Details for: SPINK5

Gene ID: 11005

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: SPINK5

Ensembl ID: ENSG00000133710

Description: serine peptidase inhibitor Kazal type 5

Cell Significance Landscape

Associated with

Significant Cells

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

  • squamous epithelial cell CL0000076
    CSI 16.77
    rCSI 39.8%
    PRS 94.58
  • epithelial cell of lung CL0000082
    CSI 12.33
    rCSI 10.22%
    PRS 98.29
  • keratinocyte CL0000312
    CSI 9.11
    rCSI 7.63%
    PRS 96.75
  • M cell of gut CL0000682
    CSI 8.52
    rCSI 9.05%
    PRS 97.82
  • enterocyte CL0000584
    CSI 7.52
    rCSI 12.13%
    PRS 95.6
  • melanocyte of skin CL1000458
    CSI 5.39
    rCSI 7.35%
    PRS 79.75
  • secretory cell CL0000151
    CSI 4.33
    rCSI 4.52%
    PRS 97.17
  • nasal mucosa goblet cell CL0002480
    CSI 3.91
    rCSI 4.53%
    PRS 96.9
  • intestinal tuft cell CL0019032
    CSI 3.78
    rCSI 5.78%
    PRS 97.39
  • myoepithelial cell CL0000185
    CSI 3.72
    rCSI 9.42%
    PRS 98.38
  • epithelial cell of lower respiratory tract CL0002632
    CSI 3.71
    rCSI 2.87%
    PRS 98.66
  • lung secretory cell CL1000272
    CSI 3.47
    rCSI 8.6%
    PRS 98.39
  • epithelial cell of esophagus CL0002252
    CSI 3.45
    rCSI 34.08%
    PRS 94.97
  • respiratory basal cell CL0002633
    CSI 3.15
    rCSI 3.27%
    PRS 97.98
  • club cell CL0000158
    CSI 3.09
    rCSI 4.53%
    PRS 96.27
  • tracheal goblet cell CL1000329
    CSI 3.01
    rCSI 6.58%
    PRS 97.96
  • conjunctival epithelial cell CL1000432
    CSI 2.95
    rCSI 4.51%
    PRS 96.8
  • basal cell CL0000646
    CSI 2.92
    rCSI 3.91%
    PRS 96.26
  • colon epithelial cell CL0011108
    CSI 2.89
    rCSI 3.03%
    PRS 96.72
  • extravillous trophoblast CL0008036
    CSI 2.69
    rCSI 3.33%
    PRS 96.71
  • foveolar cell of stomach CL0002179
    CSI 2.55
    rCSI 5.43%
    PRS 97.81
  • respiratory suprabasal cell CL4033048
    CSI 2.53
    rCSI 3.24%
    PRS 98.03
  • epithelial cell CL0000066
    CSI 2.43
    rCSI 3.73%
    PRS 90.69
  • renal beta-intercalated cell CL0002201
    CSI 2.11
    rCSI 5.03%
    PRS 97.33
  • respiratory hillock cell CL4030023
    CSI 2.09
    rCSI 3.74%
    PRS 98.47
  • corneal epithelial cell CL0000575
    CSI 1.87
    rCSI 5.35%
    PRS 97.53
  • basal cell of epidermis CL0002187
    CSI 1.68
    rCSI 2.97%
    PRS 78.67
  • colon goblet cell CL0009039
    CSI 1.43
    rCSI 3.41%
    PRS 97.59
  • CD8-positive, alpha-beta memory T cell, CD45RO-positive CL0001203
    CSI 1.18
    rCSI 1.43%
    PRS 84.37
  • hair follicular keratinocyte CL2000092
    CSI 0.65
    rCSI 11.36%
    PRS 96.92
  • basal cell of epithelium of trachea CL1000348
    CSI 0.65
    rCSI 4.6%
    PRS 97.42
  • Cajal-Retzius cell CL0000695
    CSI 0.58
    rCSI 4.57%
    PRS 97.37

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 [SPINK5](/details-gene/11005) (serine peptidase inhibitor Kazal type 5) encodes the protein Lympho-Epithelial Kazal-Type-related Inhibitor (LEKTI). As a multi-domain serine protease inhibitor, [SPINK5](/details-gene/11005) is fundamentally involved in regulating proteolytic cascades critical for tissue homeostasis, particularly in barrier epithelia. Its expression is highly significant in various epithelial cell types, most notably [squamous epithelial cells](/details-cell/CL0000076) and [keratinocytes](/details-cell/CL0000312). Functionally, it plays a crucial role in the terminal differentiation of the epidermis and the regulation of skin desquamation by inhibiting kallikrein-related peptidases ([Link](https://doi.org/10.1091/mbc.e07-02-0124)). Loss-of-function mutations in [SPINK5](/details-gene/11005) are the cause of Netherton syndrome ([OMIM](/entry/256500)), a severe autosomal recessive disorder characterized by congenital ichthyosis, hair shaft abnormalities, and atopic diathesis, highlighting its non-redundant role in maintaining epidermal barrier integrity ([Link](https://doi.org/10.1038/75977)). ## Cellular Roles and Expression Landscape The expression profile of [SPINK5](/details-gene/11005) strongly indicates a specialized function in maintaining the integrity of epithelial barriers throughout the body. **Overall**, the gene shows the highest significance in cells forming protective layers. It is a top marker for [squamous epithelial cell](/details-cell/CL0000076) (CSI: 16.77), [epithelial cell of lung](/details-cell/CL0000082) (CSI: 12.33), and [keratinocyte](/details-cell/CL0000312) (CSI: 9.11). This pattern extends to other mucosal and glandular epithelia, including [enterocytes](/details-cell/CL0000584) in the gut, [secretory cells](/details-cell/CL0000151) like [nasal mucosa goblet cells](/details-cell/CL0002480), and [club cells](/details-cell/CL0000158) in the respiratory tract. The high significance in these diverse epithelial lineages suggests a conserved role in regulating extracellular protease activity to control cell-cell adhesion, differentiation, and turnover at environmental interfaces. The expression in [melanocytes of skin](/details-cell/CL1000458) further supports its central role in the biology of the epidermis. The absence of high significance in immune, neuronal, or stromal cell types underscores its specific role within the epithelial compartment. ## Pathways and Molecular Function The molecular function of [SPINK5](/details-gene/11005) is precisely defined by its potent **serine-type endopeptidase inhibitor activity** ([GO:0004867](https://www.ebi.ac.uk/QuickGO/term/GO:0004867)). This activity is central to its involvement in key biological processes, primarily related to epidermal development and maintenance. Functional annotations reveal its deep integration into the processes of **epidermal cell differentiation** ([GO:0009913](https://www.ebi.ac.uk/QuickGO/term/GO:0009913)) and the broader program of **epithelial cell differentiation** ([GO:0030855](https://www.ebi.ac.uk/QuickGO/term/GO:0030855)). This is consistent with its high expression in [keratinocytes](/details-cell/CL0000312) and its critical role in skin barrier formation. Reactome pathways further specify this role, placing [SPINK5](/details-gene/11005) in **Keratinization** ([R-HSA-6805567](https://reactome.org/content/detail/R-HSA-6805567)) and the **Formation of the cornified envelope** ([R-HSA-6809371](https://reactome.org/content/detail/R-HSA-6809371)). The protein product, LEKTI, controls the activity of proteases like KLK5, KLK7, and caspase-14, which are essential for the ordered breakdown of cell adhesion molecules during desquamation ([Link](https://doi.org/10.1091/mbc.e07-02-0124), [Link](https://doi.org/10.1021/pr1003467)). Beyond the skin, its annotation for **negative regulation of immune response** ([GO:0050777](https://www.ebi.ac.uk/QuickGO/term/GO:0050777)) suggests that by maintaining barrier integrity, [SPINK5](/details-gene/11005) prevents the penetration of allergens and pathogens, thereby limiting aberrant immune activation. ## Research Directions The well-established role of [SPINK5](/details-gene/11005) in the monogenic disorder Netherton syndrome provides a strong foundation for exploring its involvement in more common, complex diseases characterized by epithelial barrier dysfunction. While its loss-of-function is catastrophic, subtle variations in its expression or activity could be significant risk factors for atopic diseases. ### Proposed Hypotheses: 1. **Hypothesis 1:** Given the high expression of [SPINK5](/details-gene/11005) in lung and intestinal epithelia, localized downregulation or dysfunction of [SPINK5](/details-gene/11005) at these mucosal surfaces may represent a key pathogenic factor in allergic asthma and inflammatory bowel disease, respectively. This barrier leakiness would lead to increased antigen exposure and chronic inflammation, mirroring the atopic manifestations seen in Netherton syndrome. 2. **Hypothesis 2:** The various isoforms of LEKTI, generated by alternative splicing of the [SPINK5](/details-gene/11005) pre-mRNA ([Link](https://doi.org/10.1038/sj.jid.5700015)), may possess distinct inhibitory specificities for different proteases. The ratio of these isoforms could be a critical regulatory node, with dysregulation in this ratio contributing to the pathophysiology of chronic inflammatory skin conditions like atopic dermatitis or psoriasis, independent of severe mutations. ### Experimental Approach: To test Hypothesis 1, one could utilize patient-derived organoid models. For example, bronchial epithelial organoids could be generated from biopsies of healthy controls and patients with allergic asthma. [SPINK5](/details-gene/11005) expression and LEKTI protein levels would be quantified via qPCR and Western blot. To establish causality, [SPINK5](/details-gene/11005) could be knocked down in healthy organoids using CRISPR interference (CRISPRi). Barrier function could then be assessed by measuring transepithelial electrical resistance (TEER) and permeability to fluorescently-labeled dextran following exposure to common allergens (e.g., house dust mite extract). Downstream inflammatory responses would be measured by quantifying cytokine secretion (e.g., TSLP, IL-33) via ELISA. A compromised barrier and heightened inflammatory response in [SPINK5](/details-gene/11005)-deficient organoids would support its role in asthma pathogenesis. ### Therapeutic Potential: As Netherton syndrome is a loss-of-function disorder, the therapeutic strategy for [SPINK5](/details-gene/11005) would be focused on **protein replacement or functional restoration**. Topical application of recombinant LEKTI or specific inhibitory domains could be a direct approach to restore balance to epidermal protease activity. Alternatively, small molecule inhibitors designed to target the specific kallikrein proteases that are overactive in the absence of LEKTI represent a viable and actively pursued therapeutic strategy. For more complex diseases where [SPINK5](/details-gene/11005) is merely downregulated, strategies aimed at boosting its endogenous expression could also be considered. Due to its essential homeostatic role, systemic inhibition of [SPINK5](/details-gene/11005) is not a therapeutically desirable goal.

Genular Protein ID: 776900364

Symbol: ISK5_HUMAN

Name: Serine protease inhibitor Kazal-type 5

UniProtKB Accession Codes:

Q9NQ38 A8MYE8 B7WPB7 D6REN5 O75770 Q3LX95 Q3LX96 Q3LX97 Q96PP2 Q96PP3

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 3 CDD 2 CTD 1 ChiTaRS 1 DMDM 1 DNASU 1 DisGeNET 1 EMBL 38 Ensembl 3 EvolutionaryTrace 1 ExpressionAtlas 1 GO 23 Gene3D 1 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 HGNC 1 HPA 1 InParanoid 1 IntAct 1 InterPro 3 KEGG 1 MANE-Select 1 MEROPS 15 MIM 3 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 Orphanet 1 OrthoDB 1 PANTHER 2 PDB 6 PDBsum 6 PRO 1 PROSITE 2 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 3 Pumba 1 RNAct 1 Reactome 2 RefSeq 3 SABIO-RK 1 SMART 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 10419450

Title: LEKTI, a novel 15-domain type of human serine proteinase inhibitor.

PubMed ID: 10419450

DOI: 10.1074/jbc.274.31.21499

PubMed ID: 10835624

Title: Mutations in SPINK5, encoding a serine protease inhibitor, cause Netherton syndrome.

PubMed ID: 10835624

DOI: 10.1038/75977

PubMed ID: 16374478

Title: SPINK5, the defective gene in netherton syndrome, encodes multiple LEKTI isoforms derived from alternative pre-mRNA processing.

PubMed ID: 16374478

DOI: 10.1038/sj.jid.5700015

PubMed ID: 15372022

Title: The DNA sequence and comparative analysis of human chromosome 5.

PubMed ID: 15372022

DOI: 10.1038/nature02919

PubMed ID: 11511292

Title: The spectrum of pathogenic mutations in SPINK5 in 19 families with Netherton syndrome: implications for mutation detection and first case of prenatal diagnosis.

PubMed ID: 11511292

DOI: 10.1046/j.1523-1747.2001.01389.x

PubMed ID: 11594460

Title: Purification and partial amino acid sequence of proteins from human epidermal keratinocyte conditioned medium.

PubMed ID: 11594460

DOI: 10.1023/a:1010902815953

PubMed ID: 17596512

Title: LEKTI fragments specifically inhibit KLK5, KLK7, and KLK14 and control desquamation through a pH-dependent interaction.

PubMed ID: 17596512

DOI: 10.1091/mbc.e07-02-0124

PubMed ID: 20533828

Title: New role for LEKTI in skin barrier formation: label-free quantitative proteomic identification of caspase 14 as a novel target for the protease inhibitor LEKTI.

PubMed ID: 20533828

DOI: 10.1021/pr1003467

PubMed ID: 12684009

Title: Homologous proteins with different folds: the three-dimensional structures of domains 1 and 6 of the multiple Kazal-type inhibitor LEKTI.

PubMed ID: 12684009

DOI: 10.1016/s0022-2836(03)00245-6

PubMed ID: 15366933

Title: The solution structure of a chimeric LEKTI domain reveals a chameleon sequence.

PubMed ID: 15366933

DOI: 10.1021/bi0492399

PubMed ID: 11544479

Title: Gene polymorphism in Netherton and common atopic disease.

PubMed ID: 11544479

DOI: 10.1038/ng728

Sequence Information:

  • Length: 1064
  • Mass: 120714
  • Checksum: 6CBEF39BB9E6D75D
  • Sequence:
    • MKIATVSVLL PLALCLIQDA ASKNEDQEMC HEFQAFMKNG KLFCPQDKKF FQSLDGIMFI 
NKCATCKMIL EKEAKSQKRA RHLARAPKAT APTELNCDDF KKGERDGDFI CPDYYEAVCG 
TDGKTYDNRC ALCAENAKTG SQIGVKSEGE CKSSNPEQDV CSAFRPFVRD GRLGCTREND 
PVLGPDGKTH GNKCAMCAEL FLKEAENAKR EGETRIRRNA EKDFCKEYEK QVRNGRLFCT 
RESDPVRGPD GRMHGNKCAL CAEIFKQRFS EENSKTDQNL GKAEEKTKVK REIVKLCSQY 
QNQAKNGILF CTRENDPIRG PDGKMHGNLC SMCQAYFQAE NEEKKKAEAR ARNKRESGKA 
TSYAELCSEY RKLVRNGKLA CTRENDPIQG PDGKVHGNTC SMCEVFFQAE EEEKKKKEGK 
SRNKRQSKST ASFEELCSEY RKSRKNGRLF CTRENDPIQG PDGKMHGNTC SMCEAFFQQE 
ERARAKAKRE AAKEICSEFR DQVRNGTLIC TREHNPVRGP DGKMHGNKCA MCASVFKLEE 
EEKKNDKEEK GKVEAEKVKR EAVQELCSEY RHYVRNGRLP CTRENDPIEG LDGKIHGNTC 
SMCEAFFQQE AKEKERAEPR AKVKREAEKE TCDEFRRLLQ NGKLFCTREN DPVRGPDGKT 
HGNKCAMCKA VFQKENEERK RKEEEDQRNA AGHGSSGGGG GNTQDECAEY REQMKNGRLS 
CTRESDPVRD ADGKSYNNQC TMCKAKLERE AERKNEYSRS RSNGTGSESG KDTCDEFRSQ 
MKNGKLICTR ESDPVRGPDG KTHGNKCTMC KEKLEREAAE KKKKEDEDRS NTGERSNTGE 
RSNDKEDLCR EFRSMQRNGK LICTRENNPV RGPYGKMHIN KCAMCQSIFD REANERKKKD 
EEKSSSKPSN NAKDECSEFR NYIRNNELIC PRENDPVHGA DGKFYTNKCY MCRAVFLTEA 
LERAKLQEKP SHVRASQEED SPDSFSSLDS EMCKDYRVLP RIGYLCPKDL KPVCGDDGQT 
YNNPCMLCHE NLIRQTNTHI RSTGKCEESS TPGTTAASMP PSDE