text: Recently it has been shown that a Michaelian signaling pathway can be converted to an ultrasensitive signaling pathway by the introduction of two positive feedback loops. In this synthetic biology approach, Palani and Sarkar began with a linear, graded response pathway, a pathway that showed a proportional increase in signal output relative to the amount of signal input, over a certain range of inputs. This simple pathway was composed of a membrane receptor, a kinase and a transcription factor. Upon activation the membrane receptor phosphorylates the kinase, which moves into the nucleus and phosphorylates the transcription factor, which turns on gene expression. To transform this graded response system into an ultrasensitive, or switch-like signaling pathway, the investigators created two positive feedback loops. In the engineered system, activation of the membrane receptor resulted in increased expression of both the receptor itself and the transcription factor. This was accomplished by placing a promoter specific for this transcription factor upstream of both genes. The authors were able to demonstrate that the synthetic pathway displayed high ultrasensitivity and bistability.
  Recent computational analysis of the effects of a signaling proteins concentration on the presence of an ultrasensitive response has come to complementary conclusions about the influence of a signaling proteins concentration on the conversion of a graded response to an ultrasensitive one. Rather than focus on the generation of signaling proteins through positive feedback, however, the study instead focused on how the dynamics of a signaling proteins exit from the system influences the response. Soyer, Kuwahara, and  Csika´sz-Nagy devised a signaling pathway composed of a protein (P) that possesses two possible states (unmodified P or modified P*) and can be modified by an incoming stimulus E. Furthermore, while the unmodified form, P, is permitted to enter or leave the system, P* is only allowed to leave (i.e. it is not generated elsewhere). After varying the parameters of this system, the researchers discovered that the modification of P to P* can shift between a graded response and an ultrasensitive response via the modification of the exit rates of P and P* relative to each other. The transition from an ultrasensitive response to E and a graded response to E was generated when the two rates went from highly similar to highly dissimilar, irrespective of the kinetics of the conversion from P to P* itself. This finding suggests at least two things: 1) the simplifying assumption that the levels of signaling molecules stay constant in a system can severely limit the understanding of ultrasensitivitys complexity; and 2) it may be possible to induce or inhibit ultrasensitivity artificially by regulating the rates of the entry and exit of signaling molecules occupying a system of interest.