Signaling Pathways

Cue-Signal-Response Pathways in Human Cells

Early achievements of the CDP Center include the development of a 500-equation compartmental model of signaling by ErbB receptors (the family of four receptor tyrosine kinases that includes ERF receptor) that accurately captures the different dynamics of early signal transduction in mutliple tumor cell lines. This model is currently being used to explore the mechanistic basis of sensitivity and resistance to anti-ErbB drugs such as Iressa (Gefitinib), Erbitux and Herceptin. A similar physicochemical model has also been built for signaling events downstream of TNF, FAS and TRAIL. Attempts to fuse these models are underway, but are pushing the limits of current simulation and modeling techniques.

A second important achievement in the CDP Center has been the completion by Kevin Janes, Suzanne Gaudet and John Albeck of a large-scale cue-signal (SCR) response data compendium. This compendium comprises about 20 different protein signals, assayed over a 24 period in human cells treated with ten different cytokine combinations. Overall, the compendium contains in excess of 10,000 data points obtained in triplicate and has served as a basis for an extensive statistical modeling. One of the most interesting results from this modeling has been the discovery that the treatment of cells with TNF elicits a three-step autocrine cascade of opposing death and survival signals. Within this cascade, extracellular crosstalk is every bit as complex as intracellular crosstalk. We surmise that opposing autocrine loops are involved in the process by which cells sense and respond to changes in their local environment. The cytokine cascade also has the interesting property of linking several pro-inflammatory pathways together, and may yield new understating of diseases such as Rheumatoid arthritis.