Drug targets for tumorigenesis: Insights from structural analysis of EGFR signaling network

Deciphering the complex network Structure IS crucial in drug target identification. This study presents a framework incorporating graph theoretic and network decomposition methods to analyze system-level properties of the comprehensive map of the epidermal growth factor receptor (EGFR) signaling, which is a good candidate Model system to study the general mechanisms of signal transduction. The graph theoretic analysis of the EGFR network indicates that it has small-world characteristics with scale-free topology. The employment of network decomposition analysis enlightened the system-level properties, Such as network cross-talk, specific molecules ill each pathway and participation of molecules in the network. Participating in a significant fraction of the fundamental paths connecting the ligands to the phenotypes, cofactor GTP and complex G beta/G gamma were identified as "housekeeping" molecules, through which all pathways of EGFR network are cross-talking. c-Src-Shc complex is identified as important due to its role in all fundamental paths through tumorigenesis and being specific to this phenotype. Inhibitors of this complex may be good anti-cancer agents having very little or no effect on other phenotypes. (C) 2008 Elsevier Inc. All rights reserved.