Details for: HTRA3

Gene ID: 94031

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: HTRA3

Ensembl ID: ENSG00000170801

Description: HtrA serine peptidase 3

Cell Significance Landscape

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • myofibroblast cell CL0000186
    CSI 13.21
    rCSI 18.3%
    PRS 94.44
  • bronchus fibroblast of lung CL2000093
    CSI 11.05
    rCSI 8.98%
    PRS 96.15
  • interstitial cell of Cajal CL0002088
    CSI 9.01
    rCSI 11.47%
    PRS 98.02
  • skin fibroblast CL0002620
    CSI 4.87
    rCSI 4.2%
    PRS 96.01
  • alveolar adventitial fibroblast CL4028006
    CSI 4.25
    rCSI 6.71%
    PRS 97.06
  • alveolar type 1 fibroblast cell CL4028004
    CSI 4.09
    rCSI 4.48%
    PRS 97.19
  • adventitial cell CL0002503
    CSI 3.7
    rCSI 8.84%
    PRS 97.48
  • myeloid leukocyte CL0000766
    CSI 3.62
    rCSI 3.34%
    PRS 97.18
  • mesenchymal stem cell of adipose tissue CL0002570
    CSI 2.71
    rCSI 15.11%
    PRS 97.04
  • mesodermal cell CL0000222
    CSI 2.66
    rCSI 3.19%
    PRS 96.32
  • adipocyte CL0000136
    CSI 2.56
    rCSI 3.28%
    PRS 91.27
  • enteric smooth muscle cell CL0002504
    CSI 2.45
    rCSI 3.5%
    PRS 96.44
  • neural progenitor cell CL0011020
    CSI 2.4
    rCSI 10.58%
    PRS 88.38
  • stromal cell of ovary CL0002132
    CSI 2.24
    rCSI 6.15%
    PRS 97.44
  • keratocyte CL0002363
    CSI 1.86
    rCSI 4.46%
    PRS 96.44
  • stromal cell CL0000499
    CSI 1.55
    rCSI 4.36%
    PRS 94.19
  • mesenchymal cell CL0008019
    CSI 1.41
    rCSI 3.59%
    PRS 94.23
  • fibroblast of breast CL4006000
    CSI 1.33
    rCSI 5.59%
    PRS 97.41
  • odontoblast CL0000060
    CSI 1.22
    rCSI 27.7%
    PRS 98.44
  • pancreatic stellate cell CL0002410
    CSI 0.86
    rCSI 5.01%
    PRS 96.69
  • mesenchymal stem cell CL0000134
    CSI 0.21
    rCSI 2.32%
    PRS 97.35

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

Comma-separated if multiple.
Comma-separated if multiple.
Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [HTRA3](/details-gene/94031), or HtrA serine peptidase 3, is a protein-coding gene located on chromosome 4p16.1. It encodes an extracellular serine protease that plays a significant role in proteolysis and the negative regulation of key signaling pathways, including the transforming growth factor-beta (TGF-beta) and bone morphogenetic protein (BMP) pathways. Expression analysis indicates that [HTRA3](/details-gene/94031) is a prominent marker for various cells of mesenchymal origin, with particularly high significance in fibroblast and myofibroblast populations. Its function as a regulator of extracellular signaling is consistent with its established roles in processes such as placentation and its potential involvement in cancer biology. ## Cellular Roles and Expression Landscape The expression profile of [HTRA3](/details-gene/94031) strongly suggests a specialized function within mesenchymal and stromal cell compartments. **Overall**, the gene shows the highest significance in cells responsible for producing and remodeling connective tissue. It is a top marker for [myofibroblast cell](/details-cell/CL0000186) (CSI: 13.21), a key cell type in wound healing and fibrosis, as well as several other fibroblast populations, including [bronchus fibroblast of lung](/details-cell/CL2000093) (CSI: 11.05), [skin fibroblast](/details-cell/CL0002620) (CSI: 4.87), [alveolar adventitial fibroblast](/details-cell/CL4028006) (CSI: 4.25), and [alveolar type 1 fibroblast cell](/details-cell/CL4028004) (CSI: 4.09). This association extends to related structural and progenitor cells, such as [interstitial cell of Cajal](/details-cell/CL0002088) (CSI: 9.01), [adventitial cell](/details-cell/CL0002503) (CSI: 3.70), and [mesenchymal stem cell of adipose tissue](/details-cell/CL0002570) (CSI: 2.71). The consistent high significance of [HTRA3](/details-gene/94031) across these diverse yet functionally related cell types highlights its role as a key modulator of the extracellular environment and tissue architecture. ## Pathways and Molecular Function Functionally, [HTRA3](/details-gene/94031) operates as a serine-type endopeptidase, as annotated by its involvement in [proteolysis](/details-go/GO:0006508) and [serine-type endopeptidase activity](/details-go/GO:0004252). Its localization to the [extracellular region](/details-go/GO:0005576) indicates that it acts on substrates outside the cell, such as other secreted proteins or components of the extracellular matrix. A critical aspect of its function is the modulation of cell signaling. [HTRA3](/details-gene/94031) is a known negative regulator of the [transforming growth factor beta receptor signaling pathway](/details-go/GO:0030512) and the [bmp signaling pathway](/details-go/GO:0030514). These pathways are fundamental in controlling cell proliferation, differentiation, and tissue homeostasis, particularly in mesenchymal cells where [HTRA3](/details-gene/94031) is most active. This regulatory role is exemplified by its function during placentation, where decidual [HTRA3](/details-gene/94031) has been shown to negatively regulate trophoblast invasion, a process tightly controlled by TGF-beta signaling ([Link](https://doi.org/10.1093/humrep/der019)). Furthermore, studies have reported that [HTRA3](/details-gene/94031) is down-regulated in human endometrial cancers, suggesting a potential tumor-suppressive role linked to its ability to temper pro-proliferative signals ([Link](https://doi.org/10.1016/j.ygyno.2006.03.006); [Link](https://doi.org/10.3892/or_00000385)). ## Research Directions The evidence points to [HTRA3](/details-gene/94031) as a crucial extracellular protease that maintains tissue balance by restraining powerful signaling pathways like TGF-beta. Its high expression in fibroblasts and its reported downregulation in certain cancers suggest it may act as a stromal-derived tumor suppressor. Based on these observations, several testable hypotheses can be proposed: 1. Loss of [HTRA3](/details-gene/94031) expression in cancer-associated fibroblasts within the tumor microenvironment dysregulates local TGF-beta signaling, leading to enhanced tumor cell invasion and proliferation. 2. In fibrotic diseases such as idiopathic pulmonary fibrosis, the expression or activity of [HTRA3](/details-gene/94031) in lung fibroblasts is impaired, contributing to the pathological activation of myofibroblasts and excessive collagen deposition. 3. [HTRA3](/details-gene/94031) directly cleaves and inactivates specific members of the TGF-beta superfamily or their binding proteins in the extracellular space, and this substrate specificity is critical for its biological function in tissue homeostasis. To test the hypothesis regarding its role in fibrosis (Hypothesis 2), a key experiment could be designed. Primary lung fibroblasts could be isolated from both healthy donors and patients with idiopathic pulmonary fibrosis. The expression and activity of [HTRA3](/details-gene/94031) would be quantified in these cells at baseline and after stimulation with pro-fibrotic factors like TGF-beta1. Subsequently, genetic tools such as CRISPR-Cas9 or shRNA could be used to knock down [HTRA3](/details-gene/94031) in healthy fibroblasts, with endpoints including the assessment of myofibroblast differentiation markers (e.g., alpha-smooth muscle actin) and collagen secretion. Conversely, overexpressing [HTRA3](/details-gene/94031) in diseased fibroblasts could be evaluated for its potential to reverse the fibrotic phenotype. Given that its loss of function is associated with pathology (e.g., cancer progression, potentially fibrosis), [HTRA3](/details-gene/94031) presents itself as a candidate for therapeutic activation or replacement. Therapeutic strategies might involve the development of recombinant [HTRA3](/details-gene/94031) protein for localized delivery to fibrotic tissues or the screening for small-molecule compounds that enhance its endogenous proteolytic activity. Such an approach would aim to restore its natural braking mechanism on pro-fibrotic and pro-tumorigenic signaling pathways.

Genular Protein ID: 267138937

Symbol: HTRA3_HUMAN

Name: Serine protease HTRA3

UniProtKB Accession Codes:

P83110 Q7Z7A2

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 BRENDA 1 Bgee 1 BindingDB 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 2 CDD 2 CTD 1 DMDM 1 DNASU 1 DisGeNET 1 EC 1 EMBL 6 Ensembl 2 EvolutionaryTrace 1 GO 8 Gene3D 4 GeneCards 1 GeneTree 1 GenomeRNAi 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 8 KEGG 1 MANE-Select 1 MEROPS 1 MIM 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PDB 2 PDBsum 2 PRINTS 1 PRO 1 PROSITE 3 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 4 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 2 Pumba 1 RNAct 1 RefSeq 2 SMART 3 SMR 1 STRING 1 SUPFAM 4 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 12513693

Title: Identification and cloning of two isoforms of human high-temperature requirement factor A3 (HtrA3), characterization of its genomic structure and comparison of its tissue distribution with HtrA1 and HtrA2.

PubMed ID: 12513693

DOI: 10.1042/bj20021569

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 15815621

Title: Generation and annotation of the DNA sequences of human chromosomes 2 and 4.

PubMed ID: 15815621

DOI: 10.1038/nature03466

PubMed ID: 16650464

Title: Serine proteases HTRA1 and HTRA3 are down-regulated with increasing grades of human endometrial cancer.

PubMed ID: 16650464

DOI: 10.1016/j.ygyno.2006.03.006

PubMed ID: 19424634

Title: Expression of human HtrA1, HtrA2, HtrA3 and TGF-beta1 genes in primary endometrial cancer.

PubMed ID: 19424634

DOI: 10.3892/or_00000385

PubMed ID: 21321049

Title: Decidual HtrA3 negatively regulates trophoblast invasion during human placentation.

PubMed ID: 21321049

DOI: 10.1093/humrep/der019

PubMed ID: 22229724

Title: Application of the wheat-germ cell-free translation system to produce high temperature requirement A3 (HtrA3) proteases.

PubMed ID: 22229724

DOI: 10.2144/000113798

PubMed ID: 17962403

Title: Structural and functional analysis of the PDZ domains of human HtrA1 and HtrA3.

PubMed ID: 17962403

DOI: 10.1110/ps.073049407

PubMed ID: 26110759

Title: Structural and functional analysis of human HtrA3 protease and its subdomains.

PubMed ID: 26110759

DOI: 10.1371/journal.pone.0131142

Sequence Information:

  • Length: 453
  • Mass: 48608
  • Checksum: 3046FCDA1AB24FA6
  • Sequence:
    • MQARALLLAA LAALALAREP PAAPCPARCD VSRCPSPRCP GGYVPDLCNC CLVCAASEGE 
PCGGPLDSPC GESLECVRGL CRCRWSHAVC GTDGHTYANV CALQAASRRA LQLSGTPVRQ 
LQKGACPLGL HQLSSPRYKF NFIADVVEKI APAVVHIELF LRHPLFGRNV PLSSGSGFIM 
SEAGLIITNA HVVSSNSAAP GRQQLKVQLQ NGDSYEATIK DIDKKSDIAT IKIHPKKKLP 
VLLLGHSADL RPGEFVVAIG SPFALQNTVT TGIVSTAQRE GRELGLRDSD MDYIQTDAII 
NYGNSGGPLV NLDGEVIGIN TLKVTAGISF AIPSDRITRF LTEFQDKQIK DWKKRFIGIR 
MRTITPSLVD ELKASNPDFP EVSSGIYVQE VAPNSPSQRG GIQDGDIIVK VNGRPLVDSS 
ELQEAVLTES PLLLEVRRGN DDLLFSIAPE VVM