| Name | HtrA serine peptidase 4 |
| Description | This gene encodes a member of the HtrA family of proteases. The encoded protein contains a putative signal peptide, an insulin growth factor binding domain, a Kazal protease inhibitor domain, a conserved trypsin domain and a PDZ domain. Based on studies on other related family members, this enzyme may function as a secreted oligomeric chaperone protease to degrade misfolded secretory proteins. Other human HtrA proteins have been implicated in arthritis, tumor suppression, unfolded stress response, apoptosis, and aging. [provided by RefSeq, Oct 2008] |
| Summary |
{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n HtrA4 is a placenta‐specific serine protease that modulates key processes in placental development and has been implicated in the pathogenesis of preeclampsia as well as in cancer cell death. In the placenta, HtrA4 is transcriptionally activated by factors such as GCM1 to promote trophoblast invasion by facilitating extracellular matrix remodeling (via cleavage of fibronectin) and by inhibiting excessive cell–cell fusion through its interaction with syncytin‑1, thereby contributing to proper extravillous trophoblast differentiation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Aberrant expression of HtrA4 under hypoxic conditions leads to its up‐regulation in preeclamptic placentas and elevated levels in the circulation, where it has been associated with shallow trophoblast invasion and features of endothelial dysfunction. Elevated HtrA4 disrupts endothelial integrity by altering junctional protein organization and directly cleaving the VEGFA receptor KDR, which inhibits Akt phosphorylation and impairs angiogenesis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "6"}]}, {"type": "t", "text": " In addition, studies in cancer models indicate that both the full‐length and N‑terminally truncated forms of HtrA4 can enhance apoptosis in response to chemotherapeutic challenges by degrading anti‑apoptotic factors such as XIAP and by targeting critical components of the cytoskeleton."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Collectively, these findings suggest that HtrA4 regulates trophoblast invasion and endothelial stability in the placenta and modulates apoptosis in cancer cells, thereby representing a potential biomarker and therapeutic target in both pregnancy complications and oncogenic contexts.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Liang-Jie Wang, Mei-Leng Cheong, Yun-Shien Lee, et al. "}, {"type": "b", "children": [{"type": "t", "text": "High-temperature requirement protein A4 (HtrA4) suppresses the fusogenic activity of syncytin-1 and promotes trophoblast invasion."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.00223-12"}], "href": "https://doi.org/10.1128/MCB.00223-12"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22778138"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22778138"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Yueh Ho Chiu, Hungwen Chen "}, {"type": "b", "children": [{"type": "t", "text": "GATA3 inhibits GCM1 activity and trophoblast cell invasion."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/srep21630"}], "href": "https://doi.org/10.1038/srep21630"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26899996"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26899996"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Chunhong Liu, Feng Xing, Yuanying He, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Elevated HTRA1 and HTRA4 in severe preeclampsia and their roles in trophoblast functions."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Med Rep (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3892/mmr.2018.9289"}], "href": "https://doi.org/10.3892/mmr.2018.9289"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30015931"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30015931"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "A Inagaki, H Nishizawa, S Ota, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Upregulation of HtrA4 in the placentas of patients with severe pre-eclampsia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Placenta (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.placenta.2012.08.003"}], "href": "https://doi.org/10.1016/j.placenta.2012.08.003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22964307"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22964307"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Harmeet Singh, Min Zhao, Qi Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Human HtrA4 Expression Is Restricted to the Placenta, Is Significantly Up-Regulated in Early-Onset Preeclampsia, and High Levels of HtrA4 Cause Endothelial Dysfunction."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Endocrinol Metab (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1210/jc.2014-3969"}], "href": "https://doi.org/10.1210/jc.2014-3969"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25946029"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25946029"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Yao Wang, Mylinh La, Tam Pham, et al. "}, {"type": "b", "children": [{"type": "t", "text": "High levels of HtrA4 detected in preeclamptic circulation may disrupt endothelial cell function by cleaving the main VEGFA receptor KDR."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FASEB J (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1096/fj.201802151RR"}], "href": "https://doi.org/10.1096/fj.201802151RR"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30601675"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30601675"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Raghupathi Kummari, Shubhankar Dutta, Lalith K Chaganti, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Discerning the mechanism of action of HtrA4: a serine protease implicated in the cell death pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem J (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1042/BCJ20190224"}], "href": "https://doi.org/10.1042/BCJ20190224"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31036715"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31036715"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Tomasz Wenta, Miroslaw Jarzab, Michal Rychlowski, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cellular substrates and pro-apoptotic function of the human HtrA4 protease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Proteomics (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jprot.2019.103505"}], "href": "https://doi.org/10.1016/j.jprot.2019.103505"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31470122"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31470122"}]}]}]}
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| Proteins | HTRA4_HUMAN |
| NCBI Gene ID | 203100 |
| API | |
| Download Associations | |
| Predicted Functions |
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| Co-expressed Genes |
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| Expression in Tissues and Cell Lines |
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HTRA4 has 2,960 functional associations with biological entities spanning 8 categories (molecular profile, organism, functional term, phrase or reference, disease, phenotype or trait, chemical, structural feature, cell line, cell type or tissue, gene, protein or microRNA) extracted from 72 datasets.
Click the + buttons to view associations for HTRA4 from the datasets below.
If available, associations are ranked by standardized value
| Dataset | Summary | |
|---|---|---|
| Achilles Cell Line Gene Essentiality Profiles | cell lines with fitness changed by HTRA4 gene knockdown relative to other cell lines from the Achilles Cell Line Gene Essentiality Profiles dataset. | |
| Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles | tissues with high or low expression of HTRA4 gene relative to other tissues from the Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles dataset. | |
| Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray | tissue samples with high or low expression of HTRA4 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray dataset. | |
| Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles | tissues with high or low expression of HTRA4 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 HTRA4 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 HTRA4 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 HTRA4 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 HTRA4 gene relative to other cell lines from the CCLE Cell Line Gene Expression Profiles dataset. | |
| ChEA Transcription Factor Binding Site Profiles | transcription factor binding site profiles with transcription factor binding evidence at the promoter of HTRA4 gene from the CHEA Transcription Factor Binding Site Profiles dataset. | |
| ChEA Transcription Factor Targets | transcription factors binding the promoter of HTRA4 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 HTRA4 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 HTRA4 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores dataset. | |
| COMPARTMENTS Text-mining Protein Localization Evidence Scores | cellular components co-occuring with HTRA4 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 HTRA4 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025 dataset. | |
| COSMIC Cell Line Gene CNV Profiles | cell lines with high or low copy number of HTRA4 gene relative to other cell lines from the COSMIC Cell Line Gene CNV Profiles dataset. | |
| COSMIC Cell Line Gene Mutation Profiles | cell lines with HTRA4 gene mutations from the COSMIC Cell Line Gene Mutation Profiles dataset. | |
| DepMap CRISPR Gene Dependency | cell lines with fitness changed by HTRA4 gene knockdown relative to other cell lines from the DepMap CRISPR Gene Dependency dataset. | |
| DISEASES Text-mining Gene-Disease Association Evidence Scores | diseases co-occuring with HTRA4 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 HTRA4 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 HTRA4 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Disease Associations dataset. | |
| DisGeNET Gene-Phenotype Associations | phenotypes associated with HTRA4 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 HTRA4 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 HTRA4 gene from the ENCODE Transcription Factor Binding Site Profiles dataset. | |
| ENCODE Transcription Factor Targets | transcription factors binding the promoter of HTRA4 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 HTRA4 from the ESCAPE Omics Signatures of Genes and Proteins for Stem Cells dataset. | |
| GeneRIF Biological Term Annotations | biological terms co-occuring with HTRA4 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 HTRA4 from the GeneSigDB Published Gene Signatures dataset. | |
| GEO Signatures of Differentially Expressed Genes for Gene Perturbations | gene perturbations changing expression of HTRA4 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 HTRA4 gene from the GEO Signatures of Differentially Expressed Genes for Kinase Perturbations dataset. | |
| GEO Signatures of Differentially Expressed Genes for Small Molecules | small molecule perturbations changing expression of HTRA4 gene from the GEO Signatures of Differentially Expressed Genes for Small Molecules dataset. | |
| GEO Signatures of Differentially Expressed Genes for Viral Infections | virus perturbations changing expression of HTRA4 gene from the GEO Signatures of Differentially Expressed Genes for Viral Infections dataset. | |
| GO Biological Process Annotations 2015 | biological processes involving HTRA4 gene from the curated GO Biological Process Annotations 2015 dataset. | |
| GO Biological Process Annotations 2023 | biological processes involving HTRA4 gene from the curated GO Biological Process Annotations 2023 dataset. | |
| GO Biological Process Annotations 2025 | biological processes involving HTRA4 gene from the curated GO Biological Process Annotations2025 dataset. | |
| GO Cellular Component Annotations 2015 | cellular components containing HTRA4 protein from the curated GO Cellular Component Annotations 2015 dataset. | |
| GO Molecular Function Annotations 2015 | molecular functions performed by HTRA4 gene from the curated GO Molecular Function Annotations 2015 dataset. | |
| GO Molecular Function Annotations 2023 | molecular functions performed by HTRA4 gene from the curated GO Molecular Function Annotations 2023 dataset. | |
| GO Molecular Function Annotations 2025 | molecular functions performed by HTRA4 gene from the curated GO Molecular Function Annotations 2025 dataset. | |
| GTEx Tissue Gene Expression Profiles | tissues with high or low expression of HTRA4 gene relative to other tissues from the GTEx Tissue Gene Expression Profiles dataset. | |
| GTEx Tissue Gene Expression Profiles 2023 | tissues with high or low expression of HTRA4 gene relative to other tissues from the GTEx Tissue Gene Expression Profiles 2023 dataset. | |
| GTEx Tissue Sample Gene Expression Profiles | tissue samples with high or low expression of HTRA4 gene relative to other tissue samples from the GTEx Tissue Sample Gene Expression Profiles dataset. | |
| Heiser et al., PNAS, 2011 Cell Line Gene Expression Profiles | cell lines with high or low expression of HTRA4 gene relative to other cell lines from the Heiser et al., PNAS, 2011 Cell Line Gene Expression Profiles dataset. | |
| HPA Cell Line Gene Expression Profiles | cell lines with high or low expression of HTRA4 gene relative to other cell lines from the HPA Cell Line Gene Expression Profiles dataset. | |
| HPA Tissue Gene Expression Profiles | tissues with high or low expression of HTRA4 gene relative to other tissues from the HPA Tissue Gene Expression Profiles dataset. | |
| HPA Tissue Protein Expression Profiles | tissues with high or low expression of HTRA4 protein relative to other tissues from the HPA Tissue Protein Expression Profiles dataset. | |
| HPA Tissue Sample Gene Expression Profiles | tissue samples with high or low expression of HTRA4 gene relative to other tissue samples from the HPA Tissue Sample Gene Expression Profiles dataset. | |
| InterPro Predicted Protein Domain Annotations | protein domains predicted for HTRA4 protein from the InterPro Predicted Protein Domain Annotations dataset. | |
| JASPAR Predicted Transcription Factor Targets | transcription factors regulating expression of HTRA4 gene predicted using known transcription factor binding site motifs from the JASPAR Predicted Transcription Factor Targets dataset. | |
| Klijn et al., Nat. Biotechnol., 2015 Cell Line Gene CNV Profiles | cell lines with high or low copy number of HTRA4 gene relative to other cell lines from the Klijn et al., Nat. Biotechnol., 2015 Cell Line Gene CNV Profiles dataset. | |
| Klijn et al., Nat. Biotechnol., 2015 Cell Line Gene Mutation Profiles | cell lines with HTRA4 gene mutations from the Klijn et al., Nat. Biotechnol., 2015 Cell Line Gene Mutation Profiles dataset. | |
| KnockTF Gene Expression Profiles with Transcription Factor Perturbations | transcription factor perturbations changing expression of HTRA4 gene from the KnockTF Gene Expression Profiles with Transcription Factor Perturbations dataset. | |
| LOCATE Predicted Protein Localization Annotations | cellular components predicted to contain HTRA4 protein from the LOCATE Predicted Protein Localization Annotations dataset. | |
| MGI Mouse Phenotype Associations 2023 | phenotypes of transgenic mice caused by HTRA4 gene mutations from the MGI Mouse Phenotype Associations 2023 dataset. | |
| MiRTarBase microRNA Targets | microRNAs targeting HTRA4 gene in low- or high-throughput microRNA targeting studies from the MiRTarBase microRNA Targets dataset. | |
| MotifMap Predicted Transcription Factor Targets | transcription factors regulating expression of HTRA4 gene predicted using known transcription factor binding site motifs from the MotifMap Predicted Transcription Factor Targets dataset. | |
| PerturbAtlas Signatures of Differentially Expressed Genes for Gene Perturbations | gene perturbations changing expression of HTRA4 gene from the PerturbAtlas Signatures of Differentially Expressed Genes for Gene Perturbations dataset. | |
| PerturbAtlas Signatures of Differentially Expressed Genes for Mouse Gene Perturbations | gene perturbations changing expression of HTRA4 gene from the PerturbAtlas Signatures of Differentially Expressed Genes for Gene Perturbations dataset. | |
| PFOCR Pathway Figure Associations 2023 | pathways involving HTRA4 protein from the PFOCR Pathway Figure Associations 2023 dataset. | |
| PFOCR Pathway Figure Associations 2024 | pathways involving HTRA4 protein from the Wikipathways PFOCR 2024 dataset. | |
| Roadmap Epigenomics Cell and Tissue DNA Methylation Profiles | cell types and tissues with high or low DNA methylation of HTRA4 gene relative to other cell types and tissues from the Roadmap Epigenomics Cell and Tissue DNA Methylation Profiles dataset. | |
| Roadmap Epigenomics Histone Modification Site Profiles | histone modification site profiles with high histone modification abundance at HTRA4 gene from the Roadmap Epigenomics Histone Modification Site Profiles dataset. | |
| RummaGEO Drug Perturbation Signatures | drug perturbations changing expression of HTRA4 gene from the RummaGEO Drug Perturbation Signatures dataset. | |
| RummaGEO Gene Perturbation Signatures | gene perturbations changing expression of HTRA4 gene from the RummaGEO Gene Perturbation Signatures dataset. | |
| Tabula Sapiens Gene-Cell Associations | cell types with high or low expression of HTRA4 gene relative to other cell types from the Tabula Sapiens Gene-Cell Associations dataset. | |
| TargetScan Predicted Conserved microRNA Targets | microRNAs regulating expression of HTRA4 gene predicted using conserved miRNA seed sequences from the TargetScan Predicted Conserved microRNA Targets dataset. | |
| TargetScan Predicted Nonconserved microRNA Targets | microRNAs regulating expression of HTRA4 gene predicted using nonconserved miRNA seed sequences from the TargetScan Predicted Nonconserved microRNA Targets dataset. | |
| TCGA Signatures of Differentially Expressed Genes for Tumors | tissue samples with high or low expression of HTRA4 gene relative to other tissue samples from the TCGA Signatures of Differentially Expressed Genes for Tumors dataset. | |
| TISSUES Curated Tissue Protein Expression Evidence Scores | tissues with high expression of HTRA4 protein from the TISSUES Curated Tissue Protein Expression Evidence Scores dataset. | |
| TISSUES Curated Tissue Protein Expression Evidence Scores 2025 | tissues with high expression of HTRA4 protein from the TISSUES Curated Tissue Protein Expression Evidence Scores 2025 dataset. | |
| TISSUES Experimental Tissue Protein Expression Evidence Scores | tissues with high expression of HTRA4 protein in proteomics datasets from the TISSUES Experimental Tissue Protein Expression Evidence Scores dataset. | |
| TISSUES Text-mining Tissue Protein Expression Evidence Scores | tissues co-occuring with HTRA4 protein in abstracts of biomedical publications from the TISSUES Text-mining Tissue Protein Expression Evidence Scores dataset. | |
| TISSUES Text-mining Tissue Protein Expression Evidence Scores 2025 | tissues co-occuring with HTRA4 protein in abstracts of biomedical publications from the TISSUES Text-mining Tissue Protein Expression Evidence Scores 2025 dataset. | |
