Systems Modeling of EphB4/ephrinB2 Signaling Pathways
K. Peskov(1), A. Demidenko(1), A. Dorodnov(1), O. Demin (1), D. Nowlin(2), E. Kraynov(2), K. Luu(2)
(1) Institute for Systems Biology SPb, Moscow, Russia; (2) Pfizer Global Research and Development, La Jolla, California, USA
Objectives: It has recently been shown that Eph-ephrin interactions play an essential role not only in tumor angiogenesis but also in tumor progression and/or suppression. The exact mechanism contributing to such a multitude of responses, however, remains unclear. In order to better understand this problem we studied the intricacies of EphB4 biology using a systems modeling approach. The main aims of this study were to: (1) reconstruct the EphB4/ephrinB2 signaling pathways based on information mined from the literature; (2) develop a kinetic model for EphB4/ephrinB2 forward signaling, and (3) analyze the model behavior and prediction to gain deeper insight into EphB4/ephrinB2 forward signaling and its influence on tumor progression and/or suppression mechanisms.
Methods: DBSolve Optimum software was used for all model development and analysis steps. Kinetic model verification was performed using data from ephrinB2-Fc induced EphB4 activation, internalization and degradation obtained in a MCF7 breast cancer cell line and other datasets (approx. 30 datasets) published in the literature.
Results: The signaling pathways of EphB4-ephrinB2 interactions were successfully reconstructed and a kinetic model of EphB4-ephrinB2 forward signaling was developed. Analysis of the model behavior allowed us to make the following predictions about the system regulation and possible cellular responses at different physiological conditions: (1) the Abl/Rac/Rap branch of EphB4-induced forward signaling was cell specific, (2) one of the main reasons for (1) was an inhibition of Abl function by filament actin. In addition, it followed that cell types with high concentration of filament actin were less sensitive to EphB4 inhibition of migration, (3) cell proliferation potential had low sensitivity against EphB4 activation and (4) EphB4 activation had an important influence on AKT phosphorylation.
Conclusions: It was shown that EphB4-ephrinB2 forward signaling had a negative effect on cell proliferative, survival and migratory potential. However, those effects were cell specific and can be weakened in certain cell types. In these cases, increasing the concentration of filament actin could completely inhibit the Rac/Rap branch of EphB4-ephrinB2 signaling.