April 2007
Cellular responses to environmental signals are mediated through complex arrays of signaling pathways and networks involving protein phosphorylation events that ultimately induce changes in gene expression. An example is the Ras signaling network that integrates extracellular growth signals from receptor tyrosine kinases and then propogates these signals to induce activities controlling cell proliferation and fate (Shaw and Cantley, 2006). Analyses of protein phosphorylation events establishes the framework of the pathway, but does not provide sufficient information to address the complexity of pathway function such as is reflected in heterogeneous responses to input stimuli. In contrast, genome-scale gene expression has demonstrated precision and potential to reveal subtle and otherwise obscure phenotypes; the challenge is that of integrating gene expression information with the known, pathway-defining biochemistry. Here we address this with gene expression analysis methods for pathway dissection, using the Ras signaling pathway as a key and important example. The novel pathway decomposition analysis characterises individual facets of pathway activity, generates distinct expression signatures that overlay and reflect known pathway sub-structures, and leads to opportunities for development of more finely tuned personal therapeutics linked to pathway components.
The manuscript will be available here shortly.