  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.
