Figure 8. Introducing allosteric-based positive feedback into the Ras signaling network reduces transient overshoot and smooths the OUTPUT dynamics.

(A) Illustration of Ras system that now includes allosteric-based positive feedback and the naturally occurring GEF (SOScat) that was used to implement the feedback. (B) Experimentally determined absolute effector OUTPUT responses across 96 different system configurations. Each graph corresponds to a particular GEF/GAP configuration, and each of the curves within that plot corresponds to a different Ras density as indicated by the color of the curve. (C) Examples of output responses for systems under equivalent network configurations (high GEF, high GAP) that do (green line) or do not (grey line) contain allosteric feedback. (D) Schematic depiction of how an OFF->ON feedback mechanisms converts a step input in SOScat levels into a ramp input in SOScat activity. GAP, GTPase-activating protein; GEF, guanine exchange factor

DOI: http://dx.doi.org/10.7554/eLife.12435.021

Figure 8—figure supplement 1. Normalized (to maximum output) responses of p120GAP/ SOScat feedback /RafRBD/Ras signaling system under a variety of network configurations.

Normalized (to the maximum output value of the response) signaling responses for different network GEF/GAP/Ras density configurations. The allosteric-based positive feedback GEF SOScat was used as the activating GEF in these experiments. The p120GAP catalytic domain was used as the GAP in these experiments. 50 nM cRaf-RBD was used as the effector in these experiments. The response for differing densities of Ras in each GEF/GAP configuration is shown by different color lines in each plot, with estimated densities indicated in the key. GAP, GTPase-activating protein; GEF, guanine exchange factor; RBD, Ras-binding domain

DOI: http://dx.doi.org/10.7554/eLife.12435.022