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Papers In Press, published online ahead of print May 9, 2005
Pharmacology Dept., UT Southwestern, Dallas, TX 75390-9041
Corresponding Author: mcobb{at}mednet.swmed.edu
WNKs are large serine/threonine protein kinases structurally distinct from all other members of the protein kinase superfamily. Of the four human WNK family members, WNK1 and WNK4 have been linked to a hereditary form of hypertension, pseudohypoaldosteronism type II. We are characterizing the biochemical properties and regulation of WNK1 that may contribute to its physiological activities and abnormal function in disease. We show that WNK1 is activated by hypertonic stress in kidney epithelial cells and in breast and colon cancer cell lines. In addition, hypotonic stress also leads to a modest increase in WNK1 activity. Gel filtration suggests that WNK1 exists as a tetramer, and yeast two-hybrid data show that the N-terminus of WNK1 (residues 1-222) interacts with residues 481-660, which includes the WNK1 autoinhibitory domain and a C-terminal coiled-coil domain. Although cell biological studies have suggested a functional interaction between WNK1 and WNK4, we find no evidence of stable interactions between these kinases. However, WNK1 phosphorylates both WNK4 and WNK2. In addition, the WNK1 autoinhibitory domain can inhibit the catalytic activity of these WNKs. These findings suggest potential mechanisms for inter-connected regulation of WNK family members.
J. Biol. Chem, 10.1074/jbc.M502598200
Submitted on March 9, 2005
Revised on May 2, 2005
Accepted on May 9, 2005
Properties of WNK1 and implications for other family members
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