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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.