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Molecular and Cellular Biology, September 2003, p. 5979-5988, Vol. 23, No. 17
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.17.5979-5988.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Extracellular Signal-Regulated Kinase 7, a Regulator of Hormone-Dependent Estrogen Receptor Destruction

Lorin M. Henrich,1,2 Jeffrey A. Smith,2,3 Danielle Kitt,1,2 Timothy M. Errington,1,2 Binh Nguyen,1,2 Abdulmaged M. Traish,4 and Deborah A. Lannigan1,2*

Department of Microbiology,1 Department of Pathology,3 Center for Cell Signaling, University of Virginia, Charlottesville, Virginia 22908,2 Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 021184

Received 16 December 2002/ Returned for modification 31 January 2003/ Accepted 19 May 2003

Estrogen receptor alpha (ER{alpha}) degradation is regulated by ubiquitination, but the signaling pathways that modulate ER{alpha} turnover are unknown. We found that extracellular signal-regulated kinase 7 (ERK7) preferentially enhances the destruction of ER{alpha} but not the related androgen receptor. Loss of ERK7 was correlated with breast cancer progression, and all ER{alpha}-positive breast tumors had decreased ERK7 expression compared to that found in normal breast tissue. In human breast cells, a dominant-negative ERK7 mutant decreased the rate of endogenous ER{alpha} degradation >4-fold in the presence of hormone and potentiated estrogen responsiveness. ERK7 targets the ER{alpha} ligand-binding domain for destruction by enhancing its ubiquitination. Thus, ERK7 is a novel regulator of estrogen responsiveness through its control of ER{alpha} turnover.

* Corresponding author. Mailing address: Center for Cell Signaling, Box 800577, Health Sciences Center, University of Virginia, Charlottesville, VA 22908-0577. Phone: (434) 924-1144. Fax: (434) 924-1236. E-mail: dal5f{at}virginia.edu.

Molecular and Cellular Biology, September 2003, p. 5979-5988, Vol. 23, No. 17
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.17.5979-5988.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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