Complex Systems Biology of Networks: The Riddle and the Challenge - Systems Biology of Metabolic and Signaling Networks - page 22

2.2 Reciprocal Interactions Between Signaling
and Mass-Energy/Information Networks:
Two Case Studies

2.2.1 The AMPK Signaling Network

This evolutionarily conserved signaling network functions as a cellular switch that
activates catabolic pathways and turns off anabolic processes thereby restoring
cellular energy levels (Poels et al. 2009 ). In physiological situations, AMPK senses
energy deficiency (in the form of an increased AMP/ATP ratio), but it is also
activated by metabolic stress such as glucose or oxygen deprivation triggering
transient behavior regulation (Fig. 2.2 ). It has recently been shown that
mitochondria-generated ROS induces autophagy mediated by the AMPK pathway
under starvation conditions (Li et al. 2013 ). The decline in the responsiveness of
AMPK signaling toward cellular stress with aging impairs metabolic regulation,
increases oxidative stress, and reduces autophagic clearance (Salminen and
Kaarniranta 2012 ).
The AMPK signaling network is paradigmatic, because the molecular
components and mechanisms involved (i.e., kinetic properties of AMPK toward
main effectors), demonstrating physiological impact as well as conditions in which
the signaling operates, are all well understood and thus clearly identifiable (Fig. 2.2 ).
As a specific example of the AMPK signaling network function in the context of
ischemia in the heart: (1) components: AMPK allosterically modulated by AMP and
phosphorylation (Hardie and Hawley 2001 ); (2) targets (changes in the metabolome):
6-phosphofructo-2-kinase (PFK-2) activity, fructose 2,6-bisphosphate (F2,6BP)

Fig. 2.2 (continued) SIRT1 appears to be a mediator of AMPK action on PGC-1 α transcriptional
activity. The acute actions of AMPK on lipid oxidation (fluxome) alter the balance between
cellular NAD + :NADH (metabolome), which acts as a messenger to activate SIRT1 (signaling),
and the latter closes the circle by acting on the genome (information) which then again modifies
the fluxome (mitochondrial respiration, lipid oxidation).
Tumor suppressor protein P53: a transcription factor that acts in response to cellular stress signals
(e.g., DNA damage, hypoxia, oxidative, and nitrosative stress) and is redox sensitive because of
the presence of conserved Cys residues that contain redox-sensitive thiol groups (see Fig. 2.3 )
(Vurusaner et al. 2012 ). P53 is also able to inhibit the nutrient-sensitive kinase target of rapamycin
complex 1, mTORC1, by activation of AMPK, which is subsequently followed by induction of
autophagy (Li et al. 2013 ; Melnik 2012 ; Poels et al. 2009 ). The interaction between p53 and TOR
plays an important role in normal cell growth and proliferation (Jones et al. 2005 ), and it is likely
that the AMPK-dependent induction of autophagy by p53 contributes to its role in tumor suppres-
sion (Poels et al. 2009 ).
Abbreviations: AMPK AMP-activated protein kinase, CaMKK β calcium/calmodulin-dependent

protein kinase kinase β , p53 tumor suppression protein, TOR target of rapamycin, PGC-1 α

peroxisome proliferator-activated receptor- γ coactivator 1 α , PTMs posttranslational modifications