Information Technology Reference
In-Depth Information
As indicated above, it is possible to consider the protein components of
signaling pathways to be “smart thermodynamic machines” [7]. In this respect,
protein kinases and protein phosphatases display “cognitive” capacities such as
pattern recognition, ability to handle fuzzy data, memory capacity, and context
sensitivity [7]. For example, the major signal-sensitive protein kinases (PKA,
PKC, and calmodulin-dependent kinase II [CaMK]) are obviously all catalysts
of phosphorylation. Additionally, they are all switches that can be activated by
the appropriate secondary messenger (cyclic AMP/PKA; diacylglycerol/PKC;
Ca
2
+
/CaMK). Specific isoforms of these enzymes may also be subject to au-
tophosphorylation. Phosphorylation of the RII isoform of the PKA regulatory
subunit prolongs the dissociated, activated state of PKA [21]. Similarly, CaMK
carries out autophosphorylation of an inhibitory domain, thereby prolonging
the activated state of the enzyme [19]. As a consequence, protein kinases can
be considered to have a capacity for memory (i.e., even when secondary mes-
senger signals have diminished, their phosphorylating power is preserved).
Protein kinases and protein phosphatases may also possess positional or tar-
geting information [9]. For example, isoforms of the PKA catalytic subunit
can be modified by the addition of a myristoyl group. This fatty acid-derived
group may direct PKA to specific membrane locations, or alternatively, into
specific protein-protein interactions. The spatial organization of PKA also de-
pends on its association with structural elements of the cell via anchor proteins,
or AKAPs—A kinase anchor proteins [18]. Specific isoforms of CaMK also
possess positional information in that nuclear-specific localization sequences
target this enzyme to the cell nucleus, and, consequently, CaMKs play a role in
the phosphorylation of proteins involved in the control of gene expression [8].
Perhaps the most sophisticated example of spatial organization of signaling
pathway components concerns the mitogen-activated protein kinase cascades
(MAPK cascades). The spatial organization of these protein kinase cascades
leads to distinct cellular responses to a diverse group of environmental stimuli
[20]. MAPK cascades are organized into discrete, parallel signaling complexes
by scaffold proteins; the signaling cascade components are brought into close
physical contact allowing rapid and direct transfer of signaling information (see
Figure 2.2). An intriguing feature of these signaling pathways is that, despite
sharing common components, they are normally extremely well insulated from
each other and show little if any crosstalk or cross-activation [6].
CONCLUSIONS
We have given an overview of our approach to individual-based modeling
of interactions between components in spatially heterogeneous and changing
environments. The key perspective in our discussion has been on protein in-
teractions as manifesting information-processing capabilities. The notion of
