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 in 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 Gbeta/Ggamma 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.
Durmuş Tekir
Saliha
S
Department of Chemical Engineering, Boğaziçi University, 34342 Bebek-Istanbul, Turkey. saliha.durmus@boun.edu.tr
Yalçin Arga
Kazim
K
Ulgen
Kutlu O
KO
D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D016503:Drug Delivery Systems; D055808:Drug Discovery; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D009363:Neoplasm Proteins / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D015398:Signal Transduction
D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D066246:ErbB Receptors