Skip to main content

Advertisement

Figure 1 | BMC Systems Biology

Figure 1

From: Kinase inhibitors can produce off-target effects and activate linked pathways by retroactivity

Figure 1

Retroactivity arises due to enzyme sequestration in covalently modified cascades. A simple signaling cascade is depicted where each sequential cycle represents the activation (denoted by *) and inactivation of protein Y i . Y1* serves as the activating enzyme of Y2 and Y2* serves as the activating enzyme of Y3. The cycles can be thought of as modules where each module's substrate sequesters a key component of the previous module, limiting the component's ability to participate in the previous module. This sequestration induces a natural change in the preceding module which may propagate upstream through one or more preceding modules. In this example, a perturbation in the deactivation reaction of cycle 3 induces an effect in cycle 2. If the perturbation takes the form of an increase in the concentration or activity of the enzyme catalyzing the conversion of Y3* to Y3, more Y3 will be available to react with and sequester Y2*, resulting in less Y2 substrate availability for the reaction with Y1*. Thus, a reverse response can propagate upstream to a preceding cycle or cycles. In the schematic, black arrows represent the cell surface to nucleus direction of cellular signaling and red arrows represent the direction of retroactive signaling.

Back to article page