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J. Biol. Chem., Vol. 283, Issue 10, 6110-6117, March 7, 2008

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p66^shc Inhibits Pro-survival Epidermal Growth Factor Receptor/ERK Signaling during Severe Oxidative Stress in Mouse Renal Proximal Tubule Cells^*

Istvan Arany¹, Amir Faisal^¶, Yoshikuni Nagamine^||, and Robert L. Safirstein

From the Department of Internal Medicine, University of Arkansas for Medical Sciences and the Central Arkansas Veterans Healthcare System, Little Rock, Arkansas 72205, the Department of Pediatrics, Division of Pediatric Nephrology, University of Mississippi Medical Center, Jackson, Mississippi 39126, the ^¶Protein Phosphorylation Laboratory, Cancer Research UK London Research Institute, Lincoln's Inn Fields Laboratories, London WC2A 3PX, United Kingdom, and the ^||Friedrich Miescher Institute for Biomedical Research, 4058 Basel, Switzerland

The fully executed epidermal growth factor receptor (EGFR)/Ras/MEK/ERK pathway serves a pro-survival role in renal epithelia under moderate oxidative stress. We and others have demonstrated that during severe oxidative stress, however, the activated EGFR is disconnected from ERK activation in cultured renal proximal tubule cells and also in renal proximal tubules after ischemia/reperfusion injury, resulting in necrotic death. Studies have shown that the tyrosine-phosphorylated p46/52 isoforms of the ShcA family of adaptor proteins connect the activated EGFR to activation of Ras and ERK, whereas the p66^shc isoform can inhibit this p46/52^shc function. Here, we determined that severe oxidative stress (after a brief period of activation) terminates activation of the Ras/MEK/ERK pathway, which coincides with ERK/JNK-dependent Ser³⁶ phosphorylation of p66^shc. Isoform-specific knockdown of p66^shc or mutation of Ser³⁶ to Ala, but not to Asp, attenuated severe oxidative stress-mediated ERK inhibition and cell death in vitro. Also, severe oxidative stress (unlike ligand stimulation and moderate oxidative stress, both of which support survival) increased binding of p66^shc to the activated EGFR and Grb2. This binding dissociated the SOS1 adaptor protein from the EGFR-recruited signaling complex, leading to termination of Ras/MEK/ERK activation. Notably, Ser³⁶ phosphorylation of p66^shc and its increased binding to the EGFR also occurred in the kidney after ischemia/reperfusion injury in vivo. At the same time, SOS1 binding to the EGFR declined, similar to the in vitro findings. Thus, the mechanism we propose in vitro offers a means to ameliorate oxidative stress-induced cell injury by either inhibiting Ser³⁶ phosphorylation of p66^shc or knocking down p66^shc expression in vivo.

Received for publication, October 24, 2007 , and in revised form, December 11, 2007.

^* This work was supported by Grant-in-aid 0655716Z from the American Heart Association, Heartland Affiliate (to I. A.), by a Seed Grant from the Department of Internal Medicine, University of Arkansas for Medical Sciences (to I. A.), by NIDDK Grant PO1 DK58324-01A1 from the National Institutes of Health (to R. L. S.), and in part the Central Arkansas Veterans Healthcare System, Little Rock, AR. 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.

The on-line version of this article (available at http://www.jbc.org) contains a supplemental figure.

¹ To whom correspondence should be addressed: Dept. of Pediatrics, Div. of Pediatric Nephrology, University of Mississippi Medical Center, 2500 N. State St., Jackson, MS 39126. E-mail: iarany{at}ped.umsmed.edu.

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