Figure 1

A hypothetical multi-step signaling cascade. The diagram shown is based on the classical MAP kinase activation pathway. The core of such signaling cascades comprises a series of enzymes (protein kinases) that sequentially activate each other (shown as A1, A2 and A3 in the unphosphorylated and inactive state, and as A1*, A2* and A3* in the phosphorylated and active state) so as to propagate a cellular response to a signal, as well as the opposing enzymes (for example, phosphatases) and other factors (such as ubiquitin-mediated degradation) that inactivate them (shown as I1*, I2* and I3*). Upstream and downstream factors in this schematic multi-tiered signal transduction cascade are not shown. The in silico analyses discussed in this article indicate that activating processes primarily control the strength of both the basal and signal-induced output (indicated by bars), whereas inhibitory processes control both output strength and the rate and/or duration of signal propagation (indicated by clocks). These studies conclude that, compared with single-step pathways (like the TGFβ- and PKA-mediated transcription factor activation described in the text), a cascade exhibits ultrasensitivity (resistance to stochastic noise and switch-like responsiveness), signal amplification and optimized signal transmission speed (see also Table 1). In addition, in a cascade, there is the opportunity potentially to exert very fine-tuned regulation of pathway output because there are multiple points at which different factors can be used to control the amount and/or level of activity of the pathway constituents and their temporal response characteristics.