Noise in cellular signaling pathways: causes and effects

Abstract

Noise caused by stochastic fluctuations in genetic circuits (transcription and translation) is now appreciated as a central aspect of cell function and phenotypic behavior. Noise has also been detected in signaling networks, but the origin of this noise and how it shapes cellular outcomes remain poorly understood. Here, we argue that noise in signaling networks results from the intrinsic promiscuity of protein-protein interactions (PPIs), and that this noise has shaped cellular signal transduction. Features promoted by the presence of this molecular signaling noise include multimerization and clustering of signaling components, pleiotropic effects of gross changes in protein concentration, and a probabilistic rather than a linear view of signal propagation.

Figure 1

Classical linear signaling versus the high-connectivity interactome. The high number and intricacy of protein-protein interactions revealed by the human interactome ^- (Figure taken from http://www.unihi.org/) (right panel) and kinome is in contrast to the traditionally depicted linear signaling cascades, where each component of the pathway interacts with only a few others (left panel), from the membrane-localized receptor (elongated blue oval) to the nucleus (gray oval).

Figure 2

Ligand binding surfaces of SH3 domains. Despite belonging to different proteins, and despite being implicated in different signaling pathways[sta12], the molecular characteristics of SH3 ligand binding surfaces are highly similar. From top to bottom:[sta13] CIN85 (PDB id 2BZ8), Fyn (1SHF), Grb2 C-terminal (2W0Z), Abl (1BBZ). Surfaces are colored according to blue, positively charged atoms; red, negatively charged atoms; green, hydrophobic atoms; salmon, polar oxygens; marine, polar nitrogens; yellow, sulfur.

Figure 3

Examples of how signaling noise shapes cellular signal transduction. (A) Left: The signal (arrow) arising from one signaling receptor (elongated blue oval) at the membrane (beige) is not enough to overcome the threshold created by signaling noise. Right: Receptor multimerization is required to amplify the signal sufficiently to overcome the signaling threshold created by noise from promiscuous PPIs. Red dot: biologically relevant ligand; black dot: biologically nonrelevant ligand. (B) Functional selectivity through formation of multicomponent signaling complexes allows proofreading; a structurally similar but physiologically nonrelevant partner may bind to certain partially assembled components, but only the synergy of a correctly assembled complex (second from left) allows signal transduction to occur. First complex from left and first from right represent stalled complexes misassembled at different stages; second from right represents an incompletely assembled complex. Biologically nonrelevant homologues are indicated by the same shape and different color as the biologically relevant ligand in the correct signaling complex. (C) Grossly changing the concentration of one molecule may influence even signaling pathways for which this molecule is not a biologically relevant component. For example, before overexpression of the biologically nonrelevant ligand (black dot), a sufficient number of the biologically relevant ligand (red dot) could bind to its cognate receptor, initiating an above-threshold signal. After overexpression of the nonrelevant ligand, competition causes the number of biologically relevant ligands bound to the receptor to decrease. As a result, the ensuing signal remains below the noise threshold and cannot trigger a cellular response.