In particular, computing the likelihood of parameters with respect to various signaling regimes, we identify conditions on biochemical parameters which enhance a specific direction of propagation corresponding to forward or retro-signaling regimes. In this section we consider a 3-tier signaling cascade and numerically estimate the probability of finding one of the possible signaling regimes, in function of key system’s parameters. .
Upon coupling to Hh, Ptc relieves suppression of Smo which then activates the intracellular signaling cascade which ultimately releases zinc-finger transcription factors, ‘cubitus interruptus’ (Ci) in Drosophila and its ortholog Gli in humans. We consider the 5 signaling regimes corresponding to motifs of Fig. As there is one restriction for each parameter, the intersection of those restricted intervals could leave, at the end, no more than 0.1 % of the initial number of simulation sets. Modular cell biology: retroactivity and insulation. \(s'(x_{n}) = \frac {d s}{d x_{n}}\), is given by, The slope of the dose-response function x
These two regimes involved the relaxation of a perturbation, and was actually a first evidence that separated regions in the parameter space of a cascade might characterize the propagatation of a signal downstream or upstream. Computational simulation and experimental variation of the IκB expression rate gave comparable results, demonstrating that increased IκB expression damped the oscillation in NFκB localization. regimes (1k 3T =0) and \({\lim }_{d_{T} \to +\infty } x_{i}(d_{T})\), for i=1,2. ∗ to be already maximized. i Indeed the optimization of the efficiency of the forward signaling is based on the following approach. We use/store this info to ensure you have proper access and that your account is secure. n′(0) and \(\alpha = {\lim }_{s\to \infty } x_{n}(s)\). In the context of theoretical studies of signaling systems, the use of random scans of biochemical parameters, in order to determine parameter ranges or conditions giving a sought property, has been considered by several authors. The system of equations describing the steady states of the n-cycle cascade depicted on Fig. Ptc forms a complex with an other serpentine transmembrane protein, ‘Smoothened’ (Smo). ≫1) promotes first order retroactivity, i.e. 2<1 so preventing an upper propagation), or global (e i Retroactive signaling in short signaling pathways. These conditions are listed as follows : E Receptors and ligands are common upstream signaling molecules that dictate the downstream elements of the signal pathway. These findings revealed the molecular mechanisms underlying MAPK functions in plant disease resistance. once again, we find. One main goal of our numerical simulations is to draw and to compare the curves of normalized likelihoods, defined by: The reason why we normalize by the the maximum is that the maximum probability of each regimes can be quite different (see Table 1 in Additional file 1, and Fig.
Biophys J. , draw Y z
Independent of the parameter values, it was not possible to fit the experimental data with the linear feed-forward cascade model, but only with the model including the cycling behavior of STAT5, which was modeled using a delay term reflecting the sojourn time of STAT5 in the nucleus. The last one is obtained analytically as a sum of 2 (or 4) uniform distributions. BMC Syst Biol 10, 84 (2016). ∗)