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J. Biol. Chem., Vol. 280, Issue 13, 13148-13152, April 1, 2005

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Heat Shock Protein 90 Stabilization of ErbB2 Expression Is Disrupted by ATP Depletion in Myocytes^*

Xuyang Peng, Xinxin Guo, Steven C. Borkan, Ajit Bharti, Yukio Kuramochi, Stuart Calderwood¶, and Douglas B. Sawyer||

From the Whitaker Cardiovascular Institute and Center for Molecular Stress Response, Renal Division, Boston University Medical Center, Boston, Massachusetts 02118 and the ^¶Division of Molecular and Cellular Biology, Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115

Heat shock protein (Hsp) 90 is a ubiquitously expressed chaperone that stabilizes expression of multiple signaling kinases involved in growth regulation, including ErbB2, Raf-1, and Akt. The chaperone activity of Hsp90 requires ATP, which binds with 10-fold lower affinity than ADP. This suggests that Hsp90 may be a physiological ATP sensor, regulating the stability of growth signaling cascades in relation to cellular energy charge. Here we show that lowering ATP concentration by inhibiting glycolysis or mitochondrial respiration in isolated myocytes triggers rapid dissociation of Hsp90 from ErbB2 and degradation of ErbB2 along with other client proteins. The effect of disrupting Hsp90 chaperone activity by ATP depletion was similar to the effect of the pharmacological Hsp90 inhibitor geldanamycin. ATP depletion-induced disruption of Hsp90 chaperone activity was associated with cellular resistance to growth factor activation of intracellular signaling. ErbB2 degradation was also induced by the physiological stress of -adrenergic receptor stimulation in electrically stimulated cells. These results support a role for Hsp90 as an ATP sensor that modulates tissue growth factor responsiveness under metabolically stressed conditions and provide a novel mechanism by which cellular responsiveness to growth factor stimulation is modulated by cellular energy charge.

Received for publication, September 21, 2004 , and in revised form, January 7, 2005.

^* This study was funded by National Institutes of Health Grant HL68144 and a grant from the Juvenile Diabetes Research Foundation (to D. B. S.). This work was presented in part at the American Heart Association Annual Scientific Sessions, November 9–12, 2003 in Orlando, Florida. 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.

^|| To whom correspondence should be addressed: Whitaker Cardiovascular Inst. and Center for Molecular Stress Response, Boston University Medical Center, 650 Albany St., Boston, MA 02118. Tel.: 617-6388071; Fax: 617-414-1719; E-mail: douglas.sawyer{at}bmc.org.

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