The pERK of being a target: Kinase regulation of the orphan nuclear receptor ERRγ

Abstract

Estrogen-related receptors (ERRs) are orphan members of the nuclear receptor superfamily that are important regulators of mitochondrial metabolism with emerging roles in cancer. In the absence of an endogenous ligand, ERRs are reliant upon other regulatory mechanisms that include protein/protein interactions and post-translational modification, though the cellular and clinical significance of this latter mechanism is unclear. We recently published a study in which we establish estrogen-related receptor gamma (ERRγ) as a target for extracellular signal-regulated kinase (ERK), and show that regulation of ERRγ by ERK has important consequences for the function of this receptor in cellular models of estrogen receptor-positive (ER+) breast cancer. In this Research Highlight, we discuss the implications of these findings from a molecular and clinical perspective.

Keywords: ERK/MAPK; ERRgamma; ESRRG; orphan nuclear receptor; tamoxifen; transcription.

Figure 1. Model for ERK-mediated regulation of ERRγ

Hyper activationof ERK/MAPK, through receptor tyrosine kinase (RTK) engagement or other means, leads to increased ERRγ expression and transcriptional activity in a Serine 57, 81, and/or 219-dependent manner. N – amino-terminal activation function 1 (AF1) region; DBD – DNA binding domain; LBD – ligand binding domain.