Signal transduction driving technology driving signal transduction: Factors in the design of targeted therapies

A significant number of human diseases can be attributed to defects in cellular signal transduction pathways. Large-scale proteomics projects now in progress seek to better define critical components of signal transduction networks, to enable more intelligent design of therapeutic agents that can specifically correct disease-specific signaling alterations by targeting individual proteins. A complicating factor in this endeavor is the fact that intracellular signaling involves many diverse mechanisms that in sum finely modulate the activity of individual proteins in response to different biological inputs. Ability to develop reagents that selectively correct disease-associated signaling activities, while leaving intact benign or essential activities, encompassed within a single protein requires an intimate knowledge of pathway-specific control mechanisms. To illustrate these points, we provide examples of some of the complex control mechanisms regulating the Cas proteins, which contribute to integrin-dependent biological response. We then discuss issues involved in systematically incorporating information related to complex control mechanisms in proteomic databases. Finally, we describe some recent instances in which protein interaction technologies have been specifically adapted to identify small molecule agents that regulate protein response in physiologically desirable ways, and discuss issues relevant to future drug discovery efforts.