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Open cascades as simple solutions to providing ultrasensitivity and adaptation in cellular signaling.

Abstract：

:Cell signaling is achieved predominantly by reversible phosphorylation-dephosphorylation reaction cascades. Up until now, circuits conferring adaptation have all required the presence of a cascade with some type of closed topology: negative-feedback loop with a buffering node, or incoherent feed-forward loop with a proportioner node. In this paper--using Goldbeter and Koshland-type expressions--we propose a differential equation model to describe a generic, open signaling cascade that elicits an adaptation response. This is accomplished by coupling N phosphorylation-dephosphorylation cycles unidirectionally, without any explicit feedback loops. Using this model, we show that as the length of the cascade grows, the steady states of the downstream cycles reach a limiting value. In other words, our model indicates that there are a minimum number of cycles required to achieve a maximum in sensitivity and amplitude in the response of a signaling cascade. We also describe for the first time that the phenomenon of ultrasensitivity can be further subdivided into three sub-regimes, separated by sharp stimulus threshold values: OFF, OFF-ON-OFF, and ON. In the OFF-ON-OFF regime, an interesting property emerges. In the presence of a basal amount of activity, the temporal evolution of early cycles yields damped peak responses. On the other hand, the downstream cycles switch rapidly to a higher activity state for an extended period of time, prior to settling to an OFF state (OFF-ON-OFF). This response arises from the changing dynamics between a feed-forward activation module and dephosphorylation reactions. In conclusion, our model gives the new perspective that open signaling cascades embedded in complex biochemical circuits may possess the ability to show a switch-like adaptation response, without the need for any explicit feedback circuitry.

journal_name

Phys Biol

journal_title

Physical biology

authors

Srividhya J,Li Y,Pomerening JR

doi

10.1088/1478-3975/8/4/046005

subject

Has Abstract

pub_date

2011-08-01 00:00:00

pages

046005

issue

eissn

1478-3967

issn

1478-3975

pii

S1478-3975(11)87140-2

journal_volume

pub_type

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Open cascades as simple solutions to providing ultrasensitivity and adaptation in cellular signaling.