Apoptosis is a highly regulated cell death mechanism involved in many physiological processes. One of the key components of extrinsically activated apoptosis is the death receptor Fas, which, on binding to its cognate ligand  , oligomerize to form the death-inducing signaling complex , a pivotal trigger of apoptosis . Motivated by recent experimental data demonstrating the capacity of Fas to self-stabilize in their signaling forms , we propose a mathematical model of death ligand-receptor interaction that exhibits hysteresis. This provides an upstream mechanism for bistability in apoptosis, which is seen to be a consequence of biologically observed receptor trimerization. We analyze the bistabilitythresholds of the model, which furthermore possesses robustness of bistability , and provide a model assessment criterion using tools from algebraic geometry . Our results strongly suggest a role for Fas and other death receptors in generating robust threshold switching between coherent life and death states. Discussion includes an analogy with ferromagnetism and the generalization of self-stabilization to other apoptotic complexes such as the apoptosome .
Apoptosis is a highly regulated cell death mechanism involved in many physiological processes. A key component of extrinsically activated apoptosis is the death receptor Fas, which, on binding to its cognate ligand FasL , oligomerize to form the death-inducing signaling complex . Motivated by recent experimental data , we propose a mathematical model of death ligand-receptor dynamics where FasL acts as a clustering agent for Fas, which form locally stable signaling platforms through proximity-induced receptor interactions. Significantly, the model exhibits hysteresis, providing an upstream mechanism for bistability and robustness. At low receptor concentrations, the bistability is contingent on the trimerism of FasL. Moreover, irreversible bistability , representing a committed cell death decision, emerges at high concentrations, which may be achieved through receptor pre-association or localization onto membrane lipid rafts. Thus, our model provides a novel theory for these observed biological phenomena within the unified context of bistability. Importantly, as Fas interactions initiate the extrinsic apoptotic pathway, our model also suggests a mechanism by which cells may function as bistable life/death switches independently of any such dynamics in their downstream components . Our results highlight the role of death receptors in deciding cell fate and add to the signal processing capabilities attributed to receptor clustering .
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One of the key components
A key component
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FasL
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, a pivotal trigger of apoptosis
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demonstrating the capacity of Fas to self-stabilize in their signaling forms
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interaction that exhibits hysteresis. This provides
dynamics where FasL acts as a clustering agent for Fas, which form locally stable signaling platforms through proximity-induced receptor interactions. Significantly, the model exhibits hysteresis, providing
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in apoptosis, which is seen to be a consequence of biologically observed receptor trimerization. We analyze the bistabilitythresholds of the model, which furthermore possesses robustness of bistability
and robustness. At low receptor concentrations, the bistability is contingent on the trimerism of FasL. Moreover, irreversible bistability
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and provide a model assessment criterion using tools from algebraic geometry
representing a committed cell death decision, emerges at high concentrations, which may be achieved through receptor pre-association or localization onto membrane lipid rafts. Thus, our model provides a novel theory for these observed biological phenomena within the unified context of bistability. Importantly, as Fas interactions initiate the extrinsic apoptotic pathway, our model also suggests a mechanism by which cells may function as bistable life/death switches independently of any such dynamics in their downstream components
R
strongly suggest a role for Fas and other
highlight the role of
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generating robust threshold switching between coherent life and death states. Discussion includes an analogy with ferromagnetism and the generalization of self-stabilization to other apoptotic complexes such as the apoptosome
deciding cell fate and add to the signal processing capabilities attributed to receptor clustering