A-kinase anchoring proteins and neuronal signaling mechanisms
- Howard Hughes Medical Institute, Vollum Institute, Oregon Health and Sciences University, Portland, Oregon 97201, USA
This extract was created in the absence of an abstract.
The rapid and reversible phosphorylation of proteins catalyzed by protein kinases and protein phosphatases is a well recognized mechanism of regulation in cells. This bidirectional process is a highly flexible method of influencing cellular activity in response to a variety of incoming stimuli. A physiological role for protein phosphorylation was first identified about 50 years ago while investigating the regulation of glycogen metabolism (Fischer and Krebs 1955; Sutherland 1972). In fact, many aspects of gene regulation; cell cycle control, transport, and secretion; actin remodeling; and cell adhesion are controlled by this mechanism (Krebs 1985; Hunter 1995; Pawson and Scott 1997; Cohen 2000; Goodman and Smolik 2000; Pawson and Nash 2000). The utility of protein phosphorylation as the predominant form of covalent modification of proteins in vivo is exemplified by the finding that ∼30% of intracellular proteins are phosphoproteins (Hunter 1987). Not surprisingly, the breakdown in signal transduction may be the cause or consequence of many diseases, including cancer, diabetes, arthritis, and Alzheimer's (Cohen 1999).
Most signaling pathways are composed of common elements. The initial signal is transduced through a receptor at the plasma membrane (such as a G-protein coupled receptor, or a receptor tyrosine kinase or phosphatase), which results in activation of the receptor or the mobilization of receptor-associated proteins to generate some form of intracellular message. This signal is then directed throughout the cell either by the diffusion of a small soluble second messenger or the translocation of an activated enzyme. At a molecular level, phosphorylation mediates the regulation of enzymatic activities by causing allosteric conformational changes, or by directly enhancing or blocking access to enzyme catalytic sites (Johnson and Barford 1990; Barford et al. 1991; Johnson and O'Reilly 1996). More recently it has been realized that an essential feature …