Article

CREB and the CRTC co-activators: Sensors for hormonal and metabolic signals

Sanford-Burnham Medical Research Institute at Lake Nona, 6400 Sanger Road, Orlando, Florida 32827, USA.
Nature Reviews Molecular Cell Biology (Impact Factor: 36.46). 03/2011; 12(3):141-51. DOI: 10.1038/nrm3072
Source: PubMed

ABSTRACT The cyclic AMP-responsive element-binding protein (CREB) is phosphorylated in response to a wide variety of signals, yet target gene transcription is only increased in a subset of cases. Recent studies indicate that CREB functions in concert with a family of latent cytoplasmic co-activators called cAMP-regulated transcriptional co-activators (CRTCs), which are activated through dephosphorylation. A dual requirement for CREB phosphorylation and CRTC dephosphorylation is likely to explain how these activator-co-activator cognates discriminate between different stimuli. Following their activation, CREB and CRTCs mediate the effects of fasting and feeding signals on the expression of metabolic programmes in insulin-sensitive tissues.

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    • "The PKA-dependent action of GLP-1R agonists is mediated by cAMP response elements (CREs) located in the human insulin gene (Hay et al. 2005). As illustrated in Fig. 3, CREs bind the cAMP response elementbinding protein (CREB), a basic region leucine zipper transcription factor (bZIP) that is regulated by PKA and co-activators p300 and CRTC in β-cells (Altarejos and Montminy 2011; Dalle et al. 2011b). These CREs also bind bZIPs that mediate Fig. 3 cAMP-stimulated gene expression in β-cells results from PKA holoenzyme activation with consequent translocation of PKA catalytic subunits to the nucleus where PKA phosphorylates CREB on Ser-133. "
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    • "Sustained phosphorylation of serine 133 (S133) is crucial for transcriptional activity of CREB (Shaywitz and Greenberg, 1999) because it enhances the transactivational properties of CREB by recruiting the co-activator CREB-binding protein (CBP/p300), which then results in the expression of plasticity-related genes such as brain-derived neurotrophic factor (BDNF) and activity-regulated cytoskeleton-associated protein (Arc/ Arg3.1) (Yamamoto et al., 1988; Impey and Goodman, 2001; Patterson et al., 2001; Vanhoutte and Bading, 2003; Kalkhoven, 2004; Hardingham and Bading, 2010). However, additional phosphorylation sites on CREB like serine 117, 129, 142, 143 have also been implicated in regulating CREB's transcriptional activity (Johannessen et al., 2004, 2007; Altarejos and Montminy, 2011). CRTC1 was recently shown to be a synapse-to-nucleus transcriptional co-activator (Ch'ng et al., 2012), which specifically associates with the bZIP domain of promoter bound CREB (Luo et al., 2012). "
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