Fig. 5. SPARCED-I model suggests that a SOCS1-based sequestration mechanism can explain IFNγ-induced cell proliferation decreases.
a Experimental setup and simulation workflow for SPARCED-I model variant analysis. See Methods. b Candidate mechanism schematic: SOCS1 sequesters activated ligand-receptor complexes. c The reactions show one set of examples added to capture the inhibitory mechanism. pSCD: activated ligand-receptor complexes. Kd: Disassociation constant. d Simulation of 100 stochastic cells for SPARCED-I-SOCS1 model at different Kd values (varied uniformly between −1 and 6 in log10 scale) for SOCS1 binding (blue bars) showed that SOCS1 sequestration of activated receptor complexes can explain the IFNγ effect on cell proliferation inhibition, compared to experiments (gray bar). The number of cells in S-phase at 48 h of simulation time are shown on the x-axis (first row: Kd values, second row: cells with EGF, third row: cells with EGF + IFNγ). The y-axis is the ratio of number of cells in S-phase with IFNγ to without IFNγ. The experimental data (Exp.) are from three independent replicates (dots) and represent mean ± s.e.m. The mean of each experimental condition is given in x-axis. The orange bar is Kd set at the estimated initial value (from GRB2-Receptor binding/unbinding reactions). e The Kd value used for these trajectories corresponds to the orange bar in (d). Normalized ppAKT and ppMAPK levels show a significant decrease after IFNγ treatment, when EGF + IFNγ SPARCED-I-SOCS1 model simulations are compared to EGF alone case. RPPA data (synapse.org/LINCS_MCF10A) are shown in black, from three independent replicates (error bars are s.e.m.). Colored dark lines represent median cell trajectories from simulations, dark and light-colored regions represent 70th and 95th quantiles, respectively. Source data are provided in Source Data.