Computational and modeling aspects of RTK networks

Receptor tyrosine kinases, along with G protein-coupled receptors and the group of cytokine receptors, transmit a great majority of extracellular cues to the cytoplasm and nucleus of target cells. Here we focus on one subgroup of receptor tyrosine kinases, whose prototype is the epidermal growth factor receptor (EGFR). Due to ligand-induced homo- and heterodimerization by EGFR (also called ERBB1) and other family members, extracellular signals are processed by a layered signaling network, which generates a complex, time-dependent output. Mass-action models well describe the emergent behavior of the network, but their establishment requires detailed experimental data. For example, mass-action models incorporate feedback regulatory loops and explain ligand-specific rewiring of the network, as well as the emergence of ultrasensitivity. Other computational models are employed when the volume of experimental data is limited. Both mass-action models and the more abstractive models help uncover fragile nodes amenable for therapeutic intervention. Likewise, co-option of network’s robustness by disease states might be modeled and help understand sensitivity, as well as resistance, to drugs targeting signal transduction by the ERBB and related networks.