Regulation of signal transduction by protein targeting: the case for CaMKII.

Protein targeting is increasingly being recognized as a mechanism to ensure speed and specificity of intracellular signal transduction in a variety of biological systems. Conceptually, this is of particular importance for second-messenger-regulated protein kinases with a broad spectrum of substrates, such as the serine/threonine protein kinases PKA, PKC, and CaMKII (cyclic-AMP-dependent protein kinase, Ca(2+)-phospholipid-dependent protein kinase, and Ca(2+)/calmodulin-dependent protein kinase II). The activating second messengers of these enzymes can be produced or released in response to a large variety of "upstream" signals, and they can, in turn, regulate a large variety of "downstream" proteins. Targeting, e.g., via anchoring proteins, can link certain incoming stimuli with specific outgoing signals by restricting the subcellular compartment at which activation and/or action of a signaling molecule can take place. Elegant research on PKA and PKC reinforced the biological importance of such mechanisms. We will focus here on CaMKII, as recent advances in the understanding of its targeting have some significant general implications for signal transduction. The interaction of CaMKII with the NMDA receptor, for instance, shows that a targeting protein can not only specify the subcellular localization of a signaling effector, but can also directly influence its regulation.