Affinage

KLK3

Prostate-specific antigen · UniProt P07288

Round 2 corrected
Length
261 aa
Mass
28.7 kDa
Annotated
2026-04-28
130 papers in source corpus 28 papers cited in narrative 28 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KLK3 encodes prostate-specific antigen (PSA), a kallikrein-family serine protease with chymotrypsin-like specificity (catalytic triad His-41, Asp-96, Ser-192) that is secreted as an inactive zymogen (proPSA) and activated principally by KLK2-mediated cleavage of its 7-amino-acid propeptide (PMID:9261179, PMID:20058238). Active PSA liquefies the seminal coagulum by cleaving semenogelin I, semenogelin II, and fibronectin, and also proteolyzes IGFBP-3 (reducing IGF-I binding) and galectin-3 (at Tyr-107, blocked by c-Abl phosphorylation), while exerting enzymatic-activity-dependent antiangiogenic effects (PMID:1702714, PMID:1383255, PMID:22232548, PMID:19551556). In circulation, active PSA is rapidly sequestered by alpha1-antichymotrypsin (forming SDS-stable 1:1 complexes) or alpha2-macroglobulin; tumor-derived PSA displays distinct neutral, hyperfucosylated N-glycans compared to the sialylated biantennary structures of normal seminal PSA (PMID:1702714, PMID:12626390). KLK3 transcription is androgen receptor-driven, with AR occupancy enhanced by MRGBP/MRG15/TIP60-mediated H2A.Z acetylation and RNF6-mediated AR ubiquitination, and further modulated by NF-κB, FOXM1, p53-dependent histone deacetylation, and miR-99 family repression of SMARCA5 (PMID:11006269, PMID:11909978, PMID:30076933, PMID:19345326, PMID:11791186, PMID:21212412).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1986 High

    Establishing that PSA is a serine protease with chymotrypsin-like specificity resolved the molecular identity of this abundant prostatic secretory protein, revealing its catalytic triad and substrate preferences.

    Evidence Complete amino acid sequencing plus in vitro kinetic assays with chromogenic substrates and protease inhibitor profiling

    PMID:2422647

    Open questions at the time
    • Three-dimensional structure not yet determined
    • Physiological substrates not yet identified
    • Activation mechanism unknown
  2. 1987 High

    Cloning the KLK3 cDNA established its gene structure — signal peptide, propeptide, and mature chain — and placed it within the kallikrein protease family.

    Evidence cDNA library screening from human prostate with nucleotide sequencing

    PMID:2436946

    Open questions at the time
    • Zymogen activation mechanism not characterized
    • Genomic organization and regulatory elements undefined
  3. 1990 High

    Identifying semenogelin as the principal PSA substrate and demonstrating SDS-stable complex formation with alpha1-antichymotrypsin defined the physiological function of PSA in semen liquefaction and established why circulating PSA is predominantly ACT-complexed.

    Evidence In vitro enzymatic assay with purified PSA and seminal substrates; SDS-PAGE analysis of PSA-ACT and PSA-alpha2-macroglobulin complexes

    PMID:1702714

    Open questions at the time
    • Mechanism of zymogen activation in vivo unresolved
    • Semenogelin cleavage sites not fully mapped
  4. 1992 High

    Demonstration that PSA specifically cleaves IGFBP-3 (but not IGFBP-2 or -4), reducing IGF-I binding, expanded its substrate repertoire beyond semenogelin to a growth-factor regulatory axis.

    Evidence In vitro protease assay with purified PSA and radiolabeled IGFBP-3; Western ligand blot

    PMID:1383255

    Open questions at the time
    • In vivo relevance of IGFBP-3 cleavage by PSA not established
    • Whether IGF signaling is altered in prostatic tissue by PSA-mediated IGFBP-3 cleavage unknown
  5. 1997 High

    Reconstituting zymogen activation in vitro showed that proPSA is activated by cleavage of its 7-residue propeptide by trypsin or KLK2, establishing the proteolytic cascade governing PSA maturation.

    Evidence Recombinant pro-PSA expression in E. coli, refolding, activation by purified trypsin and recombinant KLK2, SDS-PAGE and chromogenic assays

    PMID:9261179

    Open questions at the time
    • Relative contribution of KLK2 versus other proteases in vivo not quantified
    • Spatial and temporal regulation of activation in prostatic ducts unresolved
  6. 2000 High

    Mapping of the KLK3 promoter/enhancer revealed that androgen-independent transcription is driven by both an ARE-containing enhancer core (bound by AR even without ligand) and a pN/H element bound by a 45-kDa cell-specific factor, explaining how PSA expression persists in androgen-deprived settings.

    Evidence Promoter deletion and linker scan mutagenesis, DNase I footprinting, EMSA, UV cross-linking in LNCaP and PC-3 cells

    PMID:11006269

    Open questions at the time
    • Identity of p45 transcription factor unknown
    • Chromatin context of enhancer elements not addressed
  7. 2002 High

    Identification of four NF-κB binding sites in the PSA core enhancer and demonstration that p53 represses KLK3 through histone deacetylation revealed AR-independent transcriptional regulators that modulate PSA expression, particularly in androgen-independent prostate cancer.

    Evidence DNase I footprinting for NF-κB sites; p50/p65 overexpression and TNF-α treatment; wild-type/dominant-negative p53 transfection with trichostatin A rescue in LNCaP cells

    PMID:11791186 PMID:11909978

    Open questions at the time
    • Whether NF-κB and p53 pathways interact at the PSA enhancer unknown
    • Direct AR-NF-κB cooperativity at the locus not tested
  8. 2003 High

    Glycan structural analysis revealed that tumor-derived PSA carries neutral, hyperfucosylated N-glycans (including H2 epitope) while normal seminal PSA is sialylated, establishing a molecular basis for distinguishing cancer-derived PSA.

    Evidence Mass spectrometry-based N-glycan sequencing of PSA from seminal plasma and LNCaP cells

    PMID:12626390

    Open questions at the time
    • Whether glycan differences arise from altered glycosyltransferase expression in tumors not determined
    • Clinical diagnostic utility of glycoform discrimination not validated
  9. 2009 Medium

    Demonstrating that PSA antiangiogenic activity requires enzymatic activity (abolished by inhibitory antibodies and small molecules, enhanced by a stimulatory peptide) linked PSA's protease function to an extracellular biological process beyond semen liquefaction.

    Evidence HUVEC tube formation assay with active vs. inactive PSA isoforms, pharmacological modulation of enzymatic activity, gene expression profiling

    PMID:19551556

    Open questions at the time
    • Substrate(s) responsible for antiangiogenic effect not identified
    • In vivo antiangiogenic relevance not confirmed in animal models
  10. 2010 High

    In vivo confirmation that KLK2 is the physiological activator of proPSA — using co-culture, xenograft co-inoculation, and double-transgenic mice — validated the KLK2→PSA proteolytic cascade and showed that active PSA alone does not initiate prostate neoplasia.

    Evidence Cell co-culture, conditioned media, subcutaneous xenograft co-inoculation, PSA/KLK2 double-transgenic mice monitored for 2 years

    PMID:20058238

    Open questions at the time
    • Other prostatic proteases that may contribute to proPSA activation not excluded
    • Whether loss of PSA activation affects fertility in mice not tested
  11. 2011 Medium

    Discovery that PSA localizes to the nucleus in androgen-stimulated prostate cancer cells and positively regulates AR mRNA/protein levels revealed a feedback loop between PSA and its own transcriptional driver.

    Evidence Immunofluorescence and subcellular fractionation for nuclear localization; shRNA/siRNA knockdown of PSA with AR mRNA/protein quantification in C4-2B and VCaP cells

    PMID:21956655

    Open questions at the time
    • Mechanism by which nuclear PSA regulates AR transcription unknown
    • Whether nuclear PSA retains enzymatic activity not determined
    • Not independently replicated outside the originating lab
  12. 2012 Medium

    Showing that c-Abl-mediated phosphorylation of galectin-3 at Tyr-107 blocks PSA cleavage at that site identified a phospho-switch that regulates PSA substrate accessibility in prostate cells.

    Evidence In vitro cleavage assays with purified PSA and galectin-3, site-directed c-Abl phosphorylation, Western blot

    PMID:22232548

    Open questions at the time
    • In vivo relevance of galectin-3 cleavage by PSA in tumor microenvironment not established
    • Other phosphorylation-regulated PSA substrates not investigated
  13. 2018 Medium

    Elucidation of the MRGBP/MRG15/TIP60 chromatin remodeling axis showed that H2A.Z acetylation at AR binding regions of KLK3 enhances AR occupancy, providing a chromatin-level mechanism for AR-dependent KLK3 transcription.

    Evidence ChIP for histone modifications and factor occupancy, co-immunoprecipitation for MRGBP-MRG15-TIP60 complex, siRNA knockdown with gene expression readout in prostate cancer cells

    PMID:30076933

    Open questions at the time
    • Whether H2A.Z acetylation is specific to KLK3 or shared across all AR target genes not resolved
    • Structural basis of MRGBP-MRG15-TIP60 complex assembly unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major unresolved questions include: the identity and mechanism of the 45-kDa cell-specific factor (p45) binding the pN/H element; the substrate(s) mediating PSA's antiangiogenic activity; the mechanism by which nuclear PSA regulates AR expression; and whether KLK3 coding variants directly impair enzymatic activity to cause male infertility.
  • No structural model of proPSA activation by KLK2 exists
  • Functional validation of infertility-associated KLK3 coding SNPs not performed
  • Nuclear import signal and nuclear interactome of PSA uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0016787 hydrolase activity 4
Localization
GO:0005576 extracellular region 3 GO:0005634 nucleus 1
Pathway
R-HSA-1474165 Reproduction 4 R-HSA-392499 Metabolism of proteins 4
Partners
ARIGFBP3KLK2LGALS3SEMG1SEMG2SERPINA3

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1986 KLK3/PSA was determined to be a serine protease with chymotrypsin-like activity. The complete amino acid sequence (240 residues) revealed the catalytic triad (His-41, Asp-96, Ser-192) characteristic of serine proteases, and the protein was shown to cleave insulin A and B chains and other substrates preferentially after hydrophobic residues (Tyr, Leu, Val, Phe), with Km ~15.3 mM and kcat ~0.075 s⁻¹ for a chymotryptic substrate. Activity was inhibited by PMSF, DFP, TLCK, aprotinin, and Zn²⁺. Amino acid sequencing, chromogenic substrate in vitro enzymatic assays, protease inhibitor profiling Proceedings of the National Academy of Sciences of the United States of America High 2422647
1987 The cDNA encoding KLK3/PSA was cloned from a human prostate cDNA library. The 1415-nucleotide insert codes for a signal peptide, a short propeptide, and a mature protein of 237 amino acid residues (Mr 26,089 non-glycosylated), with one N-linked glycosylation site. Sequence analysis confirmed extensive homology with kallikrein-family proteases. cDNA library screening, nucleotide sequencing FEBS letters High 2436946
1990 Purified KLK3/PSA displayed chymotrypsin-like enzymatic activity and cleaved semenogelin and semenogelin-related proteins in a rapid and characteristic pattern (establishing semenogelin as its primary seminal substrate). Active PSA formed SDS-stable 1:1 molar complexes with alpha1-antichymotrypsin (ACT) by cleaving ACT at the same position as chymotrypsin cleaves ACT. PSA also formed complexes with alpha2-macroglobulin (which encapsulates PSA epitopes). Approximately one-third of purified PSA was enzymatically inactive due to internal cleavage C-terminal of Lys145. Aprotinin-Sepharose purification, in vitro enzymatic assay with semenogelin substrates, SDS-PAGE complex analysis, complex formation rate measurement European journal of biochemistry High 1702714
1992 KLK3/PSA was identified as an IGFBP-3 protease in seminal plasma. Purified PSA cleaved 125I-labeled IGFBP-3 with a cleavage pattern identical to that of whole seminal plasma, while IGFBP-2 and IGFBP-4 were not degraded. Cleavage of IGFBP-3 by PSA markedly reduced binding affinity of the fragments to IGF-I but not IGF-II. In vitro protease assay with purified PSA and radiolabeled IGFBP-3, Western ligand blot The Journal of clinical endocrinology and metabolism High 1383255
1995 Biochemical characterization confirmed that the mature PSA (237 amino acids, single-chain glycoprotein) is a serine protease with restricted chymotrypsin-like activity responsible for gel dissolution in ejaculated semen by proteolysis of the gel-forming proteins semenogelin I, semenogelin II, and fibronectin. In semen ~two-thirds of PSA is enzymatically active; the remaining 30–40% is inactive due to internal cleavage(s). A small fraction in semen is complexed to protein C inhibitor. PSA complexed to alpha1-antichymotrypsin (ACT) is the predominant molecular form in serum, though complex formation between purified proteins in vitro is slow. Biochemical characterization, in vitro protease assays, immunoassay, complex formation analysis Scandinavian journal of clinical and laboratory investigation. Supplementum High 7544481
1995 Recombinant PSA and hK2 (KLK2) were expressed in eukaryotic cells (Semliki Forest Virus system). Testing of 18 monoclonal anti-PSA IgGs revealed that 5 cross-reacted with recombinant hK2 with identical affinities, while 13 recognized PSA alone. Cross-reactive antibodies bind a region exposed when PSA is complexed to alpha1-antichymotrypsin, identifying the ACT-complex-exposed epitope as the shared PSA/hK2 region. Recombinant protein expression, monoclonal antibody binding assays, epitope mapping Biochemical and biophysical research communications Medium 7544581
1997 Recombinant pro-PSA (zymogen, 244 residues with 7-amino-acid N-terminal propiece Ala-Pro-Leu-Ile-Leu-Ser-Arg) was expressed in E. coli and refolded. Pro-PSA was activated by trypsin (at 50:1 weight ratio) via cleavage at the Arg-Ile peptide bond releasing the propeptide to generate active PSA. Pro-PSA was also activated by recombinant human glandular kallikrein (hK2/KLK2) and by partially purified seminal plasma proteases. Active recombinant PSA was inhibited by alpha1-antichymotrypsin (forming ~100 kDa equimolar complex) but, unlike hK2, PSA failed to activate single-chain urokinase-type plasminogen activator. Recombinant protein expression and refolding, in vitro activation assays, chromogenic substrate enzymatic assays, SDS-PAGE The Journal of biological chemistry High 9261179
1998 hK2 (KLK2) rapidly converts the inactive precursor proPSA to active PSA in biochemical studies, suggesting a key in vivo regulatory role for hK2 in controlling PSA protease activity. Both PSA and hK2 are produced as secretory proteins by the same prostate epithelial cells; the potent trypsin-like activity of hK2 contrasts with the weak chymotrypsin-like activity of PSA. In vitro protease activation assays, immunoassays, comparative biochemical characterization Critical reviews in clinical laboratory sciences Medium 9759557
1999 Trans-resveratrol (at 4-day treatment) reduced intracellular and secreted PSA protein levels in LNCaP cells by ~80% without changing androgen receptor (AR) expression levels (measured by Western blot and radioligand binding with [³H]R1881), indicating that resveratrol down-regulates PSA by an AR-independent mechanism. Cell-based treatment assay, Western blot for AR and PSA, radioligand binding assay Anticancer research Low 10769659
2000 Two cis-elements in the 5.8 kb PSA promoter drive androgen-independent PSA expression: (1) a 440-bp androgen-responsive element enhancer core (AREc) in which AR binds AREs under androgen-deprived conditions (shown by mutation analysis and supershift experiments), and (2) a 150-bp pN/H region containing a 17-bp RI site bound by a 45-kDa cell-specific transcription factor (p45) identified by EMSA and UV cross-linking, driving AR-independent promoter activity. Juxtaposing both elements produced a chimeric supra-PSA promoter with 2–3-fold higher activity than wild-type. Promoter deletion/mutation analysis, DNase I footprinting, linker scan mutagenesis, EMSA, UV cross-linking, transient transfection The Journal of biological chemistry High 11006269
2000 KLK3/PSA and KLK2/hK2 are regulated by androgens and progestins in breast cancer cell lines. In BT-474 cells, synthetic androgen mibolerone was the most potent stimulator for both kallikreins, followed by the synthetic progestin norgestrel. Estradiol induced small but significant amounts of hK2 and PSA in BT-474 cells, supporting cross-talk between estrogen and androgen receptor signaling pathways. BT-474 cells express ~500–1000-fold more hK2 than T-47D cells, revealing cell-type-specific differential regulation of the two genes. Time-resolved fluorometric immunoassays (cell culture supernatants), steroid hormone treatment of breast cancer cell lines Breast cancer research and treatment Low 10832596
2002 Unusual alternative splicing of KLK3 involving inclusion of intronic sequences adjacent to exon 1 generates a novel transcript encoding a protein called PSA-linked molecule (PSA-LM). PSA-LM shares only the signal peptide with PSA; the mature protein is entirely different and bears no similarity to the kallikrein family. PSA-LM is expressed in secretory epithelial cells of the prostate and is up-regulated by androgenic stimulation, similarly to PSA. RT-PCR, sequence analysis, immunohistochemistry, androgen stimulation experiments The Journal of biological chemistry Medium 11834722
2002 Wild-type p53 strongly repressed PSA promoter-driven transcription and PSA protein secretion in LNCaP prostate cancer cells, while dominant-negative p53 mutants stimulated PSA expression. cDNA microarray showed a ~4-fold increase in PSA mRNA when p53 was suppressed. The inhibitory effect of wild-type p53 was abolished by trichostatin A (HDAC inhibitor), implicating histone deacetylation in the negative regulation of PSA promoter activity by p53. cDNA microarray, transient transfection with wild-type and dominant-negative p53 constructs, ELISA for secreted PSA, trichostatin A treatment Oncogene Medium 11791186
2003 PSA protein (enzymatically inactive forms produced by transfection of human and rat prostate cancer cell lines) did not alter growth kinetics in vitro and did not change xenograft doubling times in vivo, demonstrating that the PSA protein itself, independent of enzymatic activity, does not significantly affect prostate cancer cell growth or angiogenesis in these models. Stable transfection of multiple prostate cancer cell lines with PSA gene, in vitro growth assays, xenograft in vivo models, fluorescent peptide substrate assay for enzymatic activity The Prostate Medium 12746846
2003 N-glycan characterization of PSA from normal seminal plasma versus LNCaP tumor cells revealed distinct glycosylation patterns. Normal PSA glycans are sialylated biantennary complex structures (mono- and disialylated). LNCaP (tumor-derived) PSA glycans are neutral (non-sialylated), have higher fucose content (including alpha1-2 fucosylation forming the H2 epitope absent in normal PSA), and increased GalNAc (65% vs. 25%). These carbohydrate differences allow distinction between PSA from normal and tumor origins. N-glycan sequencing, mass spectrometry, immunoprecipitation Glycobiology High 12626390
2010 KLK2 is the protease responsible for activating PSA in biologically relevant models. PSA was activated by KLK2 when PSA- and KLK2-expressing cells were in physical contact, through co-conditioned media, and in vivo in subcutaneous co-inoculation xenografts (reduced free-to-total PSA ratio indicating more active PSA). Double-transgenic mice expressing both PSA and KLK2 in the prostate produced more active PSA than single-PSA transgenics. Active PSA expression alone over 2 years did not induce PIN or prostate cancer in transgenic mice. Cell co-culture, co-conditioned media assays, xenograft co-inoculation, double-transgenic mouse models, PSA activity assays The Prostate High 20058238
2011 PSA localizes to nuclei of androgen-stimulated LNCaP and C4-2B prostate cancer cells (demonstrated by immunofluorescence and subcellular fractionation). Stable shRNA or transient siRNA knockdown of PSA resulted in reduced AR protein and mRNA levels in C4-2B and VCaP cells, revealing a feedback loop where PSA positively controls AR expression. This regulation was independent of Src activation and did not appear to involve integrin-mediated Src signaling. Immunofluorescence, subcellular fractionation, shRNA/siRNA knockdown, immunoblotting, real-time PCR The Prostate Medium 21956655
2011 The miR-99 family (miR-99a, -99b, miR-100) suppresses PSA expression in prostate cancer cells. Transfection of these miRNAs inhibited PSA expression and cell growth. Mechanistically, the miR-99 family targets SMARCA5 (a chromatin-remodeling factor), and PSA is posttranscriptionally regulated at least in part through repression of SMARCA5. miRNA transfection, microarray, polyribosomal loading analysis, quantitative RT-PCR, computational target prediction with experimental validation Cancer research Medium 21212412
2012 Tyrosine-107 phosphorylated galectin-3 is resistant to cleavage by PSA. PSA (a chymotrypsin-like serine protease) cleaves galectin-3 after Tyr-107, disrupting galectin-3 multivalency while preserving carbohydrate binding activity. When galectin-3 Tyr-107 is phosphorylated by c-Abl kinase, PSA-mediated cleavage at that site is blocked, linking c-Abl activity with resistance to PSA proteolysis in prostate cells. In vitro cleavage assays with purified PSA, site-directed phosphorylation by c-Abl, Western blot, loss-of-PTEN cell models The Journal of biological chemistry Medium 22232548
2009 PSA antiangiogenic activity is dependent on its enzymatic activity. Inactive PSA isoforms lack antiangiogenic activity in a HUVEC tube formation model. Inhibition of PSA enzymatic activity by a monoclonal antibody or small molecule inhibitors abolishes the antiangiogenic effect, while a peptide that stimulates PSA enzymatic activity enhances the antiangiogenic effect. Gene expression changes in HUVECs treated with PSA were opposite to those associated with tube formation. HUVEC tube formation assay, enzymatic activity modulation (antibody, small molecule inhibitors, stimulatory peptide), gene expression analysis Scandinavian journal of clinical and laboratory investigation Medium 19551556
2002 NF-κB activates PSA gene expression. By expressing dominant-active MEKK1, TNF-alpha treatment, or overexpression of p50/p65, NF-κB was shown to activate a transcriptional regulatory element of the KLK3 gene. DNase I footprinting identified four NF-κB binding sites in the PSA core enhancer. Androgen-independent prostate cancer xenografts had higher constitutive NF-κB binding activity than androgen-dependent counterparts. Transient transfection with dominant-active MEKK1 or p50/p65, TNF-alpha treatment, DNase I footprinting, NF-κB binding assay in xenografts Molecular and cellular biology High 11909978
2017 FOXM1 directly binds to Forkhead kinase (FHK) binding motifs in the PSA promoter/enhancer regions (identified by ChIP-PCR) and regulates KLK3 gene transcription. Androgen-independent C4-2 cells have more FOXM1 binding sites engaged than androgen-dependent LNCaP cells. Depletion of FOXM1 by small-molecule inhibitors significantly improved suppression of PSA transcription by the anti-AR agent Cadosax. ChIP-PCR, FOXM1 inhibitor treatment, combinatorial knockdown with anti-AR agent, gene expression analysis Oncotarget Medium 28199985
2018 MRGBP promotes androgen receptor (AR)-mediated transactivation of KLK3 (PSA) and TMPRSS2. MRGBP associates with AR binding regions of these genes during androgen treatment. MRGBP interacts with MRG15 and TIP60 in prostate cancer cells. AR stimulation enhanced H3K4me1/me3 at AR binding regions; MRGBP is recruited to active gene regions via MRG15 binding to H3K4me1/3, then promotes recruitment of TIP60 and acetylation of histone variant H2A.Z at AR binding sites, which increases AR occupancy of these regions. ChIP, Co-immunoprecipitation, siRNA knockdown, gene expression analysis, histone modification mapping Biochimica et biophysica acta. Gene regulatory mechanisms Medium 30076933
2004 HER2/ERBB3 pathway signaling stabilizes AR protein levels and optimizes AR binding to promoter/enhancer regions of androgen-regulated genes including KLK3/PSA. The dual EGFR/HER2 inhibitor PKI-166 reduced AR transcriptional activity and PSA expression. Effects were mediated by HER2/ERBB3, not EGFR, and involved kinases other than Akt. Small molecule kinase inhibition (PKI-166), genetic perturbation, AR-target gene expression analysis, AR binding to promoter regions Cancer cell Medium 15542435
2009 RNF6, a ubiquitin E3 ligase, associates with AR and induces AR ubiquitination, promoting AR transcriptional activity and expression of a subset of AR target genes including KLK3/PSA. Knockdown of RNF6 or mutation of RNF6-induced ubiquitination acceptor sites on AR selectively altered expression of this AR target gene subset and diminished recruitment of AR and coactivators to androgen-responsive elements in the KLK3 regulatory region. Proteomic screen, Co-IP, ChIP, siRNA knockdown, ubiquitination assays, gene expression analysis in prostate cancer cells Cancer cell Medium 19345326
2012 Evolutionary analysis of KLK3 and KLK2 across 22 primate species placed the KLK2-KLK3 duplication in the Catarrhini ancestor. dN/dS analysis provided evidence for adaptive evolution of KLK3 toward an expanded enzymatic spectrum with an effect on hydrolysis of the semen coagulum. Associations between mating system, number of semenogelin (SEMG) repeat units, and the number of functional KLK2 and KLK3 genes suggest that reproductive biology shaped KLK3 evolution. Comparative genomics, dN/dS calculation, phylogenetic analysis across 22 primate species Genome biology and evolution Low 23204305
2000 KLK3/PSA is a member of the expanded human kallikrein gene family (15 members on chromosome 19q13). PSA was established as a potent inhibitor of angiogenesis, and NES1/KLK10 was identified as a breast cancer tumor suppressor. Multiple newly identified kallikrein-like genes are regulated by steroid hormones. Gene family characterization by sequence analysis, hormone regulation studies, angiogenesis assay Trends in endocrinology and metabolism: TEM Low 10675891
2017 Genetic variations in the KLK3 coding region correlate with male infertility. Five SNPs (rs266881, rs174776, rs266875, rs35192866, rs1810020) were significantly associated with increased infertility risk in 875 infertile versus 290 fertile men. Since PSA/KLK3 is the chief executor of semenogelin fragmentation and semen liquefaction, and PSA levels correlate with sperm motility, these coding variants likely disrupt PSA enzymatic activity required for semen liquefaction. Complete coding region resequencing, genetic association study in a large ethnically matched cohort Scientific reports Low 28894123

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2008 Multiple newly identified loci associated with prostate cancer susceptibility. Nature genetics 673 18264097
2004 The human plasma proteome: a nonredundant list developed by combination of four separate sources. Molecular & cellular proteomics : MCP 658 14718574
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
1990 Enzymatic activity of prostate-specific antigen and its reactions with extracellular serine proteinase inhibitors. European journal of biochemistry 572 1702714
1986 Human prostate-specific antigen: structural and functional similarity with serine proteases. Proceedings of the National Academy of Sciences of the United States of America 545 2422647
1992 Prostate-specific antigen (PSA) is an insulin-like growth factor binding protein-3 protease found in seminal plasma. The Journal of clinical endocrinology and metabolism 463 1383255
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
1987 Molecular cloning of human prostate specific antigen cDNA. FEBS letters 355 2436946
2006 PSA-NCAM in mammalian structural plasticity and neurogenesis. Progress in neurobiology 352 17029752
2007 Obesity-related plasma hemodilution and PSA concentration among men with prostate cancer. JAMA 280 18029831
2012 Genomic deletion of PTEN is associated with tumor progression and early PSA recurrence in ERG fusion-positive and fusion-negative prostate cancer. The American journal of pathology 275 22705054
2004 HER2/neu kinase-dependent modulation of androgen receptor function through effects on DNA binding and stability. Cancer cell 273 15542435
1998 Human Kallikrein 2 (hK2) and prostate-specific antigen (PSA): two closely related, but distinct, kallikreins in the prostate. Critical reviews in clinical laboratory sciences 267 9759557
2005 Transcriptional regulation of a metastasis suppressor gene by Tip60 and beta-catenin complexes. Nature 264 15829968
2004 An investigation into the human serum "interactome". Electrophoresis 247 15174051
2000 The new human kallikrein gene family: implications in carcinogenesis. Trends in endocrinology and metabolism: TEM 243 10675891
2003 Altered glycosylation pattern allows the distinction between prostate-specific antigen (PSA) from normal and tumor origins. Glycobiology 228 12626390
2011 miR-99 family of MicroRNAs suppresses the expression of prostate-specific antigen and prostate cancer cell proliferation. Cancer research 202 21212412
2017 Increased PSA expression on prostate cancer exosomes in in vitro condition and in cancer patients. Cancer letters 199 28694142
2009 Regulation of androgen receptor transcriptional activity and specificity by RNF6-induced ubiquitination. Cancer cell 191 19345326
2009 Influence of trigger PSA and PSA kinetics on 11C-Choline PET/CT detection rate in patients with biochemical relapse after radical prostatectomy. Journal of nuclear medicine : official publication, Society of Nuclear Medicine 188 19690023
2012 Three-Tesla magnetic resonance-guided prostate biopsy in men with increased prostate-specific antigen and repeated, negative, random, systematic, transrectal ultrasound biopsies: detection of clinically significant prostate cancers. European urology 185 22325447
2009 Prostate-specific antigen progression predicts overall survival in patients with metastatic prostate cancer: data from Southwest Oncology Group Trials 9346 (Intergroup Study 0162) and 9916. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 185 19380444
2004 Rate of molecular evolution of the seminal protein gene SEMG2 correlates with levels of female promiscuity. Nature genetics 184 15531881
2009 Tea polyphenols decrease serum levels of prostate-specific antigen, hepatocyte growth factor, and vascular endothelial growth factor in prostate cancer patients and inhibit production of hepatocyte growth factor and vascular endothelial growth factor in vitro. Cancer prevention research (Philadelphia, Pa.) 181 19542190
2020 Upadacitinib for psoriatic arthritis refractory to biologics: SELECT-PsA 2. Annals of the rheumatic diseases 180 33272960
1997 Characterization of the precursor of prostate-specific antigen. Activation by trypsin and by human glandular kallikrein. The Journal of biological chemistry 180 9261179
1998 Growth and fate of PSA-NCAM+ precursors of the postnatal brain. The Journal of neuroscience : the official journal of the Society for Neuroscience 172 9671666
2016 Extended mortality results for prostate cancer screening in the PLCO trial with median follow-up of 15 years. Cancer 170 27911486
2002 NF-kappa B activates prostate-specific antigen expression and is upregulated in androgen-independent prostate cancer. Molecular and cellular biology 170 11909978
2009 Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip. American journal of human genetics 164 19913121
1999 Prostate-specific antigen (PSA) promoter-driven androgen-inducible expression of sodium iodide symporter in prostate cancer cell lines. Cancer research 159 10232600
2002 APS-I/APECED: the clinical disease and therapy. Endocrinology and metabolism clinics of North America 155 12092452
2001 PSA-NCAM modulates BDNF-dependent survival and differentiation of cortical neurons. The European journal of neuroscience 151 11298800
2003 Update on autoimmune polyendocrine syndromes (APS). Acta bio-medica : Atenei Parmensis 148 12817789
2007 Effects of Astragalus polysaccharides (APS) on the expression of immune response genes in head kidney, gill and spleen of the common carp, Cyprinus carpio L. International immunopharmacology 120 18068100
2001 Revisiting the function of PSA-NCAM in the nervous system. Molecular neurobiology 115 11831554
2003 Structural basis for recruitment of the adaptor protein APS to the activated insulin receptor. Molecular cell 96 14690593
2011 Expression of PSA-NCAM and synaptic proteins in the amygdala of psychiatric disorder patients. Journal of psychiatric research 91 22099865
2001 Autoimmune polyendocrine syndrome type 1 (APS I) in Norway. Clinical endocrinology 89 11207636
1999 Mutation analyses of North American APS-1 patients. Human mutation 86 9888391
1999 Identification of the APS protein as a novel insulin receptor substrate. The Journal of biological chemistry 85 10196204
2011 Identification of a novel prostate cancer susceptibility variant in the KLK3 gene transcript. Human genetics 77 21465221
2003 Increased insulin sensitivity and hypoinsulinemia in APS knockout mice. Diabetes 75 14578283
2001 SH2-B and APS are multimeric adapters that augment TrkA signaling. Molecular and cellular biology 70 11238898
2007 Mucolipin-2 localizes to the Arf6-associated pathway and regulates recycling of GPI-APs. Traffic (Copenhagen, Denmark) 68 17662026
2005 Pregnenolone sulfate enhances neurogenesis and PSA-NCAM in young and aged hippocampus. Neurobiology of aging 68 15585350
2002 Distribution of PSA-NCAM expression in the amygdala of the adult rat. Neuroscience 66 12150768
2001 Migration and multipotentiality of PSA-NCAM+ neural precursors transplanted in the developing brain. Molecular and cellular neurosciences 66 11414788
2000 Grape-derived chemopreventive agent resveratrol decreases prostate-specific antigen (PSA) expression in LNCaP cells by an androgen receptor (AR)-independent mechanism. Anticancer research 65 10769659
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2022 Application of dendritic cells in tumor immunotherapy and progress in the mechanism of anti-tumor effect of Astragalus polysaccharide (APS) modulating dendritic cells: a review. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 57 36127221
2012 PSA-NCAM: synaptic functions mediated by its interactions with proteoglycans and glutamate receptors. The international journal of biochemistry & cell biology 52 22300986
2020 NETs in APS: Current Knowledge and Future Perspectives. Current rheumatology reports 51 32845378
2004 A phenylalanine zipper mediates APS dimerization. Nature structural & molecular biology 51 15378031
2000 Differential steroid hormone regulation of human glandular kallikrein (hK2) and prostate-specific antigen (PSA) in breast cancer cell lines. Breast cancer research and treatment 51 10832596
2013 The dendritic spines of interneurons are dynamic structures influenced by PSA-NCAM expression. Cerebral cortex (New York, N.Y. : 1991) 50 23780867
2002 Unusual alternative splicing within the human kallikrein genes KLK2 and KLK3 gives rise to novel prostate-specific proteins. The Journal of biological chemistry 50 11834722
2014 Clinical and serologic parallels to APS-I in patients with thymomas and autoantigen transcripts in their tumors. Journal of immunology (Baltimore, Md. : 1950) 46 25230752
2002 Expression of prostate specific antigen (PSA) is negatively regulated by p53. Oncogene 45 11791186
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2003 The adapter protein APS associates with the multifunctional docking sites Tyr-568 and Tyr-936 in c-Kit. The Biochemical journal 44 12444928
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2012 Obstetric and vascular APS: same autoantibodies but different diseases? Lupus 42 22635208
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2019 Promoter orientation of the immunomodulatory Bacteroides fragilis capsular polysaccharide A (PSA) is off in individuals with inflammatory bowel disease (IBD). Gut microbes 36 30732524
2001 Molecular and catalytic properties of Arabidopsis thaliana adenylyl sulfate (APS)-kinase. Archives of biochemistry and biophysics 35 11488606
2010 Reciprocal regulation among miR395, APS and SULTR2;1 in Arabidopsis thaliana. Plant signaling & behavior 34 20935495
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2007 Differential evolution of PSA-NCAM expression during aging of the rat telencephalon. Neurobiology of aging 31 17904697
2001 Genetic deletions of NCAM and PSA impair circadian function in the mouse. Physiology & behavior 31 11399310
1999 pSa causes oncogenic suppression of Agrobacterium by inhibiting VirE2 protein export. Journal of bacteriology 31 9864329
2014 The prostate cancer susceptibility variant rs2735839 near KLK3 gene is associated with aggressive prostate cancer and can stratify gleason score 7 patients. Clinical cancer research : an official journal of the American Association for Cancer Research 29 25274378
1999 Developmental methylmercury administration alters cerebellar PSA-NCAM expression and Golgi sialyltransferase activity. Brain research 28 10536193
2022 Astragalus polysaccharide (APS) attenuated PD-L1-mediated immunosuppression via the miR-133a-3p/MSN axis in HCC. Pharmaceutical biology 27 36086826
2022 Genome-wide identification of the TGA gene family in kiwifruit (Actinidia chinensis spp.) and revealing its roles in response to Pseudomonas syringae pv. actinidiae (Psa) infection. International journal of biological macromolecules 27 36150565
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2021 Characteristics of α2,3-sialyl N-glycosylated PSA as a biomarker for clinically significant prostate cancer in men with elevated PSA level. The Prostate 23 34549452
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2022 Astragalus polysaccharide (APS) exerts protective effect against acute ischemic stroke (AIS) through enhancing M2 micoglia polarization by regulating adenosine triphosphate (ATP)/ purinergic receptor (P2X7R) axis. Bioengineered 21 35166175
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1998 Cloning, sequencing, and expression of the PSA genes from Leishmania infantum. European journal of biochemistry 21 9492309
2009 Ultrasensitive electrochemical immunoassay based on cadmium ion-functionalized PSA@PAA nanospheres. Biosensors & bioelectronics 20 19914818
2003 The small subunit ADP-glucose pyrophosphorylase ( ApS) promoter mediates okadaic acid-sensitive uidA expression in starch-synthesizing tissues and cells in Arabidopsis. Planta 20 12783326
1999 Lymphocyte activation and cytokine production by Pisum sativum agglutinin (PSA) in vivo and in vitro. Immunopharmacology 19 10102796
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2020 Insight into the hypercoagulable state of high-risk thrombotic APS patients: Contribution of aβ2GPI and aPS/PT antibodies. Journal of thrombosis and haemostasis : JTH 18 33249717
2015 The Obesity-Linked Gene Nudt3 Drosophila Homolog Aps Is Associated With Insulin Signaling. Molecular endocrinology (Baltimore, Md.) 17 26168034
2011 Association between saliva PSA and serum PSA in conditions with prostate adenocarcinoma. Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals 17 21854254
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2021 PSA controls hepatic lipid metabolism by regulating the NRF2 signaling pathway. Journal of molecular cell biology 15 34048566
2018 Early diagnostic role of PSA combined miR-155 detection in prostate cancer. European review for medical and pharmacological sciences 15 29630104
2019 Characterization of Entamoeba histolytica adenosine 5'-phosphosulfate (APS) kinase; validation as a target and provision of leads for the development of new drugs against amoebiasis. PLoS neglected tropical diseases 14 31425516
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