Cyclic Adenosine 3′,5′-Monophosphate Response Element Binding Protein (CREB) and Related Transcription-Activating Deoxyribonucleic Acid-Binding Proteins*

THE COMPLEX metabolic activities of cells respond to environmental cues by sensing transmitter substances known as ligands or hormones. The mechanisms of such sensing involves the activation of signaling pathways resulting in changes in gene expression and cellular metabolism (1, 2). Small hydrophobic molecules such as steroid and thyroid hormones and retinoids readily traverse the plasma membrane of the cell and bind to and activate their cognate cytoplasmic or nuclear receptors (reviewed in Refs. 3–7). More complex ligands, however, such as peptide hormones, are unable to enter the cell directly and instead recognize and bind to receptors located on the surface of the cell. Thereby the receptor serves as the communicative link between the outside and inside of the cell. In addition to binding its specific ligand the receptor has the important function of activating signal transduction pathways by way of coupling to GTP-binding proteins (G proteins) (8, 9) or to autophosphorylate itself in response to conformational changes induced by the binding of ligand (10,11).