HHIP Gene

Name	hedgehog interacting protein
Description	This gene encodes a member of the hedgehog-interacting protein (HHIP) family. The hedgehog (HH) proteins are evolutionarily conserved protein, which are important morphogens for a wide range of developmental processes, including anteroposterior patterns of limbs and regulation of left-right asymmetry in embryonic development. Multiple cell-surface receptors are responsible for transducing and/or regulating HH signals. The HHIP encoded by this gene is a highly conserved, vertebrate-specific inhibitor of HH signaling. It interacts with all three HH family members, SHH, IHH and DHH. Two single nucleotide polymorphisms (SNPs) near this gene are significantly associated with risk of chronic obstructive pulmonary disease (COPD). A single nucleotide polymorphism in this gene is also strongly associated with human height.[provided by RefSeq, Feb 2011]
Summary	{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Hedgehog‐interacting protein (HHIP) is a key negative regulator of Hedgehog signaling that functions by binding Hedgehog ligands—such as Sonic Hedgehog—to sequester them away from their signaling receptors, thereby serving as a decoy receptor. Structural studies have revealed that HHIP is composed of multiple domains, including EGF‐like modules and a six‐bladed β‐propeller; these domains coordinate metal ions (Zn²⁺ and Ca²⁺) to enable high‐affinity interactions with Hedgehog ligands, effectively “patching” the ligand’s active site and attenuating signal propagation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In addition to its biochemical role in modulating Hedgehog activity, genetic studies have implicated HHIP in the regulation of complex traits and diseases. Genome‐wide association analyses have identified variants near the HHIP locus that are associated with adult height and idiopathic short stature, underscoring a role in growth and developmental processes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " Moreover, reduced HHIP expression and risk‐associated alleles within a distal enhancer region upstream of the HHIP promoter have been robustly linked to impaired pulmonary function and an increased susceptibility to chronic obstructive pulmonary disease, suggesting that diminished HHIP-mediated antagonism of Hedgehog signaling adversely affects lung tissue homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Complementary findings in endothelial cells further support the role of HHIP as a naturally occurring inhibitor of Hedgehog-driven angiogenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Collectively, these studies emphasize that HHIP fine-tunes Hedgehog signaling during development and in adult tissues, with its dysregulation contributing to diverse pathophysiological conditions ranging from growth abnormalities to chronic respiratory disease.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Ivan Bosanac, Henry R Maun, Suzie J Scales, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The structure of SHH in complex with HHIP reveals a recognition role for the Shh pseudo active site in signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Struct Mol Biol (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nsmb.1632"}], "href": "https://doi.org/10.1038/nsmb.1632"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19561609"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19561609"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Benjamin Bishop, A Radu Aricescu, Karl Harlos, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structural insights into hedgehog ligand sequestration by the human hedgehog-interacting protein HHIP."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Struct Mol Biol (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nsmb.1607"}], "href": "https://doi.org/10.1038/nsmb.1607"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19561611"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19561611"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Michael N Weedon, Hana Lango, Cecilia M Lindgren, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genome-wide association analysis identifies 20 loci that influence adult height."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Genet (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ng.121"}], "href": "https://doi.org/10.1038/ng.121"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18391952"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18391952"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Jae-Jung Kim, Hae-In Lee, Taesung Park, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification of 15 loci influencing height in a Korean population."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Hum Genet (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/jhg.2009.116"}], "href": "https://doi.org/10.1038/jhg.2009.116"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19893584"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19893584"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Xiaobo Zhou, Rebecca M Baron, Megan Hardin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification of a chronic obstructive pulmonary disease genetic determinant that regulates HHIP."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddr569"}], "href": "https://doi.org/10.1093/hmg/ddr569"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22140090"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22140090"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "R P Young, C F Whittington, R J Hopkins, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Chromosome 4q31 locus in COPD is also associated with lung cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur Respir J (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1183/09031936.00033310"}], "href": "https://doi.org/10.1183/09031936.00033310"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21119205"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21119205"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Catherine L Olsen, Pin-Pin Hsu, Jens Glienke, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Hedgehog-interacting protein is highly expressed in endothelial cells but down-regulated during angiogenesis and in several human tumors."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "BMC Cancer (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/1471-2407-4-43"}], "href": "https://doi.org/10.1186/1471-2407-4-43"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15294024"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15294024"}]}]}]}
Synonyms	HIP
Proteins	HHIP_HUMAN
NCBI Gene ID	64399
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Predicted Functions
Co-expressed Genes
Expression in Tissues and Cell Lines

Functional Associations

HHIP has 5,430 functional associations with biological entities spanning 8 categories (molecular profile, organism, functional term, phrase or reference, chemical, disease, phenotype or trait, structural feature, cell line, cell type or tissue, gene, protein or microRNA) extracted from 112 datasets.

Click the + buttons to view associations for HHIP from the datasets below.

If available, associations are ranked by standardized value

Harmonizome 3.0

HHIP Gene

Functional Associations

Please acknowledge the Harmonizome in your publications by citing the following reference(s):

	Dataset	Summary
	Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of HHIP gene relative to other tissues from the Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles	tissue samples with high or low expression of HHIP gene relative to other tissue samples from the Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray	tissue samples with high or low expression of HHIP gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq	tissue samples with high or low expression of HHIP gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq dataset.
	Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of HHIP gene relative to other tissues from the Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles dataset.
	BioGPS Human Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of HHIP gene relative to other cell types and tissues from the BioGPS Human Cell Type and Tissue Gene Expression Profiles dataset.
	BioGPS Mouse Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of HHIP gene relative to other cell types and tissues from the BioGPS Mouse Cell Type and Tissue Gene Expression Profiles dataset.
	CCLE Cell Line Gene CNV Profiles	cell lines with high or low copy number of HHIP gene relative to other cell lines from the CCLE Cell Line Gene CNV Profiles dataset.
	CCLE Cell Line Gene Expression Profiles	cell lines with high or low expression of HHIP gene relative to other cell lines from the CCLE Cell Line Gene Expression Profiles dataset.
	CellMarker Gene-Cell Type Associations	cell types associated with HHIP gene from the CellMarker Gene-Cell Type Associations dataset.
	ChEA Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of HHIP gene from the CHEA Transcription Factor Binding Site Profiles dataset.
	ChEA Transcription Factor Targets	transcription factors binding the promoter of HHIP gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets dataset.
	ChEA Transcription Factor Targets 2022	transcription factors binding the promoter of HHIP gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets 2022 dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores	cellular components containing HHIP protein from the COMPARTMENTS Curated Protein Localization Evidence Scores dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores 2025	cellular components containing HHIP protein from the COMPARTMENTS Curated Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Experimental Protein Localization Evidence Scores	cellular components containing HHIP protein in low- or high-throughput protein localization assays from the COMPARTMENTS Experimental Protein Localization Evidence Scores dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores	cellular components co-occuring with HHIP protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025	cellular components co-occuring with HHIP protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025 dataset.
	COSMIC Cell Line Gene Mutation Profiles	cell lines with HHIP gene mutations from the COSMIC Cell Line Gene Mutation Profiles dataset.
	CTD Gene-Chemical Interactions	chemicals interacting with HHIP gene/protein from the curated CTD Gene-Chemical Interactions dataset.
	CTD Gene-Disease Associations	diseases associated with HHIP gene/protein from the curated CTD Gene-Disease Associations dataset.
	dbGAP Gene-Trait Associations	traits associated with HHIP gene in GWAS and other genetic association datasets from the dbGAP Gene-Trait Associations dataset.
	DepMap CRISPR Gene Dependency	cell lines with fitness changed by HHIP gene knockdown relative to other cell lines from the DepMap CRISPR Gene Dependency dataset.
	DISEASES Experimental Gene-Disease Association Evidence Scores	diseases associated with HHIP gene in GWAS datasets from the DISEASES Experimental Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Experimental Gene-Disease Association Evidence Scores 2025	diseases associated with HHIP gene in GWAS datasets from the DISEASES Experimental Gene-Disease Assocation Evidence Scores 2025 dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores	diseases co-occuring with HHIP gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores 2025	diseases co-occuring with HHIP gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores 2025 dataset.
	DisGeNET Gene-Disease Associations	diseases associated with HHIP gene in GWAS and other genetic association datasets from the DisGeNET Gene-Disease Associations dataset.
	DisGeNET Gene-Phenotype Associations	phenotypes associated with HHIP gene in GWAS and other genetic association datasets from the DisGeNET Gene-Phenoptype Associations dataset.
	ENCODE Histone Modification Site Profiles	histone modification site profiles with high histone modification abundance at HHIP gene from the ENCODE Histone Modification Site Profiles dataset.
	ENCODE Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of HHIP gene from the ENCODE Transcription Factor Binding Site Profiles dataset.
	ENCODE Transcription Factor Targets	transcription factors binding the promoter of HHIP gene in ChIP-seq datasets from the ENCODE Transcription Factor Targets dataset.
	ESCAPE Omics Signatures of Genes and Proteins for Stem Cells	PubMedIDs of publications reporting gene signatures containing HHIP from the ESCAPE Omics Signatures of Genes and Proteins for Stem Cells dataset.
	GAD Gene-Disease Associations	diseases associated with HHIP gene in GWAS and other genetic association datasets from the GAD Gene-Disease Associations dataset.
	GAD High Level Gene-Disease Associations	diseases associated with HHIP gene in GWAS and other genetic association datasets from the GAD High Level Gene-Disease Associations dataset.
	GeneRIF Biological Term Annotations	biological terms co-occuring with HHIP gene in literature-supported statements describing functions of genes from the GeneRIF Biological Term Annotations dataset.
	GeneSigDB Published Gene Signatures	PubMedIDs of publications reporting gene signatures containing HHIP from the GeneSigDB Published Gene Signatures dataset.
	GEO Signatures of Differentially Expressed Genes for Diseases	disease perturbations changing expression of HHIP gene from the GEO Signatures of Differentially Expressed Genes for Diseases dataset.
	GEO Signatures of Differentially Expressed Genes for Gene Perturbations	gene perturbations changing expression of HHIP gene from the GEO Signatures of Differentially Expressed Genes for Gene Perturbations dataset.
	GEO Signatures of Differentially Expressed Genes for Kinase Perturbations	kinase perturbations changing expression of HHIP gene from the GEO Signatures of Differentially Expressed Genes for Kinase Perturbations dataset.