  Interconvertible enzyme cascades, exemplified by the mitogen activated
protein kinase (MAPK) cascade, are a frequent mechanism in signal transduction
pathways. There has been much speculation as to the role of these pathways, and
how their structure is related to their function. A common conclusion is that
the cascades serve to amplify biochemical signals so that a single bound ligand
molecule might produce a multitude of second messengers. Some recent work has
focused on a particular feature present in some MAPK pathways -- a negative
feedback loop which spans the length of the cascade. This is a feature that is
shared by a man-made engineering device, the feedback amplifier. We propose a
novel interpretation: that by wrapping a feedback loop around an amplifier,
these cascades may be acting as biochemical feedback amplifiers which imparts
i) increased robustness with respect to internal perturbations; ii) a linear
graded response over an extended operating range; iii) insulation from external
perturbation, resulting in functional modularization. We also report on the
growing list of experimental evidence which supports a graded response of MAPK
with respect to Epidermal Growth Factor. This evidence supports our hypothesis
that in these circumstances MAPK cascade, may be acting as a feedback
amplifier.
