Details for: KLK3

Gene ID: 354

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: KLK3

Ensembl ID: ENSG00000142515

Description: kallikrein related peptidase 3

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

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

  • intestine goblet cell CL0019031
    CSI 5
    rCSI 4.44%
    PRS 99.88
  • luminal cell of prostate epithelium CL0002340
    CSI 3.97
    rCSI 21.37%
    PRS 99.91
  • basal cell of prostate epithelium CL0002341
    CSI 2.67
    rCSI 7.72%
    PRS 99.96
  • colon goblet cell CL0009039
    CSI 2.53
    rCSI 6.02%
    PRS 99.95
  • prostate gland microvascular endothelial cell CL2000059
    CSI 0.35
    rCSI 8.39%
    PRS 100

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
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  • 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 [KLK3](/details-gene/354) (Kallikrein Related Peptidase 3) is a protein-coding gene located on chromosome 19q13.33 that encodes the well-known protein Prostate-Specific Antigen (PSA). PSA is a serine-type endopeptidase primarily synthesized and secreted by prostate epithelial cells. Functionally, it is involved in proteolysis, particularly in the liquefaction of the seminal coagulum to allow for sperm motility. Its expression is tightly regulated by androgens, and circulating levels of PSA are widely used as a clinical biomarker for the diagnosis and monitoring of prostate cancer ([176820](https://omim.org/entry/176820)). While its highest expression is in the prostate, data also indicates significant expression in other secretory cell types, such as intestinal goblet cells, suggesting broader physiological roles beyond the male reproductive system. ## Cellular Roles and Expression Landscape The expression profile of [KLK3](/details-gene/354) underscores its identity as a specialized marker for secretory epithelial cells. **Overall**, the gene exhibits its highest significance in the prostate, with a prominent Cell Significance Index (CSI) in both the [luminal cell of prostate epithelium](/details-cell/CL0002340) (CSI: 3.97) and the [basal cell of prostate epithelium](/details-cell/CL0002341) (CSI: 2.67). This strong, cell-type-specific expression pattern is consistent with its established role as the source of PSA, a key protein in prostatic fluid. Intriguingly, the highest observed CSI for [KLK3](/details-gene/354) is found in the [intestine goblet cell](/details-cell/CL0019031) (CSI: 5.00), with a similarly high score in the [colon goblet cell](/details-cell/CL0009039) (CSI: 2.53). This suggests a significant, though less characterized, function for [KLK3](/details-gene/354) in the gastrointestinal tract, potentially related to the processing of mucins or other secreted proteins that maintain the gut's mucosal barrier. The gene also shows modest significance in [prostate gland microvascular endothelial cell](/details-cell/CL2000059) (CSI: 0.35), which may point to a paracrine role in modulating the local prostate microenvironment. The high specificity of [KLK3](/details-gene/354) expression in these distinct glandular tissues highlights its function as a secreted peptidase active in specialized extracellular environments. ## Pathways and Molecular Function The molecular functions of [KLK3](/details-gene/354) are centered on its enzymatic activity as a serine-type peptidase ([GO:0008236](https://www.ebi.ac.uk/QuickGO/term/GO:0008236)) and endopeptidase ([GO:0004175](https://www.ebi.ac.uk/QuickGO/term/GO:0004175)), primarily executing proteolysis ([GO:0006508](https://www.ebi.ac.uk/QuickGO/term/GO:0006508)). As a secreted protein, it localizes to the [extracellular space](/details-cell/GO:0005615) and [extracellular exosome](/details-cell/GO:0070062), where it can act on various substrates. Its role is well-documented in the context of male reproduction, but annotations suggest a broader impact on tissue homeostasis. Pathway analysis reveals that [KLK3](/details-gene/354) is a downstream target of androgen receptor signaling, as indicated by its inclusion in the '[Activated pkn1 stimulates transcription of ar (androgen receptor) regulated genes klk2 and klk3](/details-pathway/R-HSA-5625886)' Reactome pathway. This provides a direct molecular basis for its high expression in hormone-responsive prostate tissue. Beyond this, [KLK3](/details-gene/354) is implicated in processes that can influence the tissue microenvironment, such as the '[Negative regulation of angiogenesis](/details-go/GO:0016525)' and the '[Regulation of insulin-like growth factor (igf) transport and uptake by insulin-like growth factor binding proteins (igfbps)](/details-pathway/R-HSA-381426)'. This latter function is due to its ability to cleave IGFBPs, thereby modulating the local bioavailability of IGF, a critical growth factor in both normal and malignant tissues. ## Research Directions While [KLK3](/details-gene/354) is extensively studied as a prostate cancer biomarker, its functional roles, particularly outside the prostate, remain an active area of investigation. The high expression observed in intestinal goblet cells warrants further exploration. **Proposed Hypotheses:** 1. Given its high significance in [intestine goblet cell](/details-cell/CL0019031), [KLK3](/details-gene/354) may play a role in modulating the gut mucosal barrier. It could proteolytically process mucin proteins, altering the viscosity and protective properties of the mucus layer, which in turn could influence host-microbe interactions and susceptibility to inflammatory conditions. 2. Based on its annotated role in the negative regulation of angiogenesis ([GO:0016525](https://www.ebi.ac.uk/QuickGO/term/GO:0016525)), [KLK3](/details-gene/354) secreted by prostate cancer cells may directly act on adjacent [prostate gland microvascular endothelial cell](/details-cell/CL2000059) to suppress new blood vessel formation, potentially as part of a complex feedback mechanism that influences tumor growth and metastasis. **Experimental Approach:** To test the first hypothesis regarding the role of [KLK3](/details-gene/354) in the gut, an experiment could involve the use of human-derived intestinal organoids. Organoids could be generated from both healthy donors and those with `KLK3` genetic variants. Alternatively, CRISPR-Cas9 could be used to knock out [KLK3](/details-gene/354) in an established organoid line. The resulting organoids could then be analyzed for changes in mucus secretion, composition (via proteomic analysis of secreted mucins), and barrier function (using a permeability assay like FITC-dextran). **Therapeutic Potential:** As a therapeutic target, the protease activity of [KLK3](/details-gene/354) is a prime candidate for inhibition. Small molecule inhibitors targeting the enzyme's active site could potentially be used to modulate its effects in prostate cancer progression, where its proteolytic activity is thought to contribute to extracellular matrix degradation and invasion. Given its high specificity for prostate tissue, [KLK3](/details-gene/354) also remains an attractive target for immunotherapy approaches, such as CAR-T cells or bispecific antibodies designed to recognize and eliminate PSA-expressing cancer cells. However, its expression in other tissues, such as the breast, as reported in some studies ([Link](https://pubmed.ncbi.nlm.nih.gov/7527295)), would need to be carefully considered to minimize off-target toxicities.

Genular Protein ID: 3101474173

Symbol: KLK3_HUMAN

Name: Prostate-specific antigen

UniProtKB Accession Codes:

P07288 C9JXH3 G3V0H4 G3XAE3 Q15096 Q16272 Q86TG8 Q8IXI4

Database IDs:

ABCD 1 AGR 1 Allergome 1 AlphaFoldDB 1 Antibodypedia 1 BRENDA 1 Bgee 1 BindingDB 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 3 CDD 1 CORUM 1 CPTAC 2 CTD 1 ChEMBL 1 ChiTaRS 1 DMDM 1 DNASU 1 DisGeNET 1 DrugBank 5 DrugCentral 1 EC 2 EMBL 26 Ensembl 4 EvolutionaryTrace 1 ExpressionAtlas 1 GO 13 Gene3D 1 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyConnect 2 GlyCosmos 1 GlyGen 1 GuidetoPHARMACOLOGY 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 4 PDBsum 4 PIR 1 PRINTS 1 PRO 1 PROSITE 3 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 4 RNAct 1 Reactome 2 RefSeq 3 SIGNOR 1 SMART 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 SwissPalm 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 2436946

Title: Molecular cloning of human prostate specific antigen cDNA.

PubMed ID: 2436946

DOI: 10.1016/0014-5793(87)80078-9

PubMed ID: 2467258

Title: Human prostate specific antigen (PSA) gene: structure and linkage to the kallikrein-like gene, hGK-1.

PubMed ID: 2467258

DOI: 10.1093/nar/17.5.2137

PubMed ID: 2471958

Title: Genomic sequence of human prostate specific antigen (PSA).

PubMed ID: 2471958

DOI: 10.1093/nar/17.10.3981

PubMed ID: 2472789

Title: Characterization of the gene for prostate-specific antigen, a human glandular kallikrein.

PubMed ID: 2472789

DOI: 10.1016/0006-291x(89)91362-4

PubMed ID: 2470373

Title: cDNA coding for the entire human prostate specific antigen shows high homologies to the human tissue kallikrein genes.

PubMed ID: 2470373

DOI: 10.1016/0006-291x(89)92520-5

PubMed ID: 2466464

Title: Characterization of the prostate-specific antigen gene: a novel human kallikrein-like gene.

PubMed ID: 2466464

DOI: 10.1016/0006-291x(89)92409-1

PubMed ID: 8677566

Title: A comparative analysis of prostate-specific antigen gene sequence in benign and malignant prostate tissue.

PubMed ID: 8677566

DOI: 10.1016/s0090-4295(96)00060-x

PubMed ID: 11054574

Title: Sequencing and expression analysis of the serine protease gene cluster located in chromosome 19q13 region.

PubMed ID: 11054574

DOI: 10.1016/s0378-1119(00)00382-6

PubMed ID: 15057824

Title: The DNA sequence and biology of human chromosome 19.

PubMed ID: 15057824

DOI: 10.1038/nature02399

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: 7527295

Title: Molecular characterization of prostate-specific antigen messenger RNA expressed in breast tumors.

PubMed ID: 7527295

PubMed ID: 2456523

Title: Sequence of a cDNA clone encompassing the complete mature human prostate specific antigen (PSA) and an unspliced leader sequence.

PubMed ID: 2456523

DOI: 10.1093/nar/16.13.6226

PubMed ID: 2422647

Title: Human prostate-specific antigen: structural and functional similarity with serine proteases.

PubMed ID: 2422647

DOI: 10.1073/pnas.83.10.3166

PubMed ID: 3691515

Title: Isolation, characterization and amino-acid sequence of gamma-seminoprotein, a glycoprotein from human seminal plasma.

PubMed ID: 3691515

DOI: 10.1111/j.1432-1033.1987.tb13674.x

PubMed ID: 15340161

Title: Signal peptide prediction based on analysis of experimentally verified cleavage sites.

PubMed ID: 15340161

DOI: 10.1110/ps.04682504

PubMed ID: 23842001

Title: Identification of a novel proteoform of prostate specific antigen (SNP-L132I) in clinical samples by multiple reaction monitoring.

PubMed ID: 23842001

DOI: 10.1074/mcp.m113.028365

PubMed ID: 1725227

Title: Functionally active protein C inhibitor/plasminogen activator inhibitor-3 (PCI/PAI-3) is secreted in seminal vesicles, occurs at high concentrations in human seminal plasma and complexes with prostate-specific antigen.

PubMed ID: 1725227

DOI: 10.1016/0049-3848(91)90002-e

PubMed ID: 7535613

Title: A structural model for the prostate disease marker, human prostate-specific antigen.

PubMed ID: 7535613

DOI: 10.1002/pro.5560031116

PubMed ID: 9751643

Title: Substrate specificity of prostate-specific antigen (PSA).

PubMed ID: 9751643

DOI: 10.1016/s1074-5521(98)90004-7

PubMed ID: 18187150

Title: Crystal structure of a ternary complex between human prostate-specific antigen, its substrate acyl intermediate and an activating antibody.

PubMed ID: 18187150

DOI: 10.1016/j.jmb.2007.11.052

Sequence Information:

  • Length: 261
  • Mass: 28741
  • Checksum: AE9E732AF872141A
  • Sequence:
    • MWVPVVFLTL SVTWIGAAPL ILSRIVGGWE CEKHSQPWQV LVASRGRAVC GGVLVHPQWV 
LTAAHCIRNK SVILLGRHSL FHPEDTGQVF QVSHSFPHPL YDMSLLKNRF LRPGDDSSHD 
LMLLRLSEPA ELTDAVKVMD LPTQEPALGT TCYASGWGSI EPEEFLTPKK LQCVDLHVIS 
NDVCAQVHPQ KVTKFMLCAG RWTGGKSTCS GDSGGPLVCN GVLQGITSWG SEPCALPERP 
SLYTKVVHYR KWIKDTIVAN P