12/24/2023 0 Comments Signal transduction pathway examplesWe use the term futile cycle to highlight that β-catenin is continually synthesized only to be quickly targeted for degradation and kept at low concentration, as opposed to, for instance, being synthesized only as needed. Ligand-receptor input diminishes the degradation arm of this cycle, leading to accumulation of β-catenin output ( Kimelman and Xu, 2006 Stamos and Weis, 2013 Nusse and Clevers, 2017). In the Wnt pathway, signal transmission is characterized by a futile cycle of synthesis and rapid degradation ( Kimelman and Xu, 2006 Saito-Diaz et al., 2013 Hoppler and Moon, 2014). The Wnt, ERK, and Tgfβ pathways transmit input using different core transmission architecture ( Figure 1B–D). In the Tgfβ pathway ( D), the output is regulated through continual nucleocytoplasmic shuttling. In the ERK pathway ( C), the output is regulated by a kinase cascade coupled to negative feedback. In the Wnt pathway ( B), the output is regulated by a futile cycle of continual synthesis and rapid degradation. ( B-D) The core pathway for each metazoan signaling pathway is defined by distinct architectural features. ( A) Signaling pathways transmit inputs from ligand-receptor interaction to a change in output, the level of transcriptional regulator (white circle). We define the input to the core pathway as the ligand-receptor activation, and the output as the level of transcriptional regulator. flies have one EGF receptor whereas humans have four ), we focused on the conserved core pathway ( Figure 1A). Since the ligand-receptor module is relatively plastic across organisms (e.g. The ligand-receptor activation initiates a series of biochemical reactions within the cell, culminating in a buildup of transcriptional regulator, which regulates transcription of broad gene targets. These pathways are activated by an extracellular ligand binding to a membrane receptor ( Figure 1A). To this end, we examined three signaling pathways, the canonical Wnt, ERK and Tgfβ pathways. In this study, we sought to identify shared properties between conserved signaling pathways. Alternatively, analysis of pathway architectures may also reveal shared signaling capabilities that emerge from the distinct architectures, pointing to a fundamental property that pathways have converged upon despite their separate evolutionary trajectories. Studies over the past several decades have revealed distinct signaling capabilities that arise from pathway architecture, for example, all-or-none response in the MAPK/ERK pathway ( Huang and Ferrell, 1996 Ferrell and Machleder, 1998), oscillations in the NFκB pathway ( Hoffmann et al., 2002), or asymmetrical cell signaling in the Notch/Delta pathway ( Sprinzak et al., 2010). Indeed, distinct architectural features define each pathway. Insights into the versatility of signaling pathways may be gleaned from pathway architectures. Each signaling pathway, therefore, governs a wide range of cellular events, both within and across organisms. These signaling pathways evolved prior to the Cambrian and remain highly conserved across animal phyla ( Gerhart, 1999 Pires-daSilva and Sommer, 2003). Signaling pathways are critical to animal development and physiology, and yet there are fewer than 20 classes of metazoan signaling pathways ( Gerhart, 1999). This is orchestrated by signaling pathways: networks of multiple proteins that transmit signals and initiate cellular response. Our findings illustrate how cells tune different complex networks to converge on the same behavior.Ĭells must continually sense, interpret, and respond to their environment. Linearity is a desired property in engineering where it facilitates fidelity and superposition in signal transmission. Analytics from each model further reveal that linearity arises through different means in each pathway, which we tested experimentally in the Wnt and ERK pathways. Testing the results experimentally, we present direct measurements of linear input-output behavior in the Wnt and ERK pathways. We find an unexpected convergence: the three pathways behave in some physiological contexts as linear signal transmitters. In this study, we analyzed mathematical models of three metazoan signaling pathways: the canonical Wnt, MAPK/ERK, and Tgfβ pathways. A good system to approach this is signaling pathways, whose well-characterized molecular details allow us to relate the internal processes of each pathway to their input-output behavior. One challenge in biology is to make sense of the complexity of biological networks.
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