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Am J Physiol Cell Physiol 277: C425-C431, 1999;
0363-6143/99 $5.00
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Vol. 277, Issue 3, C425-C431, September 1999

JNK is a volume-sensitive kinase that phosphorylates the Na-K-2Cl cotransporter in vitro

Janet D. Klein1, S. Todd Lamitina1, and W. Charles O'Neill1,2

Renal Division, 1 Department of Medicine, and 2 Department of Physiology, Emory University School of Medicine, Atlanta, Georgia 30322

Cell shrinkage phosphorylates and activates the Na-K-2Cl cotransporter (NKCC1), indicating the presence of a volume-sensitive protein kinase. To identify this kinase, extracts of normal and shrunken aortic endothelial cells were screened for phosphorylation of NKCC1 fusion proteins in an in-the-gel kinase assay. Hypertonic shrinkage activated a 46-kDa kinase that phosphorylated an NH2-terminal fusion protein, with weaker phosphorylation of a COOH-terminal fusion protein. This cytosolic kinase was activated by both hypertonic and isosmotic shrinkage, indicating regulation by cell volume rather than osmolarity. Subsequent studies identified this kinase as c-Jun NH2-terminal kinase (JNK). Immunoblotting revealed increased JNK activity in shrunken cells; there was volume-sensitive phosphorylation of NH2-terminal c-Jun fusion protein; immunoprecipitation of JNK from shrunken cells but not normal cells phosphorylated NKCC1 in gel kinase assays; and treatment of cells with tumor necrosis factor, a known activator of JNK, mimicked the effect of hypertonicity. We conclude that JNK is a volume-sensitive kinase in endothelial cells that phosphorylates NKCC1 in vitro. This is the first demonstration of a volume-sensitive protein kinase capable of phosphorylating a volume-regulatory transporter.

cell volume; c-Jun NH2-terminal kinase; stress-activated protein kinase; phosphorylation; endothelia


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