Abstract
BackgroundPositive and negative feedback loops are ubiquitous motifs
in biochemical signaling pathways. The mitogen-activated protein
kinase (MAPK) pathway module is part of many distinct signaling networks
and comprises several of these motifs, whose functioning depends
on the cell line at hand and on the particular context.The maintainance
of specificity of the response of the MAPK module to distinct stimuli
has become a key paradigm especially in PC-12 cells, where the same
module leads to different cell fates, depending on the stimulating
growth factor.This cell fate is regulated by differences in the ERK
(MAPK) activation profile, which shows a transient response upon
stimulation with EGF, while the response is sustained in case of
NGF. This behavior was explained by different effective network topologies.
It is widely believed that this sustained response requires a bistable
system. ResultsIn this study we present a sampling-based Bayesian
model analysis on a dataset, in which PC-12 cells have been stimulated
with different growth factors. This is combined with novel analysis
methods to investigate the role of feedback interconnections to shape
ERK response. Results strongly suggest that, besides bistability,
an additional effect called quasi-bistability can contribute to explain
the observed responses of the system to different stimuli. Quasi-bistability
is the ability of a monostable system to maintain two distinct states
over a long time period upon a transient signal, which is also related
to positive feedback, but cannot be detected by standard steady state
analysis methods. ConclusionsAlthough applied on a specific example,
our framework is generic enough to be also relevant for other regulatory
network modeling studies that comprise positive feedback to explain
cellular decision making processes. Overall, this study advices to
focus not only on steady states, but also to take transient behavior
into account in the analysis.
Links and resources
Tags
community
