ELK1 is a transcription factor of the ETS family. Activation of the MAPK signalling pathway leads to phosphorylation of ELK1 and as a consequence activation of ELK1 target genes. To elucidate more about the mechanism that regulates the activation of ELK1, a genome-wide siRNA was performed. One of the genes that affected transcription by ELK1 was UBE3A, an E3 ubiquitin-ligase. Other studies have previously shown that knock down of UBE3A leads to incorrect chromosomal segregation and reduction in the transcriptional activation of the estrogen receptor alpha. In addition, mutation of UBE3A gene causes Angelman syndrome, a neurological disorder characterised by learning disabilities and epilepsy. In our system, knocking down UBE3A leads to constitutively high ERK activity and to an increase in basal transcription of ELK1 target genes. Unexpectedly, treatment of UBE3A deficient cells with growth factors does not further potentiate ERK activity or lead to transient activation of immediate-early target genes controlled by ELK1. This latter observation is surprising as high levels of active ERK are present. As both ERK pathway signalling and immediate-early gene activation play a key role in brain function, these findings are suggestive of a molecular link to neurological disorders caused by UBE3A loss. In summary, we have identified a new regulator of the ERK pathway and our data have potential implications for understanding the molecular basis to the defects seen in Angelman syndrome.