CREB binding protein recruitment to the transcription complex requires growth factor-dependent phosphorylation of its GF box

Growth factors such as epidermal growth factor (EGF) and insulin regulate d evelopment and metabolism via genes containing both POU homeodomain (Pit-l) and phorbol ester (AP-1) response elements. Although CREB binding protein (CBP) functions as a coactivator on these elements, the mechanism of transa ctivation was previously unclear. We now demonstrate that CBP is recruited to these elements only after it is phosphorylated at serine 436 by growth f actor-dependent signaling pathways. In contrast, p300, a protein closely re lated to CBP that lacks this phosphorylation site, binds only weakly to the transcription complex and in a growth factor-independent manner. A small r egion of CBP (amino acids 312-440), which we term GF box, contains a potent transactivation domain and mediates this effect. Direct phosphorylation re presents a novel mechanism controlling coactivator recruitment to the trans cription complex.