The confluence of genetics, biochemistry, and structural biology has given us an increasingly detailed view of how signals are transmitted from the cell surface and transduced into changes in cellular behavior. The multitude of different extracellular signals, receptors for those signals, and intracellular signal transduction pathways fall into a relatively small number of classes, and one major goal is to understand how similar signaling pathways often regulate very different cellular processes in different types of cells. As we noted, STATs, Smads, SRF, and TCF, among many others, are each activated in different cell types by the same or different hormones, yet these proteins activate very different sets of genes in different cell types. Presumably these activated transcription factors interact with different groups of “master” transcription factors and with different chromatin-modifying and reading enzymes in these different cell types, but the nature of most of these proteins and how they collaborate to induce cell-specific patterns of gene expression remain to be uncovered.

Conversely, activation of the same signal transduction component in the same cell through different receptors often elicits different cellular responses. One commonly held view is that the duration of activation of the MAP kinase and other signaling pathways affects the pattern of gene expression. But how this specificity is determined remains an outstanding question in signal transduction. A combination of genetic and molecular studies in flies, worms, mice, and humans will continue to contribute to our understanding of the interplay between different pathway components and the underlying regulatory principles controlling specificity in multicellular organisms.

Researchers have determined the three-dimensional structures of many signaling proteins during the past several years, permitting more detailed analysis of several signal transduction pathways. The molecular structures of different kinases, for example, exhibit striking similarities, yet also show many important variations that impart novel regulatory features. The activity of several kinases, such as Raf and protein kinase B (PKB), is controlled by inhibitory domains as well as by multiple phosphorylations catalyzed by several other kinases. Our understanding of how the activity of these and other kinases is precisely regulated to meet the cell’s needs will require additional structural and cell biological studies.

Abnormalities in signal transduction underlie many different diseases, including the majority of cancers and many inflammatory conditions. Detailed knowledge of the signaling pathways involved and the structure of their protein components will continue to provide important molecular clues for the design of specific therapies. Despite the close structural relationship between different signaling molecules (e.g., kinases), recent studies suggest that inhibitors selective for specific subclasses can be designed. In many tumors of epithelial origin, the EGF receptor has undergone a specific mutation that increases its activity. Remarkably, a small-molecule drug (Iressa) inhibits the kinase activity of the mutant EGF receptor, but has no effect on the normal EGF receptor or other receptors. Thus the drug slows cancer growth only in patients with this particular mutation. Similarly, monoclonal antibodies or decoy receptors (soluble proteins that contain the ligand-binding domain of a receptor and so sequester the ligand) that prevent pro-inflammatory cytokines such as IL-1 and TNF-α from binding to their cognate receptors are now being used in treatment of several inflammatory diseases such as arthritis.