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Toward a systems‐level understanding of the Hedgehog signaling pathway: defining the complex, robust, and fragile

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Abstract The Hedgehog (Hh) signaling pathway plays a fundamental role in development and tissue homeostasis, governing cell proliferation and differentiation, as well as cell fate. Hh signaling is mediated by an intricate network of proteins that have positive and negative roles that work in concert to fine‐tune signaling output. Using feedback loops, redundancy and subcellular compartmentalization, the temporal and spatial dynamics of Hh signaling have evolved to be complex and robust. Yet developmental defects and cancers that arise from perturbation of the Hh pathway reflect specific pathway fragilities. Importantly, these fragile nodes and edges present opportunities for the design of targeted therapies. Despite these significant advances, unconnected molecular links within the Hh pathway still remain, many of which revolve around the dependence of Hh signaling on the primary cilium, an antenna‐like sensory organelle. A systems‐level understanding of Hh signaling and of ciliary biology will comprehensively define all nodes and edges of the Hh signaling network and will help identify precise therapeutic targets. WIREs Syst Biol Med 2013, 5:83–100. doi: 10.1002/wsbm.1193 This article is categorized under: Biological Mechanisms > Cell Signaling Developmental Biology > Developmental Processes in Health and Disease

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The Hh signaling network. When Hh signaling is active, key events in the primary cilium prime full‐length GLI2/3 proteins for conversion into GLI2/3 transcriptional activators. Note that although this map suggests activation of GLI2/3 proteins occurs in the cilium, it remains unclear whether activation occurs in the cilium or nucleus. When Hh signaling is inactive, GLI3 repressors are formed. While GLI3 repressors cannot form in the absence of primary cilia, it is unclear whether the priming of GLI3 for processing and/or the actual processing event occurs in the cilium or in the cytoplasm. Blue circles (proteins), squares (protein complexes), octagons (processed proteins), and genes (ovals) represent nodes. Straight lines denote edges (interactions) and undulating lines denote translocation of a protein.

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Biological Mechanisms > Cell Signaling
Developmental Biology > Developmental Processes in Health and Disease

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