Transcription factor CREB binds the cAMP response element (CRE) and activates transcription in response to a variety of extracellular signals including neurotransmitters, hormones, membrane depolarization, and growth or neurotrophic factors. Protein kinase A and the calmodulin-dependent protein kinase CaMKII stimulate CREB phosphorylation at Ser133, a key regulatory site controlling transcriptional activity. Phosphorylation at Ser133 is also mediated by p44/42 MAP kinase, p90RSK, p38 MAP kinase and MSK1. CREB appears to play an important role in learning and memory in both flies and mice.