Complex Systems Biology of Networks: The Riddle and the Challenge - Systems Biology of Metabolic and Signaling Networks - page 19

associated with vital cellular functions such as division, differentiation, autophagy,
apoptosis/necrosis, or the response to key environmental signals such as starva-
tion or hypoxia. As such, the fluxome provides a true dynamic picture of the
phenotype thereby constituting a unique phenotypic signature of cells (Cascante
and Marin 2008 ) while integrating a myriad of cellular processes. In the mouse, for
example, there are only ~600 metabolites (i.e., low-molecular-weight intermediates)
(Griffin 2006 ), when as there are ~10,000 proteins, and ~22,000 protein-encoding
genes (Cortassa et al. 2012 ). Thus, an unique advantage of fluxomics over genomics
and proteomics is that the former is based on information from metabolites,
which are far fewer than genes or proteins (Gherardini and Helmer-Citterich 2013 ;
Raamsdonk et al. 2001 ).
The riddle is schematized in Fig. 2.1 and can be summarized as follows.
Transcriptional factors, proteins, and metabolites are, at the same time, the products
of mass-energy/information networks and their modulators by participating in the
signaling networks that activate or repress the same networks that produced them.
The presence of these control loops, in which network components are both cause
and effect, together with their self-organizing properties sustained by a continuous
exchange of energy and matter with the environment, is where the riddle of the
unique complexity of the living state lies.
2.1 Signaling Networks: Connecting and Modulating
the Mass-Energy-Information Networks
Information (e.g., gene, mRNA, and protein circuits) and signaling (e.g., AMPK,
MAPK) networks can be clearly distinguished, by the following differences (Kiel
et al. 2010 ):
• Signaling systems operate rapidly (ms to min) whereas transcriptional responses
are slow, ranging from minutes (prokaryotes) to hours (eukaryotes)
• Subcellular localization plays an important role in signaling
• Protein structure and folding are involved in signaling (Mitrea and Kriwacki
2013 ); these processes are less predictable than DNA conformational changes
present in information networks
• Genetic circuits tend to be noisy because they involve fewer molecules com-
pared with signaling pathways, which usually involve larger number of molecu-
lar steps and thus tend to be less stochastic
• Amplification cascades occur in signaling thus spontaneous activation is avoided
through negative feedback regulation or duplicated triggering signal.
Time-dependent regulation is of utmost importance for cellular responses,
resulting from sudden, transient changes in environmental conditions. The earliest
cellular response to an external cue usually consists in the activation of upstream