Ultrasensitive Responses and Specificity in Cell Signaling

Abstract

BackgroundInterconnected cell signaling pathways are able to efficiently and accurately transmit a multitude of different signals, despite an inherent potential for undesirable levels of cross-talk. To ensure that an appropriate response is produced, biological systems have evolved network-level mechanisms that insulate pathways from crosstalk and prevent 'leaking' or 'spillover' between pathways. Many signaling pathways have been shown to respond in an ultrasensitive (switch-like) fashion to graded input, and this behavior may influence specificity. The relationship of ultrasensitivity to signaling specificity has not been extensively explored.ResultsWe studied the behavior of simple mathematical models of signaling networks composed of two interconnected pathways that share an intermediate component, asking if the two pathways in the network could exhibit both output specificity (preferentially activate their own output) and input fidelity (preferentially respond to their own input). Previous results with weakly-activated pathways indicated that neither mutual specificity nor mutual fidelity were obtainable in the absence of an insulating mechanism, such as cross-pathway inhibition, combinatorial signaling or scaffolding/compartmentalization. Here we found that mutual specificity is obtainable for hyperbolic or ultrasensitive pathways, even in the absence of an insulating mechanism. However, mutual fidelity is impossible at steady-state, even if pathways are hyperbolic or ultrasensitive. Nevertheless, ultrasensitivity does provide advantages in attaining specificity and fidelity to networks that contain an insulating mechanism. For networks featuring cross-pathway inhibition or combinatorial signaling, ultrasensitive activation can increase specificity in a limited way, and can only be utilized by one of the two pathways. In contrast, for networks featuring scaffolding/compartmentalization, ultrasensitive activation of both pathways can dramatically improve network specificity.ConclusionsThere are constraints to obtaining performance objectives associated with signaling specificity; such constraints may have influenced the evolution of signal transduction networks. Notably, input fidelity (preferential response to an authentic input) is a more difficult objective to achieve than output specificity (preferential targeting to an authentic output). Indeed, mutual fidelity is impossible in the absence of an insulating mechanism, even if pathways are ultrasensitive. Ultrasensitivity does, however, significantly enhance the performance of several insulating mechanisms. In particular, the ultrasensitive activation of both pathways can provide substantial improvement to networks containing scaffolding/compartmentalization.

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“…However, cross-talks have to be precisely regulated to maintain output specificity (meaning that inputs preferentially activate their own output) and input fidelity (meaning that outputs preferentially respond to their own input). Regulation of crosstalks to prevent ‘leaking’ or ‘spillover’ can be achieved using different mediation mechanisms, such as scaffolding proteins, cross-pathway inhibitions, kinetic insulation, and the spatial and temporal expression patterns of proteins (Freeman, 2000; Bhattacharyya et al, 2006; Kholodenko, 2006; Behar et al, 2007; Haney et al, 2010; Lewitzky et al, 2012). …”

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“…Recent studies have begun to address how signaling networks generate stimulus-specific responses (Bardwell, 2006; Haney et al, 2010; Hao et al, 2008; Zalatan et al, 2012). For example, the activity of some pleiotropic kinases may be steered to particular targets by scaffold proteins (Berger and Iyengar, 2010; Schrofelbauer et al, 2012; Zalatan et al, 2012).…”

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“…Multiple interactions and bidirectional signalling may affect the input-output response of pathways, and may be particularly relevant to investigating signalling crosstalk [17-19]. Crosstalk occurs when multiple pathways share components.…”