Supramolecular complex formation in cell signaling and disease: An update on a recurrent theme in cell life and death

Abstract

In summary, this limited discussion of recent developments concerning a few signaling pathways and associated cellular systems hopefully underscores the importance of multiprotein complex formation in cellular signaling, the major theme of an international symposium held September 2002 in Santiago, Chile. Perhaps the most fascinating emerging subject is the importance of membranes in many aspects of signaling. Some 25 years ago, the observation that DAG serves as a physiologically-relevant activator of PKC gave rise to the concept of lipid second messengers, thereby completely changing the way lipids were viewed (reviewed in Quest, et al., 1996). Now, with the description of membrane microdomains (rafts, caveolae), we are beginning to appreciate the complexity of lipid: organization within membranes and the role these highly-dynamic surfaces play as platforms for the assembly of many of the protein complexes employed in signaling. Indeed, such surface-bound complex assembly is not limited to the plasma membrane only. Intracellular membrane surfaces such as endosomes also are employed for the assembly of complexes related, for instance, to growth factor signaling (Wang, et al., 2004). Given such insight and the already well-documented role of intracellular compartments, such as mitochondria and the ER in addition to the plasma membrane, in cell death-related events, appreciation of the importance of membranes in signaling can be expected to increase considerably in the near future. Together with the wealth of sequence information available in databases that will continue to help unravel the secrets of modular protein organization, we suspect that compartmentalization and complex formation will remain recurrent themes in cellular signaling and disease for many years to come.