Serum- and glucocorticoid-dependent kinase, cell volume, and the regulation of epithelial transport

Ample pharmacological evidence points to a role of kinases in the regulatio n of cell volume. Given the limited selectivity of most inhibitors, however , the specific molecules involved have remained largely elusive. The search for cell volume regulated genes in liver HepG2 cells led to the discovery of the human serum- and glueocorticoid-dependent serine/threonine kinase hs gk1. Transcription and expression of hsgk1 is markedly and rapidly upregula ted by osmotic and isotonic cell shrinkage. The effect of osmotic cell shri nkage on hsgk1 is mediated by p38 kinase. Further stimuli of hsgkl transcri ption include glucocorticoids, aldosterone, TGF-beta1, serum, increase of i ntracellular Ca2+ and phorbolesters, whereas cAMP downregulates hsgkl trans cription. The hsgk1 protein is expressed in several epithelial tissues incl uding human pancreas, intestine, kidney, and shark rectal gland. Co-express ion of hsgk1 with the renal epithelial Na+-channel ENaC or the Na+/K+/2Cl(- )-cotransporter NKCC2 (BSC1) in Xenopus oocytes, accelerates insertion of t he transport proteins into the cell membrane and thus, stimulates channel o r transport activity. Thus, hsgk1 participates in the regulation of transpo rt by steroids and secretagogues increasing intracellular Ca2+-activity. Th e stimulation of hsgk1 transcription by TGF-beta1 may further bear pathophy siological relevance. (C) 2001 Elsevier Science Inc. All rights reserved.