Different Behavior of Interlinked Fast and Slow Loops in Cell Decision
نویسنده
چکیده
Positive feedback is a ubiquitous regulatory motif that allows systems to convert graded inputs into decisive, all-or-none outputs. Onn Brandman et al. [1] simulated the performance of the multiple interlinked loops, and showed that linking fast and slow positive feedback loops creates a dual-time switch that is both rapidly inducible (due to the fast positive feedback loop) and resistant to noise in the upstream signaling system (due to the slow positive feedback loop). However, the two loops in their model were treated symmetrically, which did not reflect the real signaling cascade. In this project, I modified their model to better describe the real signal pathway. My model shows the different behavior of the interlinked fast and slow positive feedback loops with different orders in the pathway, and suggests the performance advantage of the fast-slow loop system of polarization in budding yeast. Introduction Positive feedback is a key regulatory motif in many biological systems to create switches with all-or-none digital output characteristics. Although a single positive feedback loop can generate a bistable all-or-none switch, it is intriguing that many biological systems have not only a single but multiple positive feedback loops. Two examples of positive feedback systems are shown in Fig. 1. Polarization in budding yeast depends on two positive feedback loops, a rapid loop involving activity cycling of the small guanosine triphosphatase Cdc42 and a slower loop that may involve actin-mediated transport of Cdc42 (Fig. 1A). When the slow positive feedback loop is selectively compromised by treatment with the actin-depolymerizing agent latrunculin, the result is rapid but unstable cell polarization. In contrast, cells lacking a functional fast loop (by deletion of Bem1) form stable poles, but with reduced speed. Figure 1. Schematic views of positive feedback loops in two systems. (A) Establishment of polarity in budding yeast. (B) Mammalian calcium signal transduction. (adapted from [1]) The role of interlinked fast and slow positive feedback loops was demonstrated computationally by recent studies [1]. They showed that linking fast and slow positive MCB 111 Final Project Jie Quan 01/17/2005 2 feedback loops creates a dual-time switch that is both rapidly inducible (due to the fast positive feedback loop) and resistant to noise in the upstream signaling system (due to the slow positive feedback loop) based on mathematical simulation. In their model, the fast and slow loops were treated symmetrically. However, in the real signaling cascade, the two interlinked loops are asymmetric; usually, one loop is upstream and the other is downstream. It is also worth noting that in both positive feedback systems shown in Fig. 1, the fast positive feedback loop is upstream of the slow one. This led to my hypothesis that the multiple positive feedback loop system with different orders of the fast and slow loops in the signal pathway may have different behavior in system’s performance and output. Figure 2. Two models of positive feedback systems containing interlinked loops. (A) The symmetric two-loop model used in [1]. (B) The asymmetric two-loop model in this project. Results To test this hypothesis computationally, I created a model of positive feedback switch containing two orderly interlinked loops. I assumed either the same or different kinetics for the two loops, specifically, either fast kinetics for both loops, slow kinetics for both loops, fast kinetics for the upstream loop and slow kinetics for the downstream loop, or slow kinetics for the upstream loop and fast kinetics for the downstream loop. The ordinary differential equations for the two-loop positive feedback switch are:
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Interlinked fast and slow positive feedback loops drive reliable cell decisions.
Positive feedback is a ubiquitous signal transduction motif that allows systems to convert graded inputs into decisive, all-or-none outputs. Here we investigate why the positive feedback switches that regulate polarization of budding yeast, calcium signaling, Xenopus oocyte maturation, and various other processes use multiple interlinked loops rather than single positive feedback loops. Mathema...
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تاریخ انتشار 2006