Introduction To Signaling

When Rodbell and co-workers discovered the role of cyclic adenosine monophosphate (cAMP) as a cellular second messenger, the world of life sciences moved to a new conceptual plateau.1-5 Since then, signaling, in and out of cells, through or bypassing the genome has become a protracted and revealing focus of investigation and discovery. In 1979, the breakthrough discovery that the activity of an enzyme can be reversibly regulated through the action of phosphatases and kinases greatly enriched the concept of cellular homeostasis: how it is maintained in health and disrupted in disease states.6 Tyrosine phosphorylation was also uncovered as a mediator of growth control,7 and mitogen-activated protein kinase signaling was discovered by groups studying transcription factor phosphorylation and protein-serine kinases activated by receptor protein tyrosine kinases.8 The identification of a large family of small monomeric G proteins was a giant step forward in understanding intracellular signaling.9 Ras was the first protein found to be conserved from yeast to vertebrates, and Ras-associated signaling pathways include Sos,10 guanosine triphosphate-guanosine diphosphate (GTP-GDP) exchange, Ras-GAP, and Raf.11 Finally, the discovery of transcription factor NFkB was important in understanding nuclear translocation of a cytoplasmically sequestered transcription factor.12

Cell death has been a topic of scientific interest for more than a century. Virchow13 suggested the importance of cell death in atheromas, and at the gross level, the process was described as degeneration, mortification, softening, and necrosis of cells. Since the acknowledgment that apoptosis is as fundamental to cellular and tissue physiology as are cell division and differentiation, apoptosis has become the focus of intense scientific inquiry. Originally, regulators of the executioner phase of apoptotic cell death were discovered in the nematode Caenorhabditis elegans.14'15 The finding that ced-3 encodes a protein that is highly homologous to the mammalian interleukin-1P-converting enzyme strongly suggests that the biochemical events governing apoptosis are highly conserved from nematodes to mammals.14

There are currently 14 known human homologues in the caspase family.16 The specificity of caspases-2, -3, and -7 and CED-3 (DEXD) suggests that these enzymes may function to incapacitate essential homeostatic pathways during the effector phase of apop-tosis by proteolyzing and deactivating functional proteins.17 Conversely, the optimal substrate specificity for caspases-6, -8, and -9 and granzyme B ([I/L/V]EXD) corresponds to cleavage sites in effector caspase proenzymes, suggesting that these enzymes may activate cleavages downstream of executioner caspases, resulting in a proteolytic cascade that amplifies the death signal.17 More than 70 caspase substrates have now been identified, which are involved in cell regulation, signaling, DNA repair, homeostasis, and survival.16 As noted, apoptosis is now known to be involved in many physiologic and pathologic processes including viral infection.

It was once thought that infection by viruses simply involved overwhelming the cellular transcriptional and translational machinery and compromise of membrane integrity.18 Indeed, acute infection by certain viruses can lead to oncotic death.19'20 However, some viruses can disrupt host cell transcriptional and translational apparatus or use viroporins to alter membrane permeability to cause cell death.21 Still other viruses take advantage of apoptotic apparatus to induce cell death.22 In fact, many of the cellular antiapoptotic or proapoptotic proteins and genes were discovered by virologists.23-25 The Src protein tyrosine kinase was originally discovered as v-Src, a Rous sarcoma virus oncogene product.25 Thus, viruses can modulate host apoptotic machinery to prolong infection or kill the cell. If an "apoptotic" virus is blocked by host antiapoptotic proteins, the virus can actively kill the cell by necrosis. Pro-life signaling may save the cell by activation of a stress response or other antiapoptotic mechanisms.

Are pro-life and pro-death signaling occurring all of the time? It is conceivable that life signaling and death signaling are in fact occurring concomitantly and continuously throughout the life of any given cell, usually balanced in opposition to each other but in favor of life. Ultimately, such a balance may swing toward death by environmental insults (like viruses) or by telomerases.26 Thus, loss or gain of specific signaling may lead to catastrophic one-sidedness and the occurrence of either cell death or cell survival.27

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