in a registry or an index.
Activation of the thiazide-sensitive Na+-Cl– cotransporter by the WNK-regulated kinases SPAK and OSR1
Open accessAbstract
Mutations increasing WNK1 kinase expression in humans cause the pseudohypoaldosteronism type II hypertension syndrome. This condition is treated effectively by thiazide diuretics, which exert their effects by inhibiting the Na+-Cl– cotransporter (NCC), suggesting a link between WNK1 and NCC. Here, we demonstrate that the SPAK and OSR1 kinases that are activated by WNK1 phosphorylate human NCC at three conserved residues (Thr46, Thr55 and Thr60). Activation of the WNK1-SPAK/OSR1 signalling pathway by treatment of HEK293 or mpkDCT kidney distal-convoluted-tubule-derived cells with hypotonic low-chloride conditions induced phosphorylation of NCC at residues phosphorylated by SPAK/OSR1. Efficient phosphorylation of NCC was dependent upon a docking interaction between an RFXI motif in NCC and SPAK/OSR1. Mutation of Thr60 to Ala in NCC markedly inhibited phosphorylation of Thr46 and Thr55 as well as NCC activation induced by hypotonic low-chloride treatment of HEK293 cells. Our results establish that the WNK1-SPAK/OSR1 signalling pathway plays a key role in controlling the phosphorylation and activity of NCC. They also suggest a mechanism by which increased WNK1 overexpression could lead to hypertension and that inhibitors of SPAK/OSR1 might be of use in reducing blood pressure by suppressing phosphorylation and hence activity of NCC.
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Cites
Human Hypertension Caused by Mutations in WNK Kinases
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., et al. (2001) · Science · doi:10.1126/science.1062844 · Cited by 1,487
Durocher, Y. (2002) · Nucleic Acids Research · doi:10.1093/nar/30.2.e9 · Cited by 1,037
Molecular Physiology and Pathophysiology of Electroneutral Cation-Chloride Cotransporters
Gamba, G. (2005) · Physiological Reviews · doi:10.1152/physrev.00011.2004 · Cited by 810
Vitari, A. C., Deak, M., Morrice, N. A., & Alessi, D. R. (2005) · Biochemical Journal · doi:10.1042/bj20051180 · Cited by 503
Self-citationMoriguchi, T., Urushiyama, S., Hisamoto, N., Iemura, S.-I., Uchida, S., Natsume, T., Matsumoto, K., & Shibuya, H. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m510042200 · Cited by 477
Wilson, F. H., Kahle, K. T., Sabath, E., Lalioti, M. D., Rapson, A. K., Hoover, R. S., Hebert, S. C., Gamba, G., & Lifton, R. P. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.242735399 · Cited by 414
Piechotta, K., Lu, J., & Delpire, E. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m208108200 · Cited by 399
Yang, S.-S., Morimoto, T., Rai, T., Chiga, M., Sohara, E., Ohno, M., Uchida, K., Lin, S.-H., Moriguchi, T., Shibuya, H., et al. (2007) · Cell Metabolism · doi:10.1016/j.cmet.2007.03.009 · Cited by 313
Vitari, A. C., Thastrup, J., Rafiqi, F. H., Deak, M., Morrice, N. A., Karlsson, H. K. R., & Alessi, D. R. (2006) · Biochemical Journal · doi:10.1042/bj20060220 · Cited by 309
Self-citationGagnon, K. B. E., England, R., & Delpire, E. (2006) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00037.2005 · Cited by 271
Cited by
Chloride sensing by WNK1 involves inhibition of autophosphorylation
Piala, A. T., Moon, T. M., Akella, R., He, H., Cobb, M. H., & Goldsmith, E. J. (2014) · Science Signaling · doi:10.1126/scisignal.2005050 · Cited by 418
Kinase Drug Discovery – What’s Next in the Field?
Cohen, P., & Alessi, D. R. (2013) · ACS Chemical Biology · doi:10.1021/cb300610s · Cited by 377
Self-citationSubramanya, A. R., & Ellison, D. H. (2014) · Clinical Journal of the American Society of Nephrology · doi:10.2215/cjn.05920613 · Cited by 299
Regulation of the Renal NaCl Cotransporter and Its Role in Potassium Homeostasis
Hoorn, E. J., Gritter, M., Cuevas, C. A., & Fenton, R. A. (2020) · Physiological Reviews · doi:10.1152/physrev.00044.2018 · Cited by 163
Schumacher, F.-R., Sorrell, F. J., Alessi, D. R., Bullock, A. N., & Kurz, T. (2014) · Biochemical Journal · doi:10.1042/bj20140153 · Cited by 76
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Metadata
- Authors
- Richardson, C., Rafiqi, F. H., Karlsson, H. K. R., Moleleki, N., Vandewalle, A., Campbell, D. G., Morrice, N. A., & Alessi, D. R.
- Venue
- Journal of Cell Science
- Publisher
- The Company of Biologists
- Published
- 2008-03-01
- Volume
- 121
- Issue
- 5
- Pages
- 675-684
- ISSN
- 0021-9533 (ISSN-L)
- 1477-9137
- OpenAlex
- W2141617464
- Cited by
- 357
- References
- 28
- FWCI
- 10.17
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- CoChat. (2026). Citation check: Activation of the thiazide-sensitive Na+-Cl– cotransporter by the WNK-regulated kinases SPAK and OSR1. https://app.cochat.ai/papers/10.1242/jcs.025312
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- Richardson, C., Rafiqi, F. H., Karlsson, H. K. R., Moleleki, N., Vandewalle, A., Campbell, D. G., Morrice, N. A., & Alessi, D. R. (2008). Activation of the thiazide-sensitive Na+-Cl– cotransporter by the WNK-regulated kinases SPAK and OSR1. Journal of Cell Science. https://doi.org/10.1242/jcs.025312
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