Phosphorylated CREB

The detailed mechanisms involved in CREB phosphorylation were first established for the cAMP pathway. A first messenger that increases cAMP concentrations leads to activation of PKA and to translocation of the free catalytic subunit of the protein kinase into the nucleus, where it phosphorylates CREB on serine 133. Such phosphorylation then promotes the binding of CREB to a CREB-binding protein (CBP). CBP, upon binding CREB, interacts directly with the RNA polymerase II complex, which mediates the initiation of transcription. In most cases, such interactions lead to the activation of transcription, although it is possible that the expression of some genes may be repressed. 

The critical feature of CREB protein activation is phosphorylation, which is required for CREB-mediated stimulation of transcription [16]. PKA phosphorylates CREB on a serine positioned at amino acid 133 in the CREB protein sequence. How phosphorylation activates... 

Strong evidence also exists that the CaMKK/CaMKIV cascade regulates CREB activity in mice. As mentioned at the beginning of this section, several CaMKs can phosphorylate CREB at S133 and activate its transcriptional function in vitro and in cultured mammalian cells. However, it required analysis of mice null for the Camk4... 

Wilson, B. E., Mochon, E. and Boxer, L. M., 1996, Induction of bcl-2 expression by phosphorylated CREB proteins during B-cell activation and rescue from apoptosis, Mol Cell Biol, 16, pp 5546-56. 

Stimulation of (3-ARs leads to activation of Gs protein, resulting in a subsequent increase in cAMP. This increase in cAMP induces stimulation of PKA and phosphorylation of the transcription factor cAMP responsive element binding protein (CREB). After this phosphorylation, CREB binds to the cAMP-responsive element in the promoter of many genes (Tan et al., 2007). 

Davies, M. F., Tsui, J., Flannery, J. A., Li, X., DeLorey, T. M. Hoffman, B. B. (2004). Activation of alpha2 adrenergic receptors suppresses fear conditioning Expression of c-fos and phosphorylated CREB in mouse amygdala. Neuropsychopharmacology, 29, 229-239. 

As indicated in Chapters 5, 7 and 8, transcription can be switched on by a variety of signalling pathways. Thus, cAMP-mediated pathways generate phosphorylated CREB proteins that activate expression of particular proteins by binding to promoters called cAMP response elements (GREs). Similarly, Ca2+-dependent PKC activation results in phosphorylation of transcription factors that bind to and activate tetradecanoylphorbol ester response element (TRE) promoters. In the immune response bacterial lipopolysaccharide (LPS) and particular cytokines can switch on signalling pathways resulting in activation of transcription factors such as NFkB (Chapter 7) with resultant expression of proteins such as cytokines,... 

How does the phosphorylation of CREB affect its ability to activate transcription Phosphorylation does not appear to alter the DNA-binding properties of this protein. Instead, phosphorylated CREB binds a coactivator protein termed CBP, for CREB-Z)inding /rotein. CBP possesses a highly revealing domain structure (Figure 31.32). 

Nine cloned mammalian adenylylcyclases (ACs) can be activated by stimulatory a subunits (Gas) and several are modulated by inhibitory a subunits (Ckti) and/or Gp/y complexes. cAMP can activate the PKA, which in turn phosphorylates a wide range of substrates, such as the cAMP responsive element binding protein (CREB). When PICA translocates to the nucleus and phosphorylates CREB, the latter is stimulated to regulate gene transcription. There are three mammalian phospholipase C (PLC) isoforms families PLC-P, PLC-y and PLC-6. The first is activated by serpentine receptors, while the second is stimulated by RTKs. 

Some signaling pathways cross from the MAP kinase pathway to phosphorylate CREB, and all heterotrimeric G protein pathways diverge to include a route to the MAP kinase pathway. These types of complex interconnections in signaling pathways are sometimes called hormone cross-talk. 

Nonreceptor kinases, such as protein kinase A, also regulate transcription factors through phosphorylation. Many hormones generate the second messenger cAMP, which activates protein kinase A. Activated protein kinase A enters the nucleus and phosphorylates the transcription factor CREB (cAMP response element binding protein). CREB is constitutively bound to the DNA response element CRE (cAMP response element) and is activated by phosphorylation. Other hormone signaling pathways, such as the MAP kinase pathway, also phosphorylate CREB (as well as many other transcription factors). 

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