Biochemical mechanisms of vertebrate hedgehog signaling

Kong, Jennifer H.; Siebold, Christian; Rohatgi, Rajat

doi:10.1242/dev.166892

Cited by 202 publications

(233 citation statements)

References 185 publications

(246 reference statements)

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“…Hh signaling in Drosophila and in mammals involves two key changes: inhibition of the proteolytic processing of Ci/Gli proteins to repressor forms, thereby also increasing full-length protein levels, and activation of full-length Ci/Gli proteins. The relative importance of repressor and activator, both of which can potentially regulate the same set of genes, varies in different mammalian tissues in part because of the Gli protein expressed (Gli3 is more efficiently converted to repressor than Gli2) and because Gli1 is itself a Hh target gene, acts only as an activator and therefore has a specialized amplification role (Briscoe and Therond, 2013;Kong et al, 2019;Liu, 2019). In Drosophila, Ci is the only transcriptional effector of Hh signaling, allowing straightforward interrogation of the relative importance of regulation through altering the levels of Ci-75 repressor, latent Ci-155 activator and conversion of Ci-155 to a potent transcriptional activator.…”

Section: Discussionmentioning

confidence: 99%

Drosophila Hedgehog can act as a morphogen in the absence of regulated Ci processing

Little

Garcia-Garcia

Sul

et al. 2020

Preprint

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a linear gradient of Hh-stimulated degradation, allowing derivation of a spatial profile of inhibition of processing of normal C-155 by Hh. The processing-resistant Ci variants were also significantly activated in the absence of Hh by elimination of Cos2, acting through association with the CORD domain of Ci, or PKA, revealing separate inhibitory roles of these two components in addition to their well-established roles in promoting Ci-155 processing.

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Section: Discussionmentioning

confidence: 99%

Drosophila Hedgehog can act as a morphogen in the absence of regulated Ci processing

Little

Garcia-Garcia

Sul

et al. 2020

Preprint

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“…Qi et al 2018;Qian et al 2019) . We have recently presented a model for how PTCH1 could reduce levels of cholesterol in the ciliary membrane by transporting it to the closely opposed membranes of the ciliary pocket ( Fig.7D ) (Kong, Siebold, and Rohatgi 2019) . The level of SM in the ciliary membrane would determine the set-point for how much cholesterol needs to be transported by PTCH1 to reduce accessible cholesterol below the threshold required to activate SMO.…”

Section: Discussionmentioning

confidence: 99%

“…Hedgehog ligands cause an increase in cholesterol accessibility at primary cilia PTCH1, the receptor for HH ligands, is thought to inhibit SMO by reducing its access to cholesterol using its transporter-like activity. Since PTCH1 is localized in and around the cilium, we have proposed that it could function to inhibit SMO by reducing accessible cholesterol in the ciliary membrane Kong, Siebold, and Rohatgi 2019;P. Huang et al 2016) .…”

Section: The Ciliary Membrane Is a Compartment With Low Cholesterol Amentioning

confidence: 99%

“…A long-standing mystery in Hedgehog (HH) signaling is how Patched 1 (PTCH1), the receptor for HH ligands, inhibits Smoothened (SMO), a G-protein-coupled receptor (GPCR) family protein that transduces the HH signal across the membrane (Kong, Siebold, and Rohatgi 2019) . The observation that cholesterol can directly bind and activate SMO has led to the proposal that PTCH1 regulates SMO by restricting its access to cholesterol (E. F. Byrne et al 2016;Luchetti et al 2016;P.…”

Section: Introductionmentioning

confidence: 99%

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Sphingomyelin suppresses Hedgehog signaling by restricting cholesterol accessibility at the ciliary membrane

Kinnebrew

Iverson

Patel

et al. 2019

Preprint

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Transmission of the Hedgehog signal across the plasma membrane by Smoothened is proposed to be triggered by its direct interaction with cholesterol. But how is cholesterol, an abundant lipid, regulated tightly enough to control a signaling system that can cause birth defects and cancer? Using toxin-based sensors that distinguish between distinct pools of cholesterol, we find here that Smoothened activation and Hedgehog signaling are driven by a biochemically defined fraction of membrane cholesterol, termed accessible cholesterol. Increasing accessible cholesterol levels by depletion of sphingomyelin, which sequesters cholesterol in complexes, potentiates Hedgehog signaling. By inactivating the transporter-like protein Patched 1, Hedgehog ligands trigger an increase in cholesterol accessibility in the ciliary membrane, the subcellular location for Smoothened signaling. Thus, compartmentalization of Hedgehog signaling in the primary cilium may allow cholesterol accessibility to be used as a second messenger to mediate the communication between Patched 1 and Smoothened, without causing collateral effects on other cellular processes. We thank Kyle Travaglini and Onn Brandman for help with the MATLAB code for automated quantitation of probe fluorescence at primary cilia, Xiaohui Zha and Kevin Courtney for helpful discussions and protocols for sphingomyelin assays, and Suzanne Pfeffer for comments on the manuscript. Author contributionsRR and AR designed the project. BP analyzed the screen data, with the exception of the KEGG analysis which was performed by MK. BP and GP designed and cloned the CRISPR library focused on lipid-related genes. BP, GP and JK generated the mutant cell library and performed the HiSHH-Bottom10% screen. MK performed the LoSHH-Top5% screen. MK performed the experiments related to cholesterol genes and MK and EJI performed experiments related to sphingomyelin genes. MK, GL and KAJ performed the lipid probe staining experiments. MK and BP designed the computational pipeline for probe quantitation at primary cilia. CS and DFC contributed key conceptual and structural insights and experimental suggestions. RR and MK wrote the paper, with input from all authors.

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“…Although this proposal was initially met with skepticism because it was difficult to see how the various actions of distinct hormones could all be mediated by a single effector molecule, we now know that second messengers like cAMP direct different cellular outcomes by interacting with different binding partners in distinct subcellular locations. Through cAMP-dependent protein kinase A (PKA), one of its primary targets, cAMP also plays a pivotal role in the regulation of Hedgehog (Hh) signaling in primary cilia [5,9,10]. This review will focus on the regulation and compartmentalization of cAMP in the primary cilium in the context of Hh signaling.…”

Section: Introductionmentioning

confidence: 99%

Hedgehog and Gpr161: Regulating cAMP Signaling in the Primary Cilium

Tschaikner

Enzler

Torres‐Quesada

et al. 2020

Cells

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Compartmentalization of diverse types of signaling molecules contributes to the precise coordination of signal propagation. The primary cilium fulfills this function by acting as a spatiotemporally confined sensory signaling platform. For the integrity of ciliary signaling, it is mandatory that the ciliary signaling pathways are constantly attuned by alterations in both oscillating small molecules and the presence or absence of their sensor/effector proteins. In this context, ciliary G protein-coupled receptor (GPCR) pathways participate in coordinating the mobilization of the diffusible second messenger molecule 3′,5′-cyclic adenosine monophosphate (cAMP). cAMP fluxes in the cilium are primarily sensed by protein kinase A (PKA) complexes, which are essential for the basal repression of Hedgehog (Hh) signaling. Here, we describe the dynamic properties of underlying signaling circuits, as well as strategies for second messenger compartmentalization. As an example, we summarize how receptor-guided cAMP-effector pathways control the off state of Hh signaling. We discuss the evidence that a macromolecular, ciliary-localized signaling complex, composed of the orphan GPCR Gpr161 and type I PKA holoenzymes, is involved in antagonizing Hh functions. Finally, we outline how ciliary cAMP-linked receptor pathways and cAMP-sensing signalosomes may become targets for more efficient combinatory therapy approaches to counteract dysregulation of Hh signaling.

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Biochemical mechanisms of vertebrate hedgehog signaling

Cited by 202 publications

References 185 publications

Drosophila Hedgehog can act as a morphogen in the absence of regulated Ci processing

Drosophila Hedgehog can act as a morphogen in the absence of regulated Ci processing

Sphingomyelin suppresses Hedgehog signaling by restricting cholesterol accessibility at the ciliary membrane

Hedgehog and Gpr161: Regulating cAMP Signaling in the Primary Cilium

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