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CREB (cAMP-response-element-binding protein) is an important transcription factor for the activation of a number of immediate early genes. CREB is phosphorylated on Ser133 by PKA (protein kinase A), promoting the recruitment of the co-activator proteins CBP (CREB-binding protein) and p300; this has been proposed to increase the transcription of CREB-dependent genes. CREB is also phosphorylated on Ser133 by MSK1/2 (mitogen- and stress-activated kinase 1/2) in cells in response to the activation of MAPK (mitogen-activated protein kinase) signalling; however, the relevance of this to gene transcription has been controversial. To resolve this problem, we created a mouse with a Ser133 to alanine residue mutation in the endogenous Creb gene. Unlike the total CREB knockout, which is perinatally lethal, these mice were viable, but born at less than the expected Mendelian frequency on a C57Bl/6 background. Using embryonic fibroblasts from the S133A-knockin mice we show in the present study that Ser133 phosphorylation downstream of PKA is required for CBP/p300 recruitment. The requirement of Ser133 phosphorylation for the PKA-mediated induction of CREB-dependent genes was, however, promoter-specific. Furthermore, we show that in cells the phosphorylation of CREB on Ser133 by MSKs does not promote strong recruitment of CBP or p300. Despite this, MSK-mediated CREB phosphorylation is critical for the induction of CREB-dependent genes downstream of MAPK signalling.