Functions of Bifans in Context of Multiple Regulatory Motifs in Signaling Networks

TL;DR

This paper investigates the functional roles of bifan motifs in cellular signaling networks, demonstrating their capacity to regulate timing, filter noise, and synchronize outputs, thus enhancing signal processing.

Contribution

It provides a systematic analysis of bifan motifs using differential equations, revealing their intrinsic regulatory functions and interactions with feedback loops in signaling networks.

Findings

Bifan motifs act as signal sorters, filters, and synchronizers.

OR gate bifans enable rapid responses, AND gates introduce delays.

Bifans promote negative feedback via MKP-1 regulation.

Abstract

Representation of intracellular signaling networks as directed graphs allows for the identification of regulatory motifs. Regulatory motifs are groups of nodes with the same connectivity structure, capable of processing information. The bifan motif, made of two source nodes directly cross-regulating two target nodes, is an over-represented motif in a mammalian cell signaling network and in transcriptional networks. One example of a bifan is the two MAP-kinases, p38 and JNK that phosphorylate and activate the two transcription factors ATF2 and Elk-1. We have used a system of coupled ordinary differential equations to analyze the regulatory capability of this bifan motif by itself, and when it interacts with other motifs such as positive and negative feedback loops. Our results indicate that bifans provide temporal regulation of signal propagation and act as signal sorters, filters, and synchronizers. Bifans that have OR gate configurations show rapid responses while AND gate bifans can introduce delays and allow prolongation of signal outputs. Bifans that are AND gates can filter noisy signal inputs. The p38/JNK-ATF2/Elk-1bifan synchronizes the output of activated transcription factors. Synchronization is a robust property of bifans and is exhibited even when the bifan is adjacent to a positive feedback loop. The presence of the bifan promotes the transcription and translation of the dual specificity protein phosphatase MKP-1 that inhibits p38 and JNK thus enabling a negative feedback loop. These results indicate that bifan motifs in cell signaling networks can contribute to signal processing capability both intrinsically and by enabling the functions of other regulatory motifs.