Cell Type-specific Inhibition of the ETS Transcription Factor ER81 by Mitogen-activated Protein Kinase-activated Protein Kinase 2

Abstract

Mitogen-activated protein kinase-activated protein kinase 2 (MK2) is an important intracellular mediator of stress signals. In this report, a novel target of MK2 has been identified, the ETS transcription factor family member ER81, whose dysregulation contributes to tumorigenesis and whose normal function is required during development. MK2 phosphorylates ER81 in vitro within its central inhibitory domain, and overexpression of MK2 leads to increased in vivo phosphorylation of ER81. Two serine residues, ER81 amino acids 191 and 216, were identified as MK2 phosphorylation sites. MK2 suppresses basal ER81-dependent transcription, and this suppressive effect is alleviated upon mutation of the MK2 phosphorylation sites in a cell type-specific manner. However, MK2 can also interfere with ER81-mediated transcription independently of serine 191 and serine 216 phosphorylation. Furthermore, MK2 overexpression counteracts the stimulation of ER81 activity by p38 mitogen-activated protein kinase. Altogether, MK2 may regulate ER81 transcriptional activity in a cell type-specific manner and thereby modulate various physiological processes beyond stress responses.