Signal Processing in the TGF-β Superfamily Ligand-Receptor Network

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Abstract
The TGF-β pathway plays a central role in tissue homeostasis and morphogenesis. It transduces a variety of extracellular signals into intracellular transcriptional responses that control a plethora of cellular processes, including cell growth, apoptosis, and differentiation. We use computational modeling to show that coupling of signaling with receptor trafficking results in a highly versatile signal-processing unit, able to sense by itself absolute levels of ligand, temporal changes in ligand concentration, and ratios of multiple ligands. This coupling controls whether the response of the receptor module is transient or permanent and whether or not different signaling channels behave independently of each other. Our computational approach unifies seemingly disparate experimental observations and suggests specific changes in receptor trafficking patterns that can lead to phenotypes that favor tumor progression. Sensing of the environment by cells relies extensively on receptors that bind extracellular molecules and trigger intracellular responses. The TGF-β pathway transduces a broad range of extracellular signals into transcriptional responses that affect many cellular processes, including cell growth, apoptosis, differentiation, homeostasis, and morphogenesis. It is used, for instance, to control the precise patterns and forms that arise during development, and its malfunction contributes to a wide variety of diseases and developmental disorders. Here the authors develop a concise computational model of the TGF-β pathway and show that the first layer of communication with the environment, the ligand-receptor network, is not merely a passive transducer of signals but rather embeds properties that makes it a signal processing unit. Receptors traffic between different cellular compartments from which they signal distinctly, leading to an unexpected richness of types of behavior that is not apparent from the simplicity of the typical cartoon representations of this pathway. At the receptor level, the system can select among different functioning modes to sense absolute levels of ligand, temporal changes in ligand concentration, and ratios of multiple ligands. This extra level of regulation can explain a wide variety of phenomena and leads to a unified interpretation of seemingly disparate experimental observations.
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