Details for: SERPINA4

Gene ID: 5267

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: SERPINA4

Ensembl ID: ENSG00000100665

Description: serpin family A member 4

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

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

  • epithelial cell CL0000066
    CSI 5.48
    rCSI 8.41%
    PRS 89.92
  • midzonal region hepatocyte CL0019028
    CSI 4
    rCSI 9.38%
    PRS 95.04
  • hepatocyte CL0000182
    CSI 3.59
    rCSI 6.43%
    PRS 95.84
  • intrahepatic cholangiocyte CL0002538
    CSI 3.42
    rCSI 8.22%
    PRS 96.81
  • M cell of gut CL0000682
    CSI 3.38
    rCSI 3.59%
    PRS 97.64
  • mucous neck cell CL0000651
    CSI 3
    rCSI 4.33%
    PRS 97.65
  • intestinal epithelial cell CL0002563
    CSI 2.49
    rCSI 2.6%
    PRS 96.18
  • pancreatic acinar cell CL0002064
    CSI 2.42
    rCSI 3.22%
    PRS 97.91
  • stem cell CL0000034
    CSI 2.38
    rCSI 2.3%
    PRS 96.11
  • periportal region hepatocyte CL0019026
    CSI 2.26
    rCSI 8.78%
    PRS 94.63
  • enterocyte CL0000584
    CSI 2.26
    rCSI 3.64%
    PRS 95.17
  • centrilobular region hepatocyte CL0019029
    CSI 1.99
    rCSI 5.2%
    PRS 94.25
  • pancreatic ductal cell CL0002079
    CSI 1.48
    rCSI 2.87%
    PRS 97.29

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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  • 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 [SERPINA4](/details-gene/5267) (serpin family A member 4) is a protein-coding gene located on chromosome 14q32.13 that encodes Kallistatin, a member of the serine protease inhibitor (serpin) superfamily. Functionally, it acts as a [serine-type endopeptidase inhibitor](/details-go/GO:0004867), primarily involved in the [negative regulation of peptidase activity](/details-go/GO:0010466) [Link](https://pubmed.ncbi.nlm.nih.gov/1334488/). As a secreted protein found in the [extracellular space](/details-go/GO:0005615), its expression is most significant in secretory tissues. **Overall**, expression data indicate that [SERPINA4](/details-gene/5267) is a prominent marker for [epithelial cells](/details-cell/CL0000066), with particularly high significance in [hepatocytes](/details-cell/CL0000182) and various cells of the gastrointestinal and pancreatic systems. Its association with pathways such as [Hemostasis](/details-pathway/R-HSA-109582) suggests a key role in regulating systemic processes involving proteolysis, such as coagulation and inflammation. Clinical relevance is noted with its association with OMIM entry [147935](https://omim.org/entry/147935). ## Cellular Roles and Expression Landscape The expression profile of [SERPINA4](/details-gene/5267) points to a specialized role in glandular and mucosal epithelial tissues responsible for secretion into the bloodstream or ducts. The gene shows its highest significance in [epithelial cells](/details-cell/CL0000066) generally, with a strong tropism for the liver, as evidenced by its high significance in multiple hepatocyte subtypes including [midzonal region hepatocytes](/details-cell/CL0019028), general [hepatocytes](/details-cell/CL0000182), and [periportal region hepatocytes](/details-cell/CL0019026). This is consistent with the liver's function as the primary source of many plasma proteins, including serpins. Beyond the liver, [SERPINA4](/details-gene/5267) is also highly expressed in other secretory and absorptive epithelial cell types. These include [intrahepatic cholangiocytes](/details-cell/CL0002538), [M cells of the gut](/details-cell/CL0000682), [mucous neck cells](/details-cell/CL0000651), and [pancreatic acinar cells](/details-cell/CL0002064). This broad expression pattern across the hepato-pancreato-biliary system and intestinal epithelium suggests a conserved function in regulating local proteolytic activity and maintaining tissue homeostasis in these environments. The expression in [stem cells](/details-cell/CL0000034) may indicate a role in development or tissue regeneration, although this broad category requires further investigation. ## Pathways and Molecular Function The primary molecular function of the [SERPINA4](/details-gene/5267) product, Kallistatin, is defined by its [serine-type endopeptidase inhibitor activity](/details-go/GO:0004867). This function is executed in the [extracellular region](/details-go/GO:0005576), consistent with its expression in secretory cells and its role as a circulating protein inhibitor. The gene product is a key player in the regulation of blood coagulation and fibrinolysis, as highlighted by its annotation to the [Hemostasis](/details-pathway/R-HSA-109582) pathway. Furthermore, pathway analysis reveals a specific connection to platelet biology. [SERPINA4](/details-gene/5267) is implicated in [Platelet activation, signaling and aggregation](/details-pathway/R-HSA-76002) and [Platelet degranulation](/details-pathway/R-HSA-114608). This is supported by its localization to the [platelet dense granule lumen](/details-go/GO:0031089), suggesting that Kallistatin may be stored in platelets and released upon activation to modulate local thrombotic and inflammatory responses. This dual role, being both a circulating inhibitor produced by the liver and a component of platelet granules, underscores its integral function in maintaining vascular homeostasis. Studies have confirmed its identity as a glycoprotein, which is typical for secreted and plasma proteins [Link](https://doi.org/10.1038/nbt827). ## Research Directions The data strongly position [SERPINA4](/details-gene/5267) as a hepatocyte-derived serpin with a significant role in hemostasis and platelet function. This provides a clear basis for exploring its involvement in both physiological and pathological processes. **Proposed Hypotheses:** 1. Given its high expression in hepatocytes and its role in hemostasis, dysregulation of [SERPINA4](/details-gene/5267) expression during chronic liver diseases (e.g., fibrosis, cirrhosis) likely contributes to the complex coagulopathies observed in these patients, potentially by altering the balance of pro- and anti-thrombotic factors in circulation. 2. The presence of Kallistatin in platelet granules suggests it acts as a localized modulator of thrombosis and inflammation. It is hypothesized that in conditions of platelet hyperactivation, such as atherosclerosis or sepsis, the release of Kallistatin from platelets serves as a negative feedback mechanism to limit excessive protease activity and vascular damage at sites of injury. **Experimental Approach:** To test the first hypothesis regarding [SERPINA4](/details-gene/5267)'s role in liver disease, a murine model of liver fibrosis (e.g., using bile duct ligation or CCl4 administration) could be employed. Wild-type and *Serpina4* knockout mice would be subjected to the fibrotic injury. The primary endpoints would include serial measurements of plasma coagulation parameters (prothrombin time, activated partial thromboplastin time), assessment of platelet count and function, and quantification of thrombin-antithrombin complexes. This would be correlated with liver histology to assess the degree of fibrosis and injury, thereby directly linking gene function to the hemostatic dysregulation seen in liver pathology. **Therapeutic Potential:** The protein product of [SERPINA4](/details-gene/5267), Kallistatin, is known to exert pleiotropic protective effects, including anti-inflammatory, anti-angiogenic, and vasodilatory actions, primarily through the inhibition of tissue kallikrein. This makes it a compelling candidate for therapeutic **activation or augmentation**, rather than inhibition. The administration of recombinant Kallistatin could represent a viable strategy for treating diseases characterized by excessive inflammation, pathological angiogenesis, or hypertension. Its role in hemostasis also suggests potential applications in modulating thrombotic disorders, although this would require careful characterization to avoid bleeding complications.

Genular Protein ID: 3586419318

Symbol: KAIN_HUMAN

Name: Kallistatin

UniProtKB Accession Codes:

P29622 Q53XB5 Q86TR9 Q96BZ5

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 1 CPTAC 2 CTD 1 ChiTaRS 1 DMDM 1 DNASU 1 DisGeNET 1 DrugBank 3 EMBL 5 Ensembl 3 ExpressionAtlas 1 GO 5 Gene3D 2 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyConnect 1 GlyCosmos 1 GlyGen 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 6 KEGG 1 MANE-Select 1 MEROPS 1 MIM 1 MINT 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PDB 1 PDBsum 1 PIR 1 PRO 1 PROSITE 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 RNAct 1 Reactome 1 RefSeq 3 SMART 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TopDownProteomics 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 8227002

Title: Kallistatin: a novel human serine proteinase inhibitor. Molecular cloning, tissue distribution, and expression in Escherichia coli.

PubMed ID: 8227002

DOI: 10.1016/s0021-9258(20)80553-5

PubMed ID: 7835886

Title: Molecular cloning, sequence analysis, and chromosomal localization of the human protease inhibitor 4 (kallistatin) gene (PI4).

PubMed ID: 7835886

DOI: 10.1006/geno.1994.1513

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: 1334488

Title: Kallistatin: a novel human tissue kallikrein inhibitor. Purification, characterization, and reactive center sequence.

PubMed ID: 1334488

DOI: 10.1016/s0021-9258(18)35690-4

PubMed ID: 12754519

Title: Identification and quantification of N-linked glycoproteins using hydrazide chemistry, stable isotope labeling and mass spectrometry.

PubMed ID: 12754519

DOI: 10.1038/nbt827

PubMed ID: 16335952

Title: Human plasma N-glycoproteome analysis by immunoaffinity subtraction, hydrazide chemistry, and mass spectrometry.

PubMed ID: 16335952

DOI: 10.1021/pr0502065

PubMed ID: 19139490

Title: A strategy for precise and large scale identification of core fucosylated glycoproteins.

PubMed ID: 19139490

DOI: 10.1074/mcp.m800504-mcp200

Sequence Information:

  • Length: 427
  • Mass: 48542
  • Checksum: 68EBE7AF956BFB77
  • Sequence:
    • MHLIDYLLLL LVGLLALSHG QLHVEHDGES CSNSSHQQIL ETGEGSPSLK IAPANADFAF 
RFYYLIASET PGKNIFFSPL SISAAYAMLS LGACSHSRSQ ILEGLGFNLT ELSESDVHRG 
FQHLLHTLNL PGHGLETRVG SALFLSHNLK FLAKFLNDTM AVYEAKLFHT NFYDTVGTIQ 
LINDHVKKET RGKIVDLVSE LKKDVLMVLV NYIYFKALWE KPFISSRTTP KDFYVDENTT 
VRVPMMLQDQ EHHWYLHDRY LPCSVLRMDY KGDATVFFIL PNQGKMREIE EVLTPEMLMR 
WNNLLRKRNF YKKLELHLPK FSISGSYVLD QILPRLGFTD LFSKWADLSG ITKQQKLEAS 
KSFHKATLDV DEAGTEAAAA TSFAIKFFSA QTNRHILRFN RPFLVVIFST STQSVLFLGK 
VVDPTKP