MAPK Cascades as Feedback Amplifiers

TL;DR

This paper proposes that MAPK cascades function as biochemical feedback amplifiers, providing robustness, linear response, and modularity, supported by experimental evidence of graded responses to growth factors.

Contribution

It introduces a novel interpretation of MAPK cascades as feedback amplifiers, linking their structure to functional advantages in signal transduction.

Findings

MAPK cascades may act as feedback amplifiers.

Experimental evidence shows graded MAPK responses to EGF.

Feedback loops enhance robustness and modularity.

Abstract

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.