Extracellular signal-regulated kinase 7, a regulator of hormone-dependent estrogen receptor destruction.
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.
Henrich
Lorin M
LM
Department of Microbiology and Center for Cell Signaling, University of Virginia, Charlottesville, Virginia 22908, USA.
Smith
Jeffrey A
JA
Kitt
Danielle
D
Errington
Timothy M
TM
Nguyen
Binh
B
Traish
Abdulmaged M
AM
Lannigan
Deborah A
DA
D000818:Animals; D001665:Binding Sites; D001940:Breast / Q000166:cytology; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D006224:Cricetinae; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D047628:Estrogen Receptor alpha; D048049:Extracellular Signal-Regulated MAP Kinases; D005260:Female; D006728:Hormones / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007668:Kidney / Q000166:cytology; D007976:Leupeptins / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D010447:Peptide Hydrolases / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex; D011960:Receptors, Estrogen / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D012016:Reference Values; D015398:Signal Transduction; D025801:Ubiquitin / Q000378:metabolism
D015853:Cysteine Proteinase Inhibitors; D047628:Estrogen Receptor alpha; D006728:Hormones; D007976:Leupeptins; D011960:Receptors, Estrogen; D025801:Ubiquitin; D048049:Extracellular Signal-Regulated MAP Kinases; C117062:Mapk15 protein, rat; D020928:Mitogen-Activated Protein Kinases; D010447:Peptide Hydrolases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde