Can Mesoscopic Models Test Spatial Mechanisms of Cell Signaling?

8 March 2007

JULIAN SHILLCOCK

Therapeutic intervention in malfunctioning signaling networks requires (at least) three levels of information. The identity of the participating proteins, and knowledge of their active sites; the network of pairwise (and higher) interactions; and the sensitivity of the network to perturbations so as to optimize the intervention. Whereas many possible drug targets are known, and whole networks of interacting proteins are being identified, the spatio- temporal mechanisms underlying signal transmission are largely unknown.

Free diffusion of proteins released from receptors at the plasma membrane to their next signalling partner, while calculationally simple, is extremely unlikely in the crowded environment of the cell (see Takahashi et al. 2005). At the other extreme, a fixed, cross-talk free, spatial arrangement of connections, along the lines of an electrical circuit, is also difficult to imagine. In between are many possible patterns for protein interactions, some associated with the cytoskeleton (Forgacs et al. 2004), whose construction and testing using particle-based mesoscopic models is perhaps now possible.

Do readers of this forum have opinions about the feasibility of constructing spatio-temporal models of a signalling network, on a micron length and millisecond (sec?) timescale, so as to extract the sensitivity of the network to perturbation? Do we have enough information on the protein-protein interactions? What simulation techniques could be used?

K. Takahashi, S. N. Arjunan, M. Tomita, Space in systems biology of signaling pathways--towards intracellular molecular crowding in silico. FEBS Letters 579, 1783-1788 (2005). [PubMed Abstract]

G. Forgacs, S. H. Yook, P. A. Janmey, H. Jeong, C. G. Burd, Role of the cytoskeleton in signaling networks. J. Cell Science 117, 2769-2775 (2004). [Abstract] [Full Text]