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J. Biol. Chem., Vol. 279, Issue 12, 10962-10972, March 19, 2004

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Inhibition of Ligand-independent ERK1/2 Activity in Kidney Proximal Tubular Cells Deprived of Soluble Survival Factors Up-regulates Akt and Prevents Apoptosis^*

Diviya Sinha, Saswati Bannergee, John H. Schwartz, Wilfred Lieberthal, and Jerrold S. Levine¶||

From the Renal Section, Boston Medical Center, Boston University School of Medicine, Boston, Massachusetts 02118 and the ^¶Section of Nephrology, The University of Chicago, Chicago, Illinois 60637

Mouse kidney proximal tubular epithelial (MK-PT) cells die by apoptosis over 7–10 days when deprived of all survival factors. We show here that withdrawal of all survival factors from MK-PT cells is associated with a progressive increase in the activity of extracellular signal-regulated kinase-1 and -2 (ERK1/2) and a progressive decrease in phosphorylated Akt, a kinase critical to cell survival. Pharmacological inhibition of MEK1/2, the immediate upstream kinase for ERK1/2, not only prevented the decrease in phosphorylated Akt, but also prolonged MK-PT cell survival. Inhibition of ERK1/2, by itself, in the absence of any other known survival factors, was as potent as epidermal growth factor in maintaining MK-PT cell viability. ERK1/2 co-immunoprecipitated with Akt in a multimolecular assembly of signaling molecules, containing at a minimum ERK1/2, Akt, Rsk, and 3-phosphoinositide dependent kinase 1 (PDK1). We hypothesize that the kinase Rsk, whose activation requires phosphorylation by both ERK1/2 and PDK1, acts as a bridge bringing ERK1/2 into proximity with PDK1-associated Akt. Although a number of interactions between the Raf-MEK-ERK and PI3K-Akt signaling pathways have been described, our results are the first to show modulation of Akt activity by signaling events originating with ERK1/2. Spontaneous activation of ERK1/2 occurs via MEK1/2 and appears to depend on oxidant stress, accompanying induction of the default pathway of apoptosis. Together, these data suggest that the spontaneous activation of ERK1/2, in the absence of known extracellular stimuli, represents a previously unrecognized major regulatory pathway determining the fate of cells destined to die by the default pathway of apoptosis.

Received for publication, November 3, 2003 , and in revised form, December 24, 2003.

^* This work was supported by National Institutes of Health Research Grants DK59793, DK52898, DK53387, and HL69722. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to this work.

^|| To whom correspondence should be addressed: The University of Chicago, Section of Nephrology, MC-5100, S-506, 5841 South Maryland Ave., Chicago, IL 60637. Tel.: 773-702-1743; Fax: 773-702-5818; E-mail: jlevine{at}medicine.bsd.uchicago.edu.

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