The signal-dependent coactivator CBP is a nuclear target for pp90(RSK)

We have examined the mechanism by which growth factor-mediated induction of the Ras pathway interferes with signaling via the second messenger cAMP. Activation of cellular Ras with insulin or NGF stimulated recruitment of the S6 kinase pp90(RSK) to the signal-dependent coactivator CBP. Formation of the pp90(RSK)-CBP complex occurred with high stoichiometry and persisted for 6-8 hr following growth factor addition. pp90(RSK) specifically recognized the E1A-binding domain of the coactivator CBP. In addition, like E1A, binding of pp90(RSK) to CBP was sufficient to repress transcription of cAMP-responsive genes via the cAMP-inducible factor CREB. By contrast with its effects on the cAMP pathway, formation of the pp90(RSK)-CBP complex was required for induction of Ras-responsive genes. These results provide a demonstration of cross-coupling between two signaling pathways that occurs at the level of a signal-dependent coactivator.