The retinoic acid related orphan receptor ROR alpha activates transcription of genes that play an important role in cerebellar development, the protection against age-related degenerative processes, the regulation of inflammatory responses, and is one of the pivotal participants that control the circadian rhythmicity in the core-clock of mammals. We identified the extracellular signal-regulated kinase 2 (ERK-2) as ROR alpha 4 phosphorylating kinase in vitro. The primary sequence of ROR alpha 4 contains an ERK-2 recognition motif (P-L-T-128-P) within the hinge domain, and mutation of Thr-128 to Ala prevents ROR alpha 4 phosphorylation by ERK. The ROR alpha 4-T128A mutant exhibits an increased DNA-binding affinity, an increased transcriptional activity and, in the interplay with the opponent RevErb alpha, acts as a stronger competitor at ROR response elements than ROR alpha 4-WT. (C) 2007 Elsevier Inc. All rights reserved.