ArticleNature communications2021
Hedgehog-Interacting Protein is a multimodal antagonist of Hedgehog signalling.
Article in Nature communications, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
What it found
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Who cites it
20 citing papers in PubMed, 32 citations in OpenAlex.
- Molecular signatures and signaling interactions of the hair follicle stem cell niche.The Journal of investigative dermatology · 2026Article
- Systemic Sonic Hedgehog Signaling Links Intestinal Nutrient Sensing With Sex-Specific Type 2 Diabetes Progression.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- HHIPL2 positively governs Hedgehog signaling to accelerate non-small cell lung cancer progression via enhancing HNRNPC-mediated HNF1A mRNA stabilization.Cell death & disease · 2025Article
- CARMN orchestrates angiogenesis from behind the opera scenes: signing love letters to the endothelium.The Journal of clinical investigation · 2025Article
- A smooth muscle cell lncRNA controls angiogenesis in chronic limb-threatening ischemia through miR-143-3p/HHIP signaling.The Journal of clinical investigation · 2025Article
- Specification of human brain regions with orthogonal gradients of WNT and SHH in organoids reveals patterning variations across cell lines.Cell stem cell · 2025Article
- Hedgehog Signaling Pathway in Fibrosis and Targeted Therapies.Biomolecules · 2024Review
- Identification of small molecule antagonists of sonic hedgehog/heparin binding with activity in hedgehog functional assays.Biochimica et biophysica acta. General subjects · 2024Article
- Hedgehog pathway and cancer: A new area (Review).Oncology reports · 2024Review
- Enhancing Proteome Coverage by Using Strong Anion-Exchange in Tandem with Basic-pH Reversed-Phase Chromatography for Sample Multiplexing-Based Proteomics.Journal of proteome research · 2024Article
- Targeting the hedgehog pathway in MET mutation cancers and its effects on cells associated with cancer development.Cell communication and signaling : CCS · 2023Review
- Cellular and molecular mechanisms of Hedgehog signalling.Nature reviews. Molecular cell biology · 2023Review
- Hedgehog signaling in tissue homeostasis, cancers, and targeted therapies.Signal transduction and targeted therapy · 2023Review
- The Inseparable Relationship Between Cholesterol and Hedgehog Signaling.Annual review of biochemistry · 2023Review
- CircFAM114A2 inhibits the progression of hepatocellular carcinoma via miR-630/HHIP axis.Cancer medicine · 2023Article
- Heparin Mimetics and Their Impact on Extracellular Matrix Protein Assemblies.Pharmaceuticals (Basel, Switzerland) · 2023Article
- Targeting heparan sulfate-protein interactions with oligosaccharides and monoclonal antibodies.Frontiers in molecular biosciences · 2023Review
- The hidden hedgehog of the pituitary: hedgehog signaling in development, adulthood and disease of the hypothalamic-pituitary axis.Frontiers in endocrinology · 2023Review
- Hedgehog-interacting protein acts in the habenula to regulate nicotine intake.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Article
Corrections and comments
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Authors and funding
12 authors at 4 institutions in 2 countries.
Funding
Abstract
Hedgehog (HH) morphogen signalling, crucial for cell growth and tissue patterning in animals, is initiated by the binding of dually lipidated HH ligands to cell surface receptors. Hedgehog-Interacting Protein (HHIP), the only reported secreted inhibitor of Sonic Hedgehog (SHH) signalling, binds directly to SHH with high nanomolar affinity, sequestering SHH. Here, we report the structure of the HHIP N-terminal domain (HHIP-N) in complex with a glycosaminoglycan (GAG). HHIP-N displays a unique bipartite fold with a GAG-binding domain alongside a Cysteine Rich Domain (CRD). We show that HHIP-N is required to convey full HHIP inhibitory function, likely by interacting with the cholesterol moiety covalently linked to HH ligands, thereby preventing this SHH-attached cholesterol from binding to the HH receptor Patched (PTCH1). We also present the structure of the HHIP C-terminal domain in complex with the GAG heparin. Heparin can bind to both HHIP-N and HHIP-C, thereby inducing clustering at the cell surface and generating a high-avidity platform for SHH sequestration and inhibition. Our data suggest a multimodal mechanism, in which HHIP can bind two specific sites on the SHH morphogen, alongside multiple GAG interactions, to inhibit SHH signalling.
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Registered trials
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.