Dynamical and integrative cell signaling: challenges for the new biology

Abstract

Years of careful experimental analysis have revealed that signaling molecules are organized into complex networks of biochemical reactions exquisitely regulated in time and space to provide a cell with highfidelity information about an extremely noisy and volatile environment. A new view of signaling networks as systems consisting of multiple complex elements interacting in a multifarious fashion is emerging, a view that conflicts with the single-gene or protein-centric approach common in biological research. The postgenomic era has brought about a different, network-centric methodology of analysis, suddenly forcing researchers toward the opposite extreme of complexity, where the networks being explored are, to a certain extent, intractable and uninterpretable. Both the cartoons of simple pathways and the very large ''hair-ball'' diagrams of large intracellular networks are also representations of static worlds, superficially devoid of dynamics and chemistry. These representations are often viewed as being analogous to stably linked computer and neural networks rather than dynamically changing networks of chemical interactions, where the notions of concentration, compartmentalization, and diffusion may be the primary determinants of connectivity. Arguably, the systems biology approach, relying on computational modeling coupled with various experimental techniques and methodologies, will be an essential component of analysis of the behavior of signal transduction pathways. Combining the dynamical view of rapidly evolving responses and the structural view arising from high-throughput analyses of the interacting species will be the best approach toward efforts toward greater understanding of intracellular signaling processes. B

Scale-free networks in cell biology

“…In addition, the diversity of metabolic fluxes (Almaas et al, 2004) and reaction rates/timescales (Papin et al, 2005) attest that only an integration of interaction and activity information will be able to give a correct dynamic picture of a cellular network (Levchenko, 2003;Ma'ayan et al, 2004). To move significantly beyond our present level of knowledge, new tools for quantifying concentrations, fluxes and interaction strengths, in both space and time, are needed.…”

Transmembrane helix-helix interactions involved in ErbB receptor signaling

“…Often, the simply stunning complexity of the triggered signaling network and its spatio-temporal organization in the cell can only be processed and illustrated with computer built models. 7 Nevertheless, due to various technical difficulties associated with analyses of the structure and function of membrane proteins, 8 even the principles governing signal transduction via then lead to a shift from one TM helix structure to another. This could then subsequently result in reorientation of the intracellular associated Janus kinase in a way that permits receptor phosphorylation (rotational or pivot movement, Fig.…”

From components to regulatory motifs in signalling networks

“…We are at a stage where there is a growing need for further understanding of the organizational and functional properties of combined pathways [5,6]. Viewing protein-protein interactions as graphs (networks) where molecules are represented as vertices (nodes) and interactions are represented as edges (links) is useful for investigating cellular signalling networks [7][8][9][10]. Scientists have used the 'balls and arrows' diagrams for several decades, but the diagrams were never large enough for network/graph theory analysis.…”