Journal of Biological Chemistry
Volume 285, Issue 33, 13 August 2010, Pages 25161-25167
Journal home page for Journal of Biological Chemistry

Signal Transduction
Serum and Glucocorticoid-induced Kinase (SGK) 1 and the Epithelial Sodium Channel Are Regulated by Multiple with No Lysine (WNK) Family Members*

https://doi.org/10.1074/jbc.M110.103432Get rights and content
Under a Creative Commons license
open access

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.

E3 Ubiquitin Ligase
Human Genetics
Membrane Proteins
Protein Kinases
Sodium Channels
Nedd4-2
SGK
WNK

Cited by (0)

*

This work was supported, in whole or in part, by National Institutes of Health Grants GM53032 (to M. H. C.) and DK59530 (to C.-L. H.), University of Texas Southwestern O'Brien Center Grant DK79328, Grant CA126832 (to Y. Z.), and Robert A. Welch Foundation Grant I1243 (to M. H. C.).

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

1

Present address: Physicians' Education Resource, 3500 Maple Ave., Suite 700, Dallas, TX 75219.

2

Present address: The Samuel Lunenfeld Research Institute, Toronto, ON M5G 1X5, Canada.

3

Present address: Laboratory of Proteomics and Protein Modifications, Ben May Dept. for Cancer Research, University of Chicago, Chicago, IL 60637.