Details for: SPINK4

Gene ID: 27290

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: SPINK4

Ensembl ID: ENSG00000122711

Description: serine peptidase inhibitor Kazal type 4

Cell Significance Landscape

Associated with

Significant Cells

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

  • goblet cell CL0000160
    CSI 28.36
    rCSI 26.8%
    PRS 97.49
  • intestine goblet cell CL0019031
    CSI 27.66
    rCSI 24.56%
    PRS 97.46
  • small intestine goblet cell CL1000495
    CSI 17.09
    rCSI 37.44%
    PRS 98.49
  • colon goblet cell CL0009039
    CSI 14.68
    rCSI 34.91%
    PRS 98.35
  • type L enteroendocrine cell CL0002279
    CSI 11.26
    rCSI 21.13%
    PRS 98.13
  • paneth cell CL0000510
    CSI 10.12
    rCSI 14.94%
    PRS 99.08
  • retinal rod cell CL0000604
    CSI 9.38
    rCSI 16.53%
    PRS 96.25
  • brush cell CL0002204
    CSI 6.59
    rCSI 13.04%
    PRS 98.07
  • rod bipolar cell CL0000751
    CSI 6.55
    rCSI 11.77%
    PRS 96.11
  • IgA plasma cell CL0000987
    CSI 6.28
    rCSI 6.43%
    PRS 96.61
  • transit amplifying cell of colon CL0009011
    CSI 4.8
    rCSI 5.64%
    PRS 98.52
  • intestinal crypt stem cell of small intestine CL0009017
    CSI 4.77
    rCSI 12.87%
    PRS 98.62
  • enteroendocrine cell CL0000164
    CSI 4.33
    rCSI 5.91%
    PRS 97.07
  • retinal cone cell CL0000573
    CSI 4.14
    rCSI 6.66%
    PRS 95.09
  • intestinal tuft cell CL0019032
    CSI 3.65
    rCSI 5.57%
    PRS 98.09
  • colonocyte CL1000347
    CSI 3.27
    rCSI 4.69%
    PRS 97.56
  • enterocyte CL0000584
    CSI 3.15
    rCSI 5.08%
    PRS 96.66
  • glutamatergic neuron CL0000679
    CSI 2.75
    rCSI 5.64%
    PRS 92.21
  • colon epithelial cell CL0011108
    CSI 2.38
    rCSI 2.49%
    PRS 97.6
  • glial cell CL0000125
    CSI 2.33
    rCSI 8.85%
    PRS 95.43
  • enteroendocrine cell of small intestine CL0009006
    CSI 1.98
    rCSI 4.36%
    PRS 98.21
  • paneth cell of epithelium of small intestine CL1000343
    CSI 1.25
    rCSI 3.51%
    PRS 98.74
  • enteroendocrine cell of colon CL0009042
    CSI 1.07
    rCSI 5%
    PRS 97.88
  • type EC enteroendocrine cell CL0000577
    CSI 1.05
    rCSI 3.71%
    PRS 97.98

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.

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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 [SPINK4](/details-gene/27290) (Serine Peptidase Inhibitor Kazal Type 4) is a protein-coding gene located on chromosome 9p13.3. It encodes a secreted protein that functions as a serine-type endopeptidase inhibitor. Based on its expression profile, [SPINK4](/details-gene/27290) is a highly specific marker for secretory epithelial cells, particularly within the gastrointestinal tract. Its principal role appears to be in the protection of mucosal surfaces by regulating protease activity in the extracellular environment, a function consistent with its high significance in [goblet cells](/details-cell/CL0000160) and other specialized secretory cell types. Foundational work on human chromosome sequencing helped characterize this gene ([Link](https://doi.org/10.1038/nature02465), [Link](https://doi.org/10.1101/gr.2596504)). ## Cellular Roles and Expression Landscape **Overall**, the expression of [SPINK4](/details-gene/27290) is exceptionally high and specific to a subset of secretory and specialized epithelial cells, suggesting a focused biological role. The gene's most prominent expression is within the gastrointestinal mucosa. It is a defining marker for [goblet cell](/details-cell/CL0000160) populations across different intestinal segments, including [intestine goblet cell](/details-cell/CL0019031) (CSI: 27.66), [small intestine goblet cell](/details-cell/CL1000495) (CSI: 17.09), and [colon goblet cell](/details-cell/CL0009039) (CSI: 14.68). This indicates a crucial function in the formation or maintenance of the protective mucus layer. High significance is also observed in other key secretory cells of the gut, such as [paneth cell](/details-cell/CL0000510) and various [enteroendocrine cells](/details-cell/CL0000164), further cementing its role in regulating the luminal environment. Its presence in progenitor populations like [transit amplifying cell of colon](/details-cell/CL0009011) and [intestinal crypt stem cell of small intestine](/details-cell/CL0009017) suggests its expression is an integral part of the differentiation program for secretory intestinal lineages. Interestingly, a distinct and significant expression signature for [SPINK4](/details-gene/27290) is also found in the retina. It shows high significance in photoreceptor cells, including [retinal rod cell](/details-cell/CL0000604) (CSI: 9.38) and [retinal cone cell](/details-cell/CL0000573) (CSI: 4.14), as well as associated neurons like the [rod bipolar cell](/details-cell/CL0000751). This secondary expression domain suggests a conserved protective function in tissues that are immunoprivileged or require tight regulation of extracellular proteolysis. ## Pathways and Molecular Function The functional annotations for [SPINK4](/details-gene/27290) align directly with its cellular expression profile. As a secreted protein found in the [extracellular region](/details-cell/GO:0005576), its primary molecular function is [serine-type endopeptidase inhibitor activity](/details-cell/GO:0004867). This activity contributes to the broader biological process of [negative regulation of peptidase activity](/details-cell/GO:0010466). This function is highly consistent with its expression in [goblet cells](/details-cell/CL0000160) and [Paneth cells](/details-cell/CL0000510). These cells secrete large quantities of proteins, including mucins and antimicrobial peptides, into the gut lumen. The co-secretion of [SPINK4](/details-gene/27290) likely serves to protect the intestinal epithelium and the secreted mucus layer itself from degradation by host-derived digestive proteases (e.g., trypsin) or proteases secreted by the gut microbiota. In the retina, a similar role may exist in maintaining the integrity of the extracellular matrix and protecting photoreceptor cells from aberrant proteolytic damage. ## Research Directions The highly specific expression of [SPINK4](/details-gene/27290) in mucosal and retinal tissues points to a specialized protective role that may be relevant in pathological conditions involving barrier dysfunction or tissue degradation. **Proposed Hypotheses:** 1. Given its profound expression in [goblet cells](/details-cell/CL0000160) and its function as a protease inhibitor, it is hypothesized that [SPINK4](/details-gene/27290) is a critical component of the intestinal mucosal barrier. Its deficiency may lead to increased susceptibility to inflammatory bowel disease (IBD) by allowing excessive proteolytic activity to degrade the mucus layer and damage the underlying epithelium. 2. The significant expression of [SPINK4](/details-gene/27290) in retinal cells suggests it plays a neuroprotective role. It is hypothesized that reduced [SPINK4](/details-gene/27290) expression could contribute to the pathogenesis of retinal degenerative diseases, such as age-related macular degeneration or retinitis pigmentosa, where uncontrolled extracellular proteolysis is implicated in tissue remodeling and cell death. **Key Experimental Approach:** To test the role of [SPINK4](/details-gene/27290) in intestinal barrier function (Hypothesis 1), a `Spink4` knockout mouse model could be utilized. These mice, along with wild-type controls, would be challenged with a chemical colitogen like dextran sodium sulfate (DSS). Key readouts would include clinical signs of colitis (weight loss, stool consistency), histological assessment of colon damage, measurement of intestinal permeability using an in vivo FITC-dextran assay, and detailed analysis of mucus layer thickness and integrity via immunofluorescence. A more severe disease phenotype in the knockout mice would strongly support a protective role for [SPINK4](/details-gene/27290). **Therapeutic Potential:** [SPINK4](/details-gene/27290) presents potential as a biologic therapeutic rather than a target for inhibition. As a naturally secreted, protective protein, its function is likely beneficial. Therefore, a recombinant human [SPINK4](/details-gene/27290) protein could be developed as a novel therapy for conditions characterized by mucosal barrier breakdown, such as IBD or certain forms of infectious colitis. The strategy would be **activation** or, more practically, **protein supplementation**, administered locally to the gut to reinforce the mucosal defense against proteases and reduce inflammation.

Genular Protein ID: 2759343254

Symbol: ISK4_HUMAN

Name: Serine protease inhibitor Kazal-type 4

UniProtKB Accession Codes:

O60575 Q2YDT7

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CTD 1 ChiTaRS 1 DNASU 1 DisGeNET 1 EMBL 3 Ensembl 1 ExpressionAtlas 1 GO 2 Gene3D 1 GeneCards 1 GeneTree 1 GenomeRNAi 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 3 KEGG 1 MANE-Select 1 MEROPS 1 MIM 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PRO 1 PROSITE 2 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 RNAct 1 RefSeq 1 SMART 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 VEuPathDB 1 eggNOG 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 15164053

Title: DNA sequence and analysis of human chromosome 9.

PubMed ID: 15164053

DOI: 10.1038/nature02465

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

Sequence Information:

  • Length: 86
  • Mass: 9454
  • Checksum: 374CD4B3CAC9AF52
  • Sequence:
    • MAVRQWVIAL ALAALLVVDR EVPVAAGKLP FSRMPICEHM VESPTCSQMS NLVCGTDGLT 
YTNECQLCLA RIKTKQDIQI MKDGKC