Signal transduction networks in cancer: quantitative parameters influence network topology

Networks of fixed topology are used to summarize the collective understanding of the flow of signaling information within a cell (i.e., canonical signaling networks). Moreover, these canonical signaling networks are used to interpret how observed oncogenic changes in protein activity or expression alter information flow in cancer cells. However, creating a novel branch within a signaling network (i.e., a noncanonical edge) provides a mechanism for a cell to acquire the hallmark characteristics of cancer. The objective of this study was to assess the existence of a noncanonical edge within a receptor tyrosine kinase (RTK) signaling network based upon variation in protein expression alone, using a mathematical model of the early signaling events associated with epidermal growth factor receptor 1 (ErbB1) signaling network as an illustrative example. The abundance of canonical protein-RTK complexes (e.g., growth factor receptor bound protein 2-ErbB1 and Src homology 2 domain containing transforming protein 1-ErbB1) were used to establish a threshold that was correlated with ligand-dependent changes in cell proliferation. Given the available data, the uncertainty associated with this threshold was estimated using an empirical Bayesian approach. Using the variability in protein expression observed among a collection of breast cancer cell lines, this model was used to assess whether a noncanonical edge (e.g., Irs1-ErbB1) exceeds the threshold and to identify cell lines where this noncanonical edge is likely to be observed. Taken together, the simulations suggest that the topology of signal transduction networks within cells is influenced by quantitative parameters, such as protein expression and binding affinity. Moreover, forming this noncanonical pathway was not due solely to overexpression of the cell surface receptor but was influenced by overexpression of all members of the multiprotein complex. Multivariate alterations in expression of signaling proteins in cancer cells may activate noncanonical pathways and may rewire the signaling network within a cell.