CREB Signaling Pathway

Introduction

cAMP response element binding protein (CREB) is an important nuclear transcription factor, and its physiological functions are widely expressed in various systems, and it plays an indispensable role in the nervous system. CREB is often used as a termination and junction of many signaling pathways in the nervous system. Its regulated upstream and downstream signaling molecules and their target genes and CREB are involved in normal physiological processes such as neural stem cell proliferation, cell cycle regulation, neuron-induced differentiation, and learning and memory.

CREB transcription factor family

Functional domains related to its transcriptional activity in the CREB molecule include KID region, X region, α region, Q1 region, and Q2 region. The KID region contains a large number of protein kinase phosphorylation sites. Therefore, phosphorylation of KID is the key to CREB activation, and the transcription of related genes can be induced by exposing the Q1 and Q2 regions only after CREB activation. Accordingly, Q1-KID-Q2 is a structure necessary for CREB to perform its transcriptional activity. The CREB/ATF small family functions by binding to the CRE (cAMP response element) element of its downstream gene promoter region, which is a highly conserved 8-base palindrome sequence, 5'-TGACGTCA-3'. Studies have shown that the loss of CRE elements upstream of the gene will result in a 7-fold decrease in the corresponding gene transcription activity. Stress in the body, as a regulatory factor binding of CREB to the CRE one kind of nucleus, by autophosphorylation achieve transcription regulating functions. However, under steady-state conditions, the three CREB isoforms are present in the adult mouse brain in an inactive, non-phosphorylated form.

Figure 1 Model of activity-dependent recruitment of CREB co-activators

CREB related signaling pathway

In cells, extracellular signals interact with receptors on the cell membrane, and after a series of signaling, phosphorylate CREB, regulate downstream gene expression, and exhibit corresponding functions. Phosphorylation of CREB is regulated by cAMP signaling pathway, Ca2+ -CaMK signaling pathway, Ras/ERK signaling pathway, PI3 kinase/Akt signaling pathway, stress-induced P38MAPK pathway, and phosphatase reverse regulation signaling pathway.

Figure 2 Mechanims of activation of CREB-mediated transcription

cAMP-CREB signaling pathway

In the PKA system, there are mainly hormonal substances as signal molecules, which can bind to G protein-coupled receptors (GPCRs) on the cell membrane to activate adenylate cyclase (AC) to regulate the level of second messenger cAMP. Activation of protein kinase A further amplifies the signal, catalyzes the phosphorylation of CREB at position 133 in the nucleus, and regulates the expression of downstream genes. In the nervous system, neurotransmitters and the like can activate adenylate cyclase by GPCR, increase intracellular cAMP levels, activate protein kinases, and phosphorylate CREB. In addition, this signaling pathway can also cause an increase in intracellular Ca 2+ concentration.

Ca2+ -CaMK-CREB signaling pathway

An increase in intracellular Ca2+ levels also phosphorylates CREB. Neurotransmitters activate gene expression through Ca2+-dependent signaling pathways. And CREB acts as a Ca2+-induced second messenger. During long-term memory formation, phosphorylation of various proteins, including CREB, is regulated by Ca2+-dependent forms to form new synaptic connections, and then the information is stored for long periods of time to form long-term memory. PKA inhibitors block this signaling pathway and inhibit the formation of long-term memory. In neurons, the increase in Ca2+ can be achieved in two different ways: one is through a voltage-gated L-type (VGCC) Ca2+ channel on the cell membrane. Depolarization of the membrane allows Ca2+ to enter the cell through the VGCC channel and then increase the intracellular Ca2+ concentration. The second is through the ligand-gated N-type (NMDA) ion channel into the cell. Ca2 + interacts with a variety of molecules, mainly Ca2+ binding proteins (calmodulin, CaM). Among them, intracellular calcium and calmodulin (CaM) have the most obvious effects. Ca2+ binds to CaM and activates CaM kinase I (CaMKI), CaM kinase II (CaMKII) and CaM kinase IV (CaMKIV). In vivo, Ca2+-activated CREB kinase is primarily CaMKIV. In addition, the regulation of the development and function of the nervous system by brain neurotrophic factor (BDNF) is also Ca2+ dependent.

PI3 kinase / Akt-CREB signaling pathway

The PI3/Akt signaling pathway is a major signaling pathway for receptor tyrosine kinase activation and has been shown to be involved in the regulation of many cellular processes including survival, apoptosis, proliferation, and metabolism. The PI3/Akt signaling pathway plays an important role in the activation of CREB. This signaling pathway is a key pathway for dopamine-induced gene expression. The proliferation of hippocampal neural progenitor cells in adults activates CREB via the PI3/Akt signaling pathway, and CREB signaling pathway plays an important role in cell proliferation and apoptosis in leukemia cells. However, it is unclear whether Akt can directly phosphorylate CREB, but there is evidence that at least two major receptor tyrosine kinases can promote CREB phosphorylation via CREB kinase.

The biological function of CREB

CREB has a wide range of biological functions. Early and current research has focused on the nervous system, such as the regulation of biological rhythms, the formation of memory and learning, emotional response, etc., but the role of CREB in other aspects of life activities has gradually been discovered.

CREB participates in immune response

Studies over the past decade have shown that CREB plays an important role in the immune response. The study found that CREB can induce transcription of immune-related genes, including IL-2, IL-6, IL-10, TNF, COX-2, and macrophage migration inhibitors. In endothelial cells and monocytes, activated CREB inhibits NF-κB activity and exerts anti-inflammatory effects. In macrophages, activated CREB induces the expression of two major anti-apoptotic genes, PAI-2 and Bfl-1/A1, which promote macrophage survival and enhance the immune response. T cells in tuberculosis patients, the expression of INF-γ induced CREB to promote Th1 cell response, which play a protective role. Other studies have found that CREB promotes B cell activation and proliferation through a variety of pathways, and whether or not the host is protective depends on the antigen.

CREB and disease

The study found that CREB mRNA and protein levels were elevated in bone marrow samples from patients with acute lymphoblastic leukemia and acute myeloid leukemia. Overexpression of CREB promotes leukemia cell growth and survival, while down-regulation of expression leads to inhibition of leukemia cell proliferation and survival. Thus, CREB expression levels are associated with clinical outcomes in patients with acute leukemia. Studies have shown that CRE-dependent expression of the target gene is deficient and plays an important role in the development of neurodegenerative changes. For example, in the human brain and experimental models of Huntington's disease, CBP is sequestered, and expression of CRE-dependent gene VGF8a, C erbA,  α thyroid hormone receptor, and cathepsin L is reduced.

RGS10 is a Gαi/q/z subunit of GTPase-activating protein that is widely expressed in the immune system and brain tissue. Studies have shown that high expression of RGS10 in differentiated dopamine neuronal cells increases the resistance of cells to TNF-induced inflammatory responses. This protective effect of RGS10 on neurons is mediated by p-CREB, and this process relies on the cAMP/PKA signaling pathway. Beta-eucalyptol (an antitumor drug extracted from plants) inhibits CREB activation through a growth factor signaling pathway, thereby inhibiting tumor angiogenesis. Histamine has an indirect anti-tumor effect. In the rat melanoma model, intraperitoneal injection of histamine can reduce the levels of angiogenic factors such as VEGF and NO in serum and NF-κB and CREB associated with angiogenesis, significantly reducing the formation of tumor capillaries and inhibiting tumors.

References:

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  7. Yamada, T., Amann, J. M., Fukuda, K., Takeuchi, S., Fujita, N., & Uehara, H., et al. (2015). Akt kinase-interacting protein 1 signals through creb to drive diffuse malignant mesothelioma. Cancer Research, 75(19), 4188-97.
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