Deactivation of a Negative Regulator: A Distinct Signal Transduction Mechanism, Pronounced in Akt Signaling

Kinase cascades, in which enzymes are sequentially activated by phosphorylation, are quintessential signaling pathways. Signal transduction is not always achieved by direct activation, however. Often, kinases activate pathways by deactivation of a negative regulator; this indirect mechanism, pervasive in Akt signaling, has yet to be systematically explored. Here, we show that the indirect mechanism has properties that are distinct from direct activation. With comparable parameters, the indirect mechanism yields a broader range of sensitivity to the input, beyond saturation of regulator phosphorylation, and kinetics that become progressively slower, not faster, with increasing input strength. These properties can be integrated in network motifs to produce desired responses, as in the case of feedforward loops.