CREB phosphorylation at Ser133 regulates transcription via distinct mechanisms downstream of cAMP and MAPK signaling

CREB is an important transcription factor for the activation of a number of immediate early genes. CREB is phosphorylated on Ser133 by PKA, promoting the recruitment of the co-activator proteins CBP and p300; this has been proposed to increase the transcription of CREB-dependent genes. CREB is also phosphorylated on Ser133 by MSK1/2 in cells in response to activation of MAPK signaling, however the relevance of this to gene transcription has been controversial. To resolve this we created a mouse with a Ser133 to Ala mutation in the endogenous CREB gene. Unlike total CREB knockout, which is perinatal lethal, these mice were viable but born at less than the expected Mendelian frequency on a C57Bl/6 background. Using embryonic fibroblasts from the Ser133Ala knockin mice we show here that Ser133 phosphorylation downstream of PKA is required for CBP/p300 recruitment. The requirement for 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 signaling.
Source: BJ Gene - Category: Biochemistry Authors: Tags: BJ Signal Source Type: research