Serum and Glucocorticoid-induced Kinase (SGK) 1 and the epithelial sodium channel are regulated by multiple with no lysine (WNK) family members

Charles J. Heise, Bing E. Xu, Staci L. Deaton, Seung Kuy Cha, Chih Jen Cheng, Svetlana Earnest, Samarpita Sengupta, Yu Chi Juang, Steve Stippec, Yingda Xu, Yingming Zhao, Chou Long Huang, Melanie H. Cobb

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Abstract

The four WNK (with no lysine (K)) protein kinases affect ion balance and contain an unusual protein kinase domain due to the unique placement of the active site lysine. Mutations in two WNKs cause a heritable form of ion imbalance culminating in hypertension. WNK1 activates the serum- and glucocorticoid-induced protein kinase SGK1; the mechanism is noncatalytic. SGK1 increases membrane expression of the epithelial sodium channel (ENaC) and sodium reabsorption via phosphorylation and sequestering of the E3 ubiquitin ligase neural precursor cell expressed, developmentally down-regulated 4-2 (Nedd4-2), which otherwise promotes ENaC endocytosis. Questions remain about the intrinsic abilities of WNK family members to regulate this pathway. We find that expression of the N termini of all four WNKs results in modest to strong activation of SGK1. In reconstitution experiments in the same cell line all four WNKs also increase sodium current blocked by the ENaC inhibitor amiloride. The N termini of the WNKs also have the capacity to interact with SGK1. More detailed analysis of activation by WNK4 suggests mechanisms in common with WNK1. Further evidence for the importance of WNK1 in this process comes from the ability of Nedd4-2 to bind to WNK1 and the finding that endogenous SGK1 has reduced activity if WNK1 is knocked down by small interfering RNA.

Original languageEnglish
Pages (from-to)25161-25167
Number of pages7
JournalJournal of Biological Chemistry
Volume285
Issue number33
DOIs
Publication statusPublished - 2010 Aug 13

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Heise, C. J., Xu, B. E., Deaton, S. L., Cha, S. K., Cheng, C. J., Earnest, S., Sengupta, S., Juang, Y. C., Stippec, S., Xu, Y., Zhao, Y., Huang, C. L., & Cobb, M. H. (2010). Serum and Glucocorticoid-induced Kinase (SGK) 1 and the epithelial sodium channel are regulated by multiple with no lysine (WNK) family members. Journal of Biological Chemistry, 285(33), 25161-25167. https://doi.org/10.1074/jbc.M110.103432