TABLE 5
Drug insensitivity of signaling cascades due to negative feedback
The response equation of a signaling network with negative feedback (Kholodenko et al., 1997; Bruggeman et al., 2002), (11)was introduced in Table 4. When negative feedback occurs, the feedback term  is negative. When  , which can occur when  or  , the previous equation can be approximated by: (12)This equation represents the slope of the dose-response curve of log D as function of log A. This equation indicates that the response of the output D of a cascade with negative feedback to a change in its input A only depends on the feedback strength, provided the above mentioned conditions are met! This result has remarkable consequences. First, it shows how cells can make their responses to signals insensitive to undesired disturbances that happen in their own signaling networks and affect  . Second, the medical consequence is that the effect of drugs, acting on the signaling cascade and changing  , will not have a huge effect as long as  ; in particular in the case of strong negative feedback, when  (Sturm et al., 2010a; Fritsche-Guenther et al., 2011). |