Details for: TMPRSS15

Gene ID: 5651

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: TMPRSS15

Ensembl ID: ENSG00000154646

Description: transmembrane serine protease 15

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

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

  • glutamatergic neuron CL0000679
    CSI 4.96
    rCSI 10.19%
    PRS 93.46
  • epithelial cell CL0000066
    CSI 4.57
    rCSI 7.02%
    PRS 94.02
  • neural progenitor cell CL0011020
    CSI 3.63
    rCSI 15.96%
    PRS 93.82
  • GABAergic neuron CL0000617
    CSI 3.18
    rCSI 10.64%
    PRS 93.19
  • colonocyte CL1000347
    CSI 2.29
    rCSI 3.29%
    PRS 98.32
  • glial cell CL0000125
    CSI 2.25
    rCSI 8.58%
    PRS 96.17
  • enterocyte of epithelium of small intestine CL1000334
    CSI 0.43
    rCSI 6.72%
    PRS 98.62

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

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  • Node Color (Target Cell CSI, relative to current network):
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    • 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 [TMPRSS15](/details-gene/5651), also known as enteropeptidase, is a type II transmembrane serine protease encoded on chromosome 21. Its canonical function is to initiate protein digestion in the small intestine by converting inactive trypsinogen into active trypsin, which in turn activates a cascade of other digestive proenzymes ([Link](https://doi.org/10.1073/pnas.91.16.7588)). Consistent with this role, the gene product localizes to the [brush border](/details-go/GO:0005903) of intestinal epithelial cells and is involved in [proteolysis](/details-go/GO:0006508). Clinically, mutations in [TMPRSS15](/details-gene/5651) are the cause of congenital enteropeptidase deficiency, a rare autosomal recessive disorder characterized by severe malabsorption and failure to thrive ([Link](https://doi.org/10.1086/338456); [226200](https://omim.org/entry/226200)). **Overall**, expression data reveals its expected significance in intestinal cells such as [colonocytes](/details-cell/CL1000347) and [enterocytes](/details-cell/CL1000334), but also points towards a potentially novel and significant role within the central nervous system, with high expression observed in [glutamatergic neurons](/details-cell/CL0000679) and [neural progenitor cells](/details-cell/CL0011020). ## Cellular Roles and Expression Landscape The expression profile of [TMPRSS15](/details-gene/5651) highlights a dual-tissue identity, with significant roles in both the digestive and nervous systems. Its well-established function in the gastrointestinal tract is supported by its expression in [enterocytes of the epithelium of the small intestine](/details-cell/CL1000334) and [colonocytes](/details-cell/CL1000347). In these cells, [TMPRSS15](/details-gene/5651) acts as the master switch for protein digestion, a role critical for nutrient absorption. Unexpectedly, the highest significance index for [TMPRSS15](/details-gene/5651) is observed in neuronal populations. Specifically, it shows high significance in [glutamatergic neurons](/details-cell/CL0000679) (CSI: 4.96), [neural progenitor cells](/details-cell/CL0011020) (CSI: 3.63), and [GABAergic neurons](/details-cell/CL0000617) (CSI: 3.18). This strong and specific expression pattern suggests that [TMPRSS15](/details-gene/5651) may perform important proteolytic functions outside of the gut, potentially related to neural development, synaptic remodeling, or the processing of neuropeptides or cell-surface proteins in the brain. The expression in [glial cells](/details-cell/CL0000125) further broadens its potential impact on central nervous system homeostasis. ## Pathways and Molecular Function The functional annotations for [TMPRSS15](/details-gene/5651) align precisely with its biochemical identity as a protease. Its annotated molecular functions include [serine-type endopeptidase activity](/details-go/GO:0004252) and [protein binding](/details-go/GO:0005515), which are essential for recognizing and cleaving its substrate, trypsinogen. The overarching biological process it participates in is [proteolysis](/details-go/GO:0006508). Its cellular localization to the [membrane](/details-go/GO:0016020), and more specifically the [brush border](/details-go/GO:0005903), is critical for its function in [enterocytes](/details-cell/CL1000334), positioning the enzyme at the luminal surface where it can interact with dietary proteins and pancreatic zymogens ([Link](https://doi.org/10.1021/bi00014a008)). While these pathways are well-understood in the intestinal context, their relevance in [glutamatergic neurons](/details-cell/CL0000679) remains to be elucidated and suggests the existence of neuronal-specific substrates and proteolytic cascades initiated by [TMPRSS15](/details-gene/5651). ## Research Directions The discovery of high [TMPRSS15](/details-gene/5651) expression in neuronal cell types opens new avenues for investigation beyond its classical role in digestion. The central research challenge is to define the function of this potent protease in the central nervous system. **Proposed Hypotheses:** 1. [TMPRSS15](/details-gene/5651) is involved in synaptic plasticity by cleaving specific extracellular matrix components or cell adhesion molecules at the synapse in [glutamatergic neurons](/details-cell/CL0000679), thereby modulating synaptic strength and structure. 2. In [neural progenitor cells](/details-cell/CL0011020), [TMPRSS15](/details-gene/5651) processes growth factors or their receptors on the cell surface, playing a regulatory role in neurodevelopment, including cell migration and differentiation. **Experimental Approach:** To test the hypothesis that [TMPRSS15](/details-gene/5651) modulates synaptic plasticity (Hypothesis 1), a targeted experiment could be performed. CRISPR-Cas9 could be used to create a knockout of [TMPRSS15](/details-gene/5651) in human induced pluripotent stem cell (iPSC)-derived [glutamatergic neurons](/details-cell/CL0000679). The resulting neuronal cultures could then be analyzed using a combination of techniques: * **Proteomics:** Activity-based protein profiling or mass spectrometry of the neuronal surface and secretome to identify novel substrates of [TMPRSS15](/details-gene/5651) in a neuronal context. * **Electrophysiology:** Multi-electrode array (MEA) or patch-clamp analysis to measure changes in baseline synaptic activity, long-term potentiation (LTP), and long-term depression (LTD) compared to wild-type controls. * **Imaging:** High-resolution microscopy to assess for morphological changes in dendritic spines and synaptic structures. **Therapeutic Potential:** The established clinical relevance of [TMPRSS15](/details-gene/5651) relates to loss-of-function mutations. Therefore, the primary therapeutic strategy for congenital enteropeptidase deficiency ([226200](https://omim.org/entry/226200)) would involve **activation or replacement**, such as through recombinant enzyme replacement therapy. Its role in the brain is unknown, but if its dysregulation (either over- or under-activity) is linked to neurodevelopmental or neurodegenerative disorders, it could emerge as a novel therapeutic target. As a cell-surface protease, it is highly accessible to biologic drugs like therapeutic antibodies or engineered proteins, but targeting would require a precise understanding of its specific substrates and effects in the brain to ensure safety and efficacy.

Genular Protein ID: 4006208978

Symbol: ENTK_HUMAN

Name: Enteropeptidase

UniProtKB Accession Codes:

P98073 Q2NKL7

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 BRENDA 1 Bgee 1 BindingDB 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 4 CTD 1 ChEMBL 1 ChiTaRS 1 DMDM 1 DNASU 1 DisGeNET 1 EC 2 EMBL 24 EMDB 4 Ensembl 1 EvolutionaryTrace 1 ExpressionAtlas 1 GO 4 Gene3D 6 GeneCards 1 GeneTree 1 GenomeRNAi 1 GlyCosmos 1 GlyGen 1 GuidetoPHARMACOLOGY 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 19 KEGG 1 MANE-Select 1 MEROPS 1 MIM 3 MINT 1 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 Orphanet 1 OrthoDB 1 PANTHER 2 PDB 3 PDBsum 3 PIR 1 PIRSF 1 PRINTS 1 PRO 1 PROSITE 10 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 6 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 Pumba 1 RNAct 1 RefSeq 1 SMART 6 SMR 1 STRING 1 SUPFAM 6 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 neXtProt 1

Citations:

PubMed ID: 7718557

Title: cDNA sequence and chromosomal localization of human enterokinase, the proteolytic activator of trypsinogen.

PubMed ID: 7718557

DOI: 10.1021/bi00014a008

PubMed ID: 11719902

Title: Mutations in the proenteropeptidase gene are the molecular cause of congenital enteropeptidase deficiency.

PubMed ID: 11719902

DOI: 10.1086/338456

PubMed ID: 10830953

Title: The DNA sequence of human chromosome 21.

PubMed ID: 10830953

DOI: 10.1038/35012518

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: 8052624

Title: Enterokinase, the initiator of intestinal digestion, is a mosaic protease composed of a distinctive assortment of domains.

PubMed ID: 8052624

DOI: 10.1073/pnas.91.16.7588

PubMed ID: 22488687

Title: Crystal structure of a supercharged variant of the human enteropeptidase light chain.

PubMed ID: 22488687

DOI: 10.1002/prot.24084

Sequence Information:

  • Length: 1019
  • Mass: 112935
  • Checksum: 45288F0636E5EC52
  • Sequence:
    • MGSKRGISSR HHSLSSYEIM FAALFAILVV LCAGLIAVSC LTIKESQRGA ALGQSHEARA 
TFKITSGVTY NPNLQDKLSV DFKVLAFDLQ QMIDEIFLSS NLKNEYKNSR VLQFENGSII 
VVFDLFFAQW VSDENVKEEL IQGLEANKSS QLVTFHIDLN SVDILDKLTT TSHLATPGNV 
SIECLPGSSP CTDALTCIKA DLFCDGEVNC PDGSDEDNKM CATVCDGRFL LTGSSGSFQA 
THYPKPSETS VVCQWIIRVN QGLSIKLSFD DFNTYYTDIL DIYEGVGSSK ILRASIWETN 
PGTIRIFSNQ VTATFLIESD ESDYVGFNAT YTAFNSSELN NYEKINCNFE DGFCFWVQDL 
NDDNEWERIQ GSTFSPFTGP NFDHTFGNAS GFYISTPTGP GGRQERVGLL SLPLDPTLEP 
ACLSFWYHMY GENVHKLSIN ISNDQNMEKT VFQKEGNYGD NWNYGQVTLN ETVKFKVAFN 
AFKNKILSDI ALDDISLTYG ICNGSLYPEP TLVPTPPPEL PTDCGGPFEL WEPNTTFSST 
NFPNSYPNLA FCVWILNAQK GKNIQLHFQE FDLENINDVV EIRDGEEADS LLLAVYTGPG 
PVKDVFSTTN RMTVLLITND VLARGGFKAN FTTGYHLGIP EPCKADHFQC KNGECVPLVN 
LCDGHLHCED GSDEADCVRF FNGTTNNNGL VRFRIQSIWH TACAENWTTQ ISNDVCQLLG 
LGSGNSSKPI FPTDGGPFVK LNTAPDGHLI LTPSQQCLQD SLIRLQCNHK SCGKKLAAQD 
ITPKIVGGSN AKEGAWPWVV GLYYGGRLLC GASLVSSDWL VSAAHCVYGR NLEPSKWTAI 
LGLHMKSNLT SPQTVPRLID EIVINPHYNR RRKDNDIAMM HLEFKVNYTD YIQPICLPEE 
NQVFPPGRNC SIAGWGTVVY QGTTANILQE ADVPLLSNER CQQQMPEYNI TENMICAGYE 
EGGIDSCQGD SGGPLMCQEN NRWFLAGVTS FGYKCALPNR PGVYARVSRF TEWIQSFLH