ArticleProceedings of the National Academy of Sciences of the United States of America2016
Mechanism of inhibition of the tumor suppressor Patched by Sonic Hedgehog.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 65 papers.
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Who cites it
65 citing papers in PubMed, 94 citations in OpenAlex.
- Receptor allostery promotes context-specific Sonic Hedgehog signaling during embryonic development.Nature communications · 2026Article
- IFT139 regulates Hedgehog signaling and cilia structure through ciliary protein localization.Biology open · 2025Article
- Hedgehog pathway, cell cycle, and primary cilium.Cell death discovery · 2025Review
- Neuroinflammatory Pathways Associated with Chronic Post-Thoracotomy Pain: A Review of Current Literature.Molecular neurobiology · 2025Review
- Inhibiting hedgehog signal by a patched-1 antibody.Cell discovery · 2025Article
- Identification of small molecule antagonists of sonic hedgehog/heparin binding with activity in hedgehog functional assays.Biochimica et biophysica acta. General subjects · 2024Article
- GRK2 kinases in the primary cilium initiate SMOOTHENED-PKA signaling in the Hedgehog cascade.PLoS biology · 2024Article
- Numb positively regulates Hedgehog signaling at the ciliary pocket.Nature communications · 2024Article
- A Residual N-Terminal Peptide Enhances Signaling of Depalmitoylated Hedgehog to the Patched Receptor.Journal of developmental biology · 2024Article
- Neurogenic Effects of Inorganic Arsenic and Cdk5 Knockdown in Zebrafish Embryos: A Perspective on Modeling Autism.International journal of molecular sciences · 2024Review
- Cellular and molecular mechanisms of Hedgehog signalling.Nature reviews. Molecular cell biology · 2023Review
- The energetics and ion coupling of cholesterol transport through Patched1.Science advances · 2023Article
- The Inseparable Relationship Between Cholesterol and Hedgehog Signaling.Annual review of biochemistry · 2023Review
- The Hedgehog Pathway as a Therapeutic Target in Chronic Myeloid Leukemia.Pharmaceutics · 2023Review
- The Energetics and Ion Coupling of Cholesterol Transport Through Patched1.bioRxiv : the preprint server for biology · 2023Article
- Noncanonical Sonic Hedgehog signaling amplifies platelet reactivity and thrombogenicity.Blood advances · 2022Article
- Hedgehog pathway modulation by glypican 3-conjugated heparan sulfate.Journal of cell science · 2022Article
- Structural basis for catalyzed assembly of the Sonic hedgehog-Patched1 signaling complex.Developmental cell · 2022Article
- Hedgehog Pathway Inhibitors as Targeted Cancer Therapy and Strategies to Overcome Drug Resistance.International journal of molecular sciences · 2022Review
- Sonic Hedgehog Signaling in Cerebellar Development and Cancer.Frontiers in cell and developmental biology · 2022Review
5 more citing papers are in PubMed but not listed here.
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
The Hedgehog cell-cell signaling pathway is crucial for animal development, and its misregulation is implicated in numerous birth defects and cancers. In unstimulated cells, pathway activity is inhibited by the tumor suppressor membrane protein, Patched. Hedgehog signaling is triggered by the secreted Hedgehog ligand, which binds and inhibits Patched, thus setting in motion the downstream events in signal transduction. Despite its critical importance, the mechanism by which Hedgehog antagonizes Patched has remained unknown. Here, we show that vertebrate Patched1 inhibition is caused by direct, palmitate-dependent interaction with the Sonic Hedgehog ligand. We find that a short palmitoylated N-terminal fragment of Sonic Hedgehog binds Patched1 and, strikingly, is sufficient to inhibit it and to activate signaling. The rest of Sonic Hedgehog confers high-affinity Patched1 binding and internalization through a distinct binding site, but, surprisingly, it is not absolutely required for signaling. The palmitate-dependent interaction with Patched1 is specifically impaired in a Sonic Hedgehog mutant causing human holoprosencephaly, the most frequent congenital brain malformation, explaining its drastically reduced potency. The palmitate-dependent interaction is also abolished in constitutively inhibited Patched1 point mutants causing the Gorlin cancer syndrome, suggesting that they might adopt a conformation distinct from the wild type. Our data demonstrate that Sonic Hedgehog signals via the palmitate-dependent arm of a two-pronged contact with Patched1. Furthermore, our results suggest that, during Hedgehog signaling, ligand binding inhibits Patched by trapping it in an inactive conformation, a mechanism that explains the dramatically reduced activity of oncogenic Patched1 mutants.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.