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

Abstract

Estrogen receptor alpha (ERα) degradation is regulated by ubiquitination, but the signaling pathways that modulate ERα turnover are unknown. We found that extracellular signal-regulated kinase 7 (ERK7) preferentially enhances the destruction of ERα but not the related androgen receptor. Loss of ERK7 was correlated with breast cancer progression, and all ERα-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 ERα degradation >4-fold in the presence of hormone and potentiated estrogen responsiveness. ERK7 targets the ERα ligand-binding domain for destruction by enhancing its ubiquitination. Thus, ERK7 is a novel regulator of estrogen responsiveness through its control of ERα turnover.

ACKNOWLEDGMENTS

We thank Ian Macara and Sarah Parsons for helpful discussions.

This work was supported by the Biotechnology Training Program no. T32 GM08715 (L.M.H.) and the University of Virginia Cancer Center Support Grant (D.A.L.).