A logic-based method to build signaling networks and propose experimental plans

Abstract

With the dramatic increase of the diversity and the sheer quantity of biological data generated, the construction of comprehensive signaling networks that include precise mechanisms cannot be carried out manually anymore. In this context, we propose a logic-based method that allows building large signaling networks automatically. Our method is based on a set of expert rules that make explicit the reasoning made by biologists when interpreting experimental results coming from a wide variety of experiment types. These rules allow formulating all the conclusions that can be inferred from a set of experimental results, and thus building all the possible networks that explain these results. Moreover, given an hypothesis, our system proposes experimental plans to carry out in order to validate or invalidate it. To evaluate the performance of our method, we applied our framework to the reconstruction of the FSHR-induced and the EGFR-induced signaling networks. The FSHR is known to induce the transactivation of the EGFR, but very little is known on the resulting FSH- and EGF-dependent network. We built a single network using data underlying both networks. This leads to a new hypothesis on the activation of MEK by p38MAPK, which we validate experimentally. These preliminary results represent a first step in the demonstration of a cross-talk between these two major MAP kinases pathways.

ERβ Regulation of Gonadotropin Responses during Folliculogenesis

“…While unliganded FSHR can amplify LHCGR signals, LHCGR can inhibit FSHR-dependent cAMP production [ 110 , 112 ]. FSHR also interacts with RTKs including IGF1R and EGFR, which is important for the AKT and ERK1/2 activation required for gonadotropin induced differentiation of GCs [ 62 , 113 , 114 ].…”

Molecular Mechanisms of Action of FSH

“…Similarly, action of the epidermal growth factor receptor (EGFR) during granulosa cell differentiation is required for activation of ERK1/2 (15). Interestingly, the interaction between FSHR and EGFR signaling networks was analyzed using an automated, logic-based approach, suggesting that the ERK1/2-pathway may be activated by EGFR-dependent signals via p38 mitogen-activated protein kinases (MAPK) (16). Moreover, this study confirmed that EGFR is trans-activated through FSHR-mediated pathways involving the proto-oncogene tyrosine-protein kinase SRC .…”

“…Moreover, this study confirmed that EGFR is trans-activated through FSHR-mediated pathways involving the proto-oncogene tyrosine-protein kinase SRC . On the other hand, EGFR signaling network overlaps, at least in part, that of FSHR, contributing to modulation of the ERK1/2, the phosphatidylinositol-4,5-bisphosphate 3-kinases (PI3K)/protein kinase B (AKT), and the Janus kinase (JAK)/signal transducer and activator of transcription protein (STAT) pathways (16).…”

Plant Synthetic Biology: Quantifying the “Known Unknowns” and Discovering the “Unknown Unknowns”

“…Several groups have developed frameworks for computational design of the optimal set of experiments to identify the mathematical relationship among the signaling inputs, network status, and the developmental outcome, i.e. model selection (Busetto et al, 2013;Apri et al, 2014;Vanlier et al, 2014;Minas et al, 2017;Rougny et al, 2018). Other statistical frameworks aim to design optimal experiments for determining parameter uncertainty in the chosen model (Dehghannasiri et al, 2015;Fan et al, 2015;Imani et al, 2018;Mohsenizadeh et al, 2018).…”