The Pleiotropic Face of CREB Family Transcription Factors

Abstract

cAMP responsive element-binding protein (CREB) is one of the most intensively studied phosphorylation-dependent transcription factors that provide evolutionarily conserved mechanisms of differential gene expression in vertebrates and invertebrates. Many cellular protein kinases that function downstream of distinct cell surface receptors are responsible for the activation of CREB. Upon functional dimerization of the activated CREB to cis-acting cAMP responsive elements within the promoters of target genes, it facilitates signal-dependent gene expression. From the discovery of CREB, which is ubiquitously expressed, it has been proven to be involved in a variety of cellular processes that include cell proliferation, adaptation, survival, differentiation, and physiology, through the control of target gene expression. In this review, we highlight the essential roles of CREB proteins in the nervous system, the immune system, cancer development, hepatic physiology, and cardiovascular function and further discuss a wide range of CREB-associated diseases and molecular mechanisms underlying the pathogenesis of these diseases.

Keywords: CREB; cAMP responsive element; differential phosphorylation; neurodegenerative diseases; pleiotropic.

Fig. 1. Signaling pathways that activate CREB.

Upon ligand binding, G protein-coupled receptors (GPCRs) can activate adenylyl cyclase (AC), converting ATP to cAMP that activates protein kinase A (PKA). The phosphorylation of CREB by PKA can promote target gene transcription through binding to cAMP response element (CRE). In addition, forskolin significantly induce activation of CREB by the stimulation of adenylyl cyclase. The binding of growth factors to receptor tyrosine kinases (RTKs) stimulates the activation of multiple protein kinases including MSK1, p90RSK, and AKT, which is then followed by phosphorylation and activation of CREB. In contrast, GSK3β-mediated phosphorylation can lead to inactivation of CREB. Stress inducers also activate CREB via p38 and MSK1. Furthermore, calcium influx via the calcium channels and NMDA receptors results in the activation of Ca²⁺/CaMKs, such as CaMKII and CaMKIV, and PKA, upregulating CREB-target gene expression. CREB, cAMP responsive element-binding protein.

Fig. 2. CREB-mediated neurite outgrowth.

CREB activation is required for neural cell adhesion molecule (NCAM)-mediated neurite outgrowth. Homophilic interactions of NCAM activate Fyn and FAK kinases that results in the sequential activation of Ras, Raf, MEK, and ERK, finally phosphorylating CREB. Activation of CREB consequently induces target gene expression responsible for neurite outgrowth. CREB, cAMP responsive element-binding protein; FGFR, fibroblast growth factor receptor; CRE, cAMP response element.

Fig. 3. CREB-induced immune response.

CREB plays crucial roles in the innate immune system that involves Toll-like receptors (TLRs) and their activation. As part of NF-κB signaling pathway that induces production of pro-inflammatory cytokines, such as interleukin (IL)-6, IL-1β, and tumor necrosis factor α (TNF-α), phosphorylated CREB directly inhibit NF-κB activation by interfering with the binding of CREB-binding protein (CBP) to the RelA/p50 complex. On the other hand, TLR signaling leads to the activation of MSK1/2, which induces phosphorylation of CREB and then production of anti-inflammatory cytokine IL-10. This CREB-induced IL-10 production can be negatively regulated by interferon-γ (IFN-γ). CREB, cAMP responsive element-binding protein; LPS, lipopolysaccharide.