cases an external molecule dramatically affects cellular function. Our goal in studying any of these processes is the same: a molecule-by-molecule accounting of information transfer in biological systems.

While the prospect of analyzing every possible biological signal is daunting, the recognition that nature tends to use the same basic mechanism in a variety of guises makes the task less formidable. The repeated use of a common pathway is nicely illustrated by the immunosuppressive agents FK506, rapamycin, and cyclosporin. Their ability to disrupt signaling in T-cells leads to immunosuppressive activity, but the same molecules that disrupt signals in T-cells also prevent the degranulation of mast cells and inhibit the proliferation of yeast (2, 4). We could equally well call them antifungal, insecticidal, antiinflammatory, antiallergic, or antiretroviral as well as immunosuppressive agents (2, 4).

Another connection between cellular signal transduction and chemical ecology is the essential role played by natural products—secondary metabolites with no known role in the internal economy of the producing organism (5). Cyclosporin A (CsA), FK506, and rapamycin are all microbial natural products that are probably synthesized to chemically defend their producing organism (5). Studying these natural products as microbial chemical warfare agents would unarguably qualify as chemical ecology. However, the similarity of signaling pathways allows us to use these same natural products as probes of cellular signaling or as important chemotherapeutic agents in human disease.

The rest of this paper will focus on the factors affecting one step in one signaling pathway in resting helper T cells. The inquiry may appear overly specialized, but the strategy nature employs, using a small natural product to link two much larger proteins, has only recently been appreciated. Now that we recognize the strategy, we can expect to see it again.


The signal to activate a resting helper T-cell can be divided into three parts: the extracellular recognition of an antigen by the membrane-spanning T-cell receptor (TCR), the cytoplasmic signal transduction cascade that transmits the recognition information to the nucleus, and the activation of genes in the nucleus (3, 6). The TCR recognizes the foreign antigen, a processed peptide held in the cleft of the major histocompatibility complex (MHC) protein on the surface of the antigen-presenting cell (7, 8). Some additional interactions be-

The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement