Growth factors and their transmembrane receptors contribute to all steps of tumor progression, from the initial phase of clonal expansion, through angiogenesis to metastasis. Hence, the information relay system involved in growth factor signaling provides potential sites for signal interception and tumor inhibition.
A relevant example comprises the epidermal growth factor (EGF) and the respective receptor tyrosine kinase, namely ErbB-1/EGFR, which belongs to a prototype signaling module that drives carcinoma development. The extended module includes two autonomous receptor, EGFR and ErbB-4, and two non-autonomous receptors, namely: a ligand-less oncogenic receptor, HER2/ErbB-2, and a kinase-dead receptor (ErbB-3). This signaling module is richly involved in human cancer and already serves as a target for several cancer drugs.
Due to the inherent complexity and a large amount of experimental data, we propose a systems approach to understanding ErbB signaling. EGF - to - ErbB signaling is envisioned as a bow-tie configured, evolvable network, sharing modularity, redundancy and control circuits with robust biological and engineered systems. My presentation will concentrate on system controls, a plethora of negative feedback loops, which include E3 ubiquitin ligases, receptor endocytosis and newly transcribed genes. Because network fragility is an inevitable tradeoff of robustness, systems level understanding is expected to identify therapeutic opportunities for targeting aberrant activation of the network in human pathologies.
|Erez M. Bublil, Gur Pines, Gargi Patel, Gilbert Fruhwirth, Tony Ng, and Yosef Yarden. "Kinase-mediated quasi-dimers of EGFR" FASEB journal 2010. PDF|
|Moshit Lindzen, Sara Lavi, Orith Leitner, and Yosef Yarden "Tailored cancer immunotherapy using combinations of chemotherapy and a mixture of antibodies against EGF-receptor ligands" PNAS 2010 107 (28) 12559-12563. PDF|
|Pines, G.Huang, P. H., Zwang, Y., White, F. M., Yarden, Y."EGFRvIV: a previously uncharacterized oncogenic mutant reveals a kinase autoinhibitory mechanism" Oncogene 2010. PDF|
|R. Avraham, A. Sas-Chen, O. Manor, I. Steinfeld, R. Shalgi, G. Tarcic, N. Bossel, A. Zeisel, I. Amit, Y. Zwang, E. Enerly, H. G. Russnes, F. Biagioni, M. Mottolese, S. Strano, G. Blandino, A.-L. Børresen-Dale, Y. Pilpel, Z. Yakhini, E. Segal, Y. Yarden, "EGF Decreases the Abundance of MicroRNAs That Restrain Oncogenic Transcription Factors." Sci. Signal. 3, ra43 (2010). PDF|
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