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

Key Points

  • Cyclic AMP-responsive element-binding protein (CREB) mediates induction of cAMP-responsive genes following its phosphorylation at Ser133 by protein kinase A (PKA). CREB phosphorylation increases its activity by promoting an association with the co-activator paralogues CREB-binding protein (CBP) and p300.

  • The cAMP-regulated transcriptional co-activators (CRTCs) mediate CREB target gene activation following their dephosphorylation and nuclear translocation, when they bind to CREB over relevant promoters. CRTCs are selectively activated by cAMP and calcium signals, perhaps explaining why only a subset of stimuli that promote CREB phosphorylation also increase target gene expression.

  • CRTC1 is expressed almost exclusively in the hypothalamus, where it mediates effects of leptin on satiety. CRTC1 reduces food intake by stimulating the expression of the neuropeptide cocaine- and amphetamine-regulated transcript 1 (CART1) in arcuate cells.

  • CRTC2 mediates effects of glucagon on induction of the gluconeogenic programme in the liver during fasting. CREB and CRTC2 activities are increased in insulin resistance, in which they contribute to the attendant hyperglycaemia.

  • CRTC3 is expressed in white and brown adipose tissue, where it promotes obesity by inhibiting catecholamine signalling. Inheritance of a gain-of-function CRTC3 mutant in certain human populations is associated with obesity.

  • The CRTCs are conserved in lower organisms, including Drosophila melanogaster and Caenorhabditis elegans, in which they mediate effects of fasting and feeding signals on glucose and lipid metabolism, as well as lifespan.

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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Figure 1: cAMP stimulates CREB phosphorylation.
Figure 2: Modular organization of CREB and its co-activators.
Figure 3: CRTC nuclear shuttling is regulated by phosphorylation.
Figure 4: CREB stimulates the gluconeogenic programme.
Figure 5: Glucagon and insulin antagonism.
Figure 6: Leptin promotes lipolysis and energy expenditure.

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Acknowledgements

We acknowledge support from the US National Institutes of Health, the Clayton Foundation for Medical Research, The Helmsley Foundation and the Kieckhefer Foundation.

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Correspondence to Marc Montminy.

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CREB Target Gene Database

Glossary

Second messenger

An intracellular molecule that mediates effects of extracellular signals on cellular function.

TATA box

An A/T-rich sequence usually located 30 nucleotides upstream from the transcriptional start site of RNA polymerase II-dependent promoters. TATA boxes specify transcriptional initiation; they are recognized by TATA-binding protein (TBP), the DNA-binding component of transcription factor IID (TFIID).

KIX domain

A domain of three helices in CREB-binding protein (CBP) and p300 that mediates binding to phosphorylated cyclic AMP-responsive element-binding protein (CREB) and other transcription factors.

Spliceosome

A multi-protein complex that mediates splicing of nascent transcripts.

Glycogenolysis

The breakdown of glycogen into glucose monomers. This occurs in liver and muscle tissues following stimulation with glucagon or catecholamines.

Gluconeogenesis

The hepatic production of 'new glucose' from glycerol, pyruvate or Ala in response to glucagon, catecholamines and cortisol.

Heterotrimeric G protein

A membrane-associated protein complex, composed of α-, β- and γ-subunits, that associates with G protein-coupled receptors and mediates induction of intracellular signalling pathways in response to ligand binding.

β-oxidation

A fatty acid metabolic pathway that occurs in mitochondria and peroxisomes. Fatty acids are metabolized to acetyl-coA and then processed through the tricarboxylic acid (TCA) cycle.

Ketogenesis

A metabolic pathway in liver tissue that generates ketones (acetoacetate and β-hydroxybutyrate) using acetyl-coA from the β-oxidation pathway. Ketones provide an important fuel source for the brain and other tissues during long term fasting.

O-glycosylation

The enzymatic addition of a glycan to Ser or Thr residues in proteins. O-glycosylation is thought to compete with phosphorylation in regulating protein function.

Hexosamine biosynthetic pathway

(HBP). An offshoot of the glycolytic pathway that normally accounts for 2–5% of glucose flux. The HBP generates UDP-glucosamine, which is used for O-glycosylation of proteins. Glucose flux through the HBP is increased in diabetes, in which it is thought to contribute to insulin resistance through the O-glycosylation of key proteins in the insulin signalling pathway.

Incretin hormones

A family of gastrointestinal hormones that are released into the circulation in response to oral feeding. They promote insulin release from β-cells of the pancreatic islets.

Sympathetic outflow

Activity of the sympathetic nervous system, which receives regulatory input from the hypothalamus. Among other functions, sympathetic nerve activity regulates heart rate, blood pressure and fat burning.

Hepatic steatosis

Pathological increases in hepatic lipid content that are often associated with obesity and insulin resistance. Also referred to as 'fatty liver'.

Arcuate cell

One of a group of neurons in the hypothalamus that mediate effects of leptin and other signals on appetite through the expression of specific neuropeptides.

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Altarejos, J., Montminy, M. CREB and the CRTC co-activators: sensors for hormonal and metabolic signals. Nat Rev Mol Cell Biol 12, 141–151 (2011). https://doi.org/10.1038/nrm3072

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