The Mammalian MAPK/ERK Pathway Exhibits Properties of a Negative Feedback Amplifier

Sci. Signal.  21 Dec 2010:
Vol. 3, Issue 153, pp. ra90
DOI: 10.1126/scisignal.2001212

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Biological Circuits Inform Drug Development

The mitogen-activated protein kinase (MAPK) pathway involves a three-tiered kinase module, which amplifies the signal. Many cells also have negative feedback loops from the last kinase in the module to various points upstream in the pathway. Sturm et al. showed that, with negative feedback loops, the MAPK module results in a system like that of a negative feedback amplifier (NFA), which is an engineering design that smoothens the output to changes in input and makes a system robust to change. These NFA-like properties may explain why some cells are sensitive to inhibition of the second kinase in the cascade (they lack feedback loops), whereas other cells are resistant to inhibition at this point (their feedback loops are intact). These results also have implications for drug development, because inhibitors that target components that are outside the NFA are more effective at inhibiting the pathway.

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