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Am J Physiol Renal Physiol 291: F874-F881, 2006. First published May 9, 2006; doi:10.1152/ajprenal.00377.2005
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MEKK3-mediated signaling to p38 kinase and TonE in hypertonically stressed kidney cells

Ranjit Padda,1 Ann Wamsley-Davis,1 Michael C. Gustin,2 Rebekah Ross,2 Christina Yu,2 and David Sheikh-Hamad1

1Renal Section, Department of Medicine, Baylor College of Medicine, and 2Department of Biochemistry and Cell Biology, Rice University, Houston, Texas

Submitted 18 September 2005 ; accepted in final form 1 May 2006

Mitogen-activated protein kinase (MAPK) cascades contain a trio of kinases, MAPK kinase kinase (MKKK) -> MAPK kinase (MKK) -> MAPK, that mediate a variety of cellular responses to different signals including hypertonicity. The signaling response to hypertonicity is conserved across evolution from yeast to mammals in that it involves activation of p38/SAPK. However, very little is known about which upstream protein kinases mediate activation of p38 by hypertonicity in mammals. The MKKKs, MEKK3 and MEKK4, are upstream regulators of p38 in many cells. To investigate these signaling proteins as potential activators of p38 in the hypertonicity response, we generated stably transfected MDCK cells that express activated versions of MEKK3 or MEKK4, utilized RNA interference to deplete MEKK3, and employed pharmacological inhibition of p38 kinase. MEKK3-transfected cells demonstrated increased betaine transporter (BGT1) mRNA levels and upregulated tonicity enhancer (TonE)-driven luciferase activity under isotonic (basal) and hypertonic conditions compared with empty vector-transfected controls; small-interference RNA-mediated depletion of MEKK3 downregulated the activity of p38 kinase and decreased the expression of BGT1 mRNA. p38 Kinase inhibition abolished the effects of MEKK3 activation on BGT1 induction. In contrast, the response to hypertonicity in MEKK4-kA-transfected cells was similar to that observed in empty vector-transfected controls. Our data are consistent with the existence of an input from MEKK3 ->-> p38 kinase ->-> TonE.

osmotic stress; tonicity enhancer; betaine transporter; TonEBP


Address for reprint requests and other correspondence: D. Sheikh-Hamad, Renal Section, Dept. of Medicine, Baylor College of Medicine, Houston, TX 77030 (e-mail: sheikh{at}bcm.tmc.edu)




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M. B. Burg, J. D. Ferraris, and N. I. Dmitrieva
Cellular Response to Hyperosmotic Stresses
Physiol Rev, October 1, 2007; 87(4): 1441 - 1474.
[Abstract] [Full Text] [PDF]


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