Affinage

KLK4

Kallikrein-4 · UniProt Q9Y5K2

Length
254 aa
Mass
27.0 kDa
Annotated
2026-06-10
100 papers in source corpus 26 papers cited in narrative 26 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KLK4 is a secreted trypsin-like serine protease (P1-Arg specificity) (PMID:15389820) whose principal physiological role is in enamel maturation: it is expressed by transition- and maturation-stage ameloblasts, where it aggressively degrades retained organic enamel matrix proteins, particularly amelogenin, to permit their replacement by mineral (PMID:18627287, PMID:10690663). Loss of KLK4 in mice causes retention of enamel proteins, failure of enamel crystallites to fuse, and rapid post-eruption enamel abrasion, establishing it as essential for crystal maturation and enamel hardening (PMID:19578120). KLK4 acts within a protease network with MMP20: MMP20 processes amelogenin during the secretory stage and activates pro-KLK4 by cleaving its propeptide, while KLK4 reciprocally inactivates MMP20 by cleaving its catalytic domain under physiological pH, defining a stage-dependent regulatory switch (PMID:19767579, PMID:24112721); the two proteases serve overlapping and complementary functions, with double-null and digenic-heterozygous mice showing more severe enamel defects than single nulls (PMID:27066511). KLK4 binds hydroxyapatite directly and hydrolyzes HAP-adsorbed amelogenin more efficiently than soluble substrate, and undergoes activity-dependent self-inactivation, aggregation, and autofragmentation upon substrate depletion, providing a built-in termination mechanism (PMID:25104939, PMID:29229389). Its expression in ameloblasts is positively driven by TGF-β/TGF-βRII signaling and by BMP2/BMP4-Smad signaling, and is suppressed by fluoride acting through reduced TGF-β and nuclear hormone receptor (AR/PR) signaling (PMID:25074495, PMID:24278477, PMID:27146352, PMID:29249975). Beyond enamel, KLK4 signals through protease-activated receptors PAR-1 and PAR-2, cleaving PAR-2 and triggering Ca2+ mobilization, ERK phosphorylation, and receptor internalization (PMID:18308730), and in prostate cancer cells it interacts with and destabilizes PLZF to integrate androgen receptor and mTOR signaling (PMID:23798432). Atomic-resolution crystal structures of KLK4 bound to SFTI-1 inhibitors reveal both active-site and an allosteric metal-binding exosite inhibition mechanism (PMID:27767076).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2000 Medium

    Establishing where KLK4 acts in tooth development was the first step toward a functional role; demonstrating stage-specific ameloblast expression localized it to the enamel maturation phase.

    Evidence In situ hybridization and immunohistochemistry on developing mouse and pig incisors

    PMID:10690663

    Open questions at the time
    • No direct functional consequence measured in same experiment
    • Odontoblast expression role undefined
  2. 2005 High

    Defining KLK4's intrinsic enzymatic specificity was needed to predict its substrates; positional-scanning libraries showed trypsin-like P1-Arg preference and reconstituted activation of pro-PSA and IGFBP degradation.

    Evidence Positional-scanning combinatorial peptide library, recombinant KLK4, in vitro substrate assays

    PMID:15389820

    Open questions at the time
    • In vitro substrates not validated in vivo
    • Physiological relevance of IGFBP/pro-PSA cleavage uncharacterized
  3. 2008 High

    Whether KLK4 acts only proteolytically or also as a signaling agonist was open; demonstration that it cleaves PAR-2 and signals via PAR-1/PAR-2 established a receptor-mediated signaling output.

    Evidence Ca2+ flux, ERK Western blot, PAR-2 siRNA, confocal internalization assays

    PMID:18308730

    Open questions at the time
    • Downstream physiological consequences of PAR signaling not defined
    • Tissue context of PAR signaling unresolved
  4. 2008 High

    The proposed enamel function was consolidated by integrating expression, biochemistry, and mutant phenotype, framing KLK4 as the maturation-stage degrader of retained matrix proteins.

    Evidence In vivo expression studies, biochemical characterization, loss-of-function analysis

    PMID:18627287

    Open questions at the time
    • Mechanism of activation in vivo not yet resolved
    • Relative contribution vs MMP20 unquantified
  5. 2009 High

    Direct genetic proof of KLK4's necessity was missing; the Klk4-null mouse showed enamel protein retention and crystal fusion failure, establishing it as essential for crystal maturation.

    Evidence Klk4 knockout/LacZ knockin mouse, SEM, immunohistochemistry

    PMID:19578120

    Open questions at the time
    • Does not resolve in vivo activation mechanism
    • Substrate spectrum in vivo not delineated
  6. 2009 High

    Distinguishing the division of labor between the two enamel proteases clarified that MMP20 performs secretory-stage amelogenin processing while KLK4 has distinct, restricted cleavage specificity.

    Evidence Native pig MMP20 and KLK4, LC-MS/MS, RP-HPLC digestion of amelogenin substrates

    PMID:19767579

    Open questions at the time
    • Functional consequence of restricted KLK4 cleavage in vivo unclear
  7. 2009 Medium

    How pro-KLK4 is activated in vivo was unknown; DPPI was identified as an ameloblast-expressed activator capable of processing pro-KLK4, with DPPI-null enamel showing reduced hardness.

    Evidence RT-PCR, IHC, in vitro fluorogenic activation assay, DPPI-null enamel microhardness/FTIR

    PMID:19407151

    Open questions at the time
    • Functional redundancy with other activators possible
    • DPPI-null lacks protein accumulation, unlike Klk4-null
  8. 2013 High

    The activation and shut-down logic of the enamel protease pair was clarified: MMP20 activates pro-KLK4 while KLK4 inactivates MMP20 under physiological pH, defining a stage-dependent regulatory switch.

    Evidence Native and recombinant proteins, zymography, Edman degradation, RP-HPLC

    PMID:24112721

    Open questions at the time
    • pH dynamics in vivo not directly measured
    • Quantitative timing of switch in enamel unknown
  9. 2013 Medium

    A non-enamel oncogenic function was uncovered: KLK4 binds and destabilizes PLZF, linking it to AR and mTOR signaling in prostate cancer cells.

    Evidence Co-IP, protein stability assays, shRNA knockdown, in vivo siRNA delivery in tumor mice

    PMID:23798432

    Open questions at the time
    • Whether interaction requires KLK4 catalytic activity unclear
    • Single lab, no reciprocal validation across systems
  10. 2014 Medium

    Upstream transcriptional control was addressed; TGF-β1 was shown to induce Klk4, and fluoride was shown to suppress Klk4 via reduced TGF-β1, mechanistically linking fluorosis to retained enamel protein.

    Evidence In vivo fluoride treatment, qPCR, Klk4-LacZ reporter mice, IHC

    PMID:25074495

    Open questions at the time
    • Direct vs indirect TGF-β regulation of Klk4 promoter not resolved
  11. 2014 Medium

    How KLK4 accesses its mineral-bound substrate and how its activity terminates were unknown; direct HAP binding, enhanced cleavage of adsorbed amelogenin, and substrate-dependent self-inactivation were demonstrated.

    Evidence Pure KLK4 + HAP binding assays, SDS-PAGE, LC-MALDI MS/MS, activity timecourses

    PMID:25104939 PMID:29229389

    Open questions at the time
    • Single lab in vitro reconstitution
    • Self-inactivation not demonstrated in vivo
  12. 2013 High

    A structural basis for KLK4 inhibition was needed for inhibitor design; crystal structures with SFTI-1 derivatives plus MD revealed active-site and allosteric exosite inhibition routes.

    Evidence X-ray crystallography (~1 Å), MD simulation, nickel- and inhibitor-bound forms

    PMID:27767076

    Open questions at the time
    • Physiological relevance of the metal-binding exosite unknown
    • No endogenous allosteric regulator identified
  13. 2016 High

    The genetic interaction between the two enamel proteases was quantified; double-null and digenic-heterozygous phenotypes established overlapping/complementary roles and digenic contributions.

    Evidence Mmp20/Klk4 single and double null mice, SEM, µCT, EDX

    PMID:27066511

    Open questions at the time
    • Molecular basis of digenic interaction not defined
  14. 2023 Medium

    Layered transcriptional control of Klk4 in ameloblasts was extended beyond TGF-β: BMP/Smad signaling, AR/PR hormone receptors, Foxo1/Runx2, and the pH-responsive Gpr111 receptor were each shown to regulate Klk4 expression.

    Evidence Conditional Bmp2/4 and TGF-βRII KO mice, AR siRNA, Foxo1/Runx2 perturbation, Gpr111 KO and pH modulation

    PMID:24278477 PMID:27146352 PMID:29249975 PMID:34781073 PMID:36929047

    Open questions at the time
    • Many regulators studied via single labs
    • Hierarchy and crosstalk among regulatory inputs unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Whether KLK4's cancer-associated functions (PAR signaling, PLZF destabilization, Wnt/β-catenin modulation) depend on its proteolytic activity and reflect bona fide endogenous roles versus overexpression artifacts remains unresolved.
  • Cancer phenotypes often used combined KLK4-7 overexpression, preventing KLK4-specific attribution
  • Endogenous in vivo cancer substrates not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0016787 hydrolase activity 3 GO:0060089 molecular transducer activity 1
Localization
GO:0005576 extracellular region 3 GO:0005634 nucleus 2 GO:0005829 cytosol 1
Pathway
R-HSA-1266738 Developmental Biology 3 GO:0140096 catalytic activity, acting on a protein 2 R-HSA-162582 Signal Transduction 2
Partners
DPPIF2RF2RL1MMP20PLZF

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 KLK4 is secreted by transition- and maturation-stage ameloblasts and functions to aggressively degrade retained organic enamel matrix proteins following termination of enamel protein secretion, facilitating replacement of organic matrix with mineral during enamel maturation. In vivo expression studies, biochemical characterization, loss-of-function mutant analysis Biological chemistry High 18627287
2009 Klk4 null mice retain enamel proteins in maturation-stage enamel, exhibit rapid post-eruption enamel abrasion, and show failure of individual enamel crystallites to fuse/interlock, demonstrating that KLK4 is essential for enamel protein removal and proper crystal maturation. Klk4 knockout/LacZ knockin mouse, X-gal histochemistry, scanning electron microscopy, immunohistochemistry The Journal of biological chemistry High 19578120
2008 KLK4 signals intracellularly via protease-activated receptors PAR-1 and PAR-2 (but not PAR-4); KLK4-induced Ca2+ mobilization via PAR-1 is more potent, while greater efficacy is observed via PAR-2. KLK4 cleaves PAR-2 extracellular domain and induces receptor internalization. Ca2+ flux assays, in vitro protease cleavage assays, anti-phospho-ERK1/2 Western blot, siRNA knockdown of PAR-2, confocal microscopy of receptor internalization The Journal of biological chemistry High 18308730
2005 KLK4 (prostase) has trypsin-like substrate specificity with preferred P1-Arg, P2-Gln/Leu/Val, P3-Gln/Ser/Val, P4-Ile/Val; recombinant KLK4 activates pro-PSA/KLK3 and degrades members of the insulin-like growth factor binding protein (IGFBP) family in vitro. Positional-scanning synthetic combinatorial peptide library (PS-SCL), Drosophila S2 cell expression, enterokinase activation, synthetic chromogenic peptide assays, in vitro substrate degradation assays The Prostate High 15389820
2009 MMP-20 alone processes amelogenin during secretory stage, generating all major cleavage products (23-kDa, 20-kDa, 13-kDa, 11-kDa, 6-kDa amelogenins). KLK4 can only cleave amelogenin after His62 among these key sites, indicating distinct substrate specificities for the two enamel proteases. Isolation of native pig MMP-20 and KLK4, LC-MSMS, SDS-PAGE, C18 RP-HPLC with fluorescence and UV detection, digestion of TRAP, LRAP, and fluorescent peptides Journal of dental research High 19767579
2013 MMP20 activates pro-KLK4 by cleaving at the propeptide-enzyme junction used in vivo. Conversely, KLK4 inactivates MMP20 by cleaving it at two sites in the catalytic domain under physiological (but not mildly acidic) conditions, suggesting a regulatory switch during enamel formation. Isolation of native pig proteases, recombinant human proteins, zymography, Edman degradation, RP-HPLC Archives of oral biology High 24112721
2009 Dipeptidyl peptidase I (DPPI) is expressed in ameloblasts throughout amelogenesis (highest at maturation) and activates pro-KLK4 in vitro to cleave a fluorogenic KLK4-specific peptide substrate; DPPI null mice show reduced enamel hardness without protein accumulation, implicating DPPI as a KLK4 activator in vivo. Real-time PCR for DPPI expression, immunohistochemistry, in vitro fluorogenic peptide cleavage assay with pro-KLK4 + DPPI, FTIR and microhardness testing of DPPI null mouse enamel Journal of dental research Medium 19407151
2000 EMSP1/KLK4 mRNA is specifically expressed in transition- and maturation-stage ameloblasts (not secretory-stage ameloblasts) in developing mouse incisors, with odontoblast expression also detected; consistent with a role in maturation-phase enamel protein degradation. In situ hybridization on postnatal day 3 mouse mandibular incisors, immunohistochemistry of pig incisors Journal of dental research Medium 10690663
2002 EMSP1/KLK4 expressed by odontoblasts concentrates at the enamel-dentin junction (EDJ) in highly mineralized enamel, but is not detected in predentin or dentin; odontoblast-secreted EMSP1 is proposed to facilitate hardening of the deepest enamel layer via cell processes. Zymography of extracellular matrix fractions from developing porcine incisors, RT-PCR of isolated cell populations, histological characterization Journal of dental research Medium 12351663
2013 KLK4 interacts with PLZF (promyelocytic leukemia zinc finger protein) and decreases PLZF stability; PLZF in turn inhibits androgen receptor (AR) transcriptional function and activates REDD1 (an mTORC1 inhibitor), forming a molecular switch that integrates AR and mTOR signaling in prostate cancer cells. Co-immunoprecipitation, protein stability assays, KLK4 knockdown with shRNA, cell proliferation and apoptosis assays, anchorage-independent growth, in vivo nanoliposomal siRNA delivery in tumor-bearing mice Proceedings of the National Academy of Sciences of the United States of America Medium 23798432
2016 X-ray crystal structures of KLK4 in complex with SFTI-1 and a rationally designed SFTI-1 derivative (~1 Å resolution) reveal direct active-site inhibition; MD simulations reveal a dynamic allosteric pathway between a metal-binding exosite (nickel-bound) and the active site, providing a structural basis for indirect (allosteric) inhibition. X-ray crystallography (1 Å resolution), MD simulation, computational analysis, crystal structures with SFTI-1 and nickel Scientific reports High 27767076
2010 KLK4 specifically activates meprin beta (but not meprin alpha) by cleaving off its propeptide; KLK5 activates both meprin alpha and beta; KLK4-activated meprin beta can process proKLK7 N-terminally to accelerate its trypsin-dependent activation. In vitro protease activation assays, N-terminal sequencing, biochemical cleavage assays Biological chemistry Medium 20128684
2014 TGF-β1 induces Klk4 expression in ameloblasts; fluoride inhibits Klk4 (but not Mmp20) transcript levels in vivo by reducing TGF-β1 expression, resulting in reduced KLK4 protein in enamel and contributing to the higher protein content of fluorosed enamel. In vivo fluoride treatment of rats, real-time PCR, LacZ reporter mice (Klk4+/LacZ), β-galactosidase staining, immunohistochemistry Journal of dental research Medium 25074495
2013 Conditional knockout of TGF-β receptor II in ameloblasts (using amelogenin-Cre) results in significantly reduced KLK4 mRNA levels (with slight MMP-20 increase), impaired enamel matrix protein removal at maturation stage, and hypomineralized enamel, demonstrating that TGF-β signaling through its receptor in ameloblasts regulates KLK4 expression during enamel maturation. Ameloblast-specific TGF-βRII conditional knockout mice, µCT, SEM, immunostaining, qRT-PCR PloS one Medium 24278477
2005 KLK4 overexpression (together with KLK5, KLK6, KLK7) in ovarian cancer cells significantly increases invasive behavior in Matrigel assays and tumor burden in a nude mouse peritoneal model, indicating that KLK4 contributes to increased malignant phenotype. Stable co-transfection, in vitro Matrigel invasion assay, in vivo peritoneal nude mouse tumor inoculation Biological chemistry Low 16800744
2001 KLK4 has two major protein isoforms in prostate cancer cells: the full-length hK4-254 (cytoplasmically localized, secreted into seminal fluid) and the N-terminal truncated hK4-205 (nuclear localized); expression of the truncated isoforms (but not KLK4-254) is regulated by androgens in LNCaP cells. V5/His6-tagged and GFP-tagged expression constructs, immunocytochemistry, anti-hK4 peptide antibodies (N-terminal and C-terminal), Western blot of seminal fluid Endocrine-related cancer Medium 16322328
2001 KLK4 full-length protein has a distinct perinuclear localization when GFP-tagged; truncated splice variants lacking the putative signal peptide are exclusively or predominantly localized to the nucleus; KLK4 expression is regulated by multiple hormones (androgens and other steroids) in LNCaP prostate cancer cells. GFP-tagged expression constructs, fluorescence microscopy, RT-PCR expression analysis in hormone-treated prostate cancer cells DNA and cell biology Medium 11506707
2015 MMP20 and KLK4 serve overlapping and complementary functions: Mmp20−/−Klk4−/− double null mice show further reduced high-density enamel volume and more severe enamel defects than either single null, and heterozygous double mutants (Mmp20+/−Klk4+/−) show unexpected enamel failure, suggesting digenic contributions. Mmp20 null, Klk4 null, and Mmp20/Klk4 double-null mice characterized by dissecting microscopy, light microscopy, backscattered SEM, µCT, EDX Molecular genetics & genomic medicine High 27066511
2014 KLK4 binds hydroxyapatite (HAP) directly; amelogenin adsorbed onto HAP is hydrolyzed by KLK4 at significantly higher rates than amelogenin in solution, with more cleavage sites accessible; KLK4 progressively loses activity, aggregates, and auto-fragments when incubated without substrate, suggesting self-inactivation after substrate depletion. In vitro binding assay (pure KLK4 + HAP), SDS-PAGE, HPLC, LC-MALDI MS/MS, spectrophotometry, biochemical activity assays Frontiers in physiology Medium 25104939
2017 KLK4 binds hydroxyapatite directly in quasi-physiological conditions; KLK4 undergoes progressive self-inactivation, aggregation, and autofragmentation in the absence of substrate (both with and without reducer), but remains active and intact in the presence of non-ionic detergent as proxy substrate, indicating activity-dependent self-destruction as a potential termination mechanism. HAP-binding assay with pure KLK4, biochemical activity timecourse assays, SDS-PAGE Biochemical and biophysical research communications Medium 29229389
2017 Fluoride reduces Klk4 expression in ameloblasts through inhibition of androgen receptor (AR) and progesterone receptor (PR) nuclear translocation; PR has a dominant role in regulating Klk4 expression in ameloblasts; fluoride-induced AR cytoplasmic retention co-localizes with HSP90, and fluoride also reduces TGF-β signaling, all contributing to downregulation of Klk4. Immunohistochemical localization of AR and PR, siRNA knockdown of AR in ameloblast-lineage cells (ALCs), qRT-PCR, immunolocalization of HSP90 and TGF-β pathway components Frontiers in physiology Medium 29249975
2021 NaF reduces KLK4 expression in ameloblast-like LS8 cells via a Foxo1/Runx2-dependent pathway: fluoride decreases Runx2 expression, Runx2 knockdown decreases KLK4, and Foxo1 overexpression increases Runx2 (and consequently KLK4), while Foxo1 knockdown decreases Runx2 and this is intensified with NaF. NaF treatment of LS8 cells, Runx2 and Foxo1 siRNA knockdown/overexpression, qRT-PCR, Western blotting Archives of oral biology Medium 34781073
2023 Gpr111/Adgrf2 (a pH-responsive G protein-coupled receptor) acts as a suppressor of Klk4 expression in mature ameloblasts; Gpr111-KO mice show enamel hypomineralization with residual enamel matrix; reduction of extracellular pH to 6.8 suppresses Gpr111 expression while increasing Klk4 expression, and Gpr111 knockdown synergistically enhances Klk4 induction under low pH. Gpr111 knockout mice, dental epithelial cell Gpr111 depletion, immunostaining, qRT-PCR, µCT, SEM, EDX, in vitro pH manipulation experiments FASEB journal Medium 36929047
2016 Epithelial-specific double deletion of Bmp2 and Bmp4 causes amelogenesis imperfecta with drastically delayed matrix protein removal, coinciding with greatly reduced expression of both MMP20 and KLK4, and impaired ameloblastin cleavage, demonstrating that BMP/Smad4 signaling in dental epithelium regulates KLK4 expression. K14-Cre;Bmp2f/f;Bmp4f/f conditional knockout mice, histology, molecular analyses, SEM, X-ray radiography Scientific reports Medium 27146352
2012 KLK4 combined overexpression (with KLK5, KLK6, KLK7) in ovarian cancer cells downregulates α5β1 and αvβ3 integrin expression, decreases cell adhesion to vitronectin and fibronectin, and confers paclitaxel resistance (not carboplatin resistance) through integrin and MAPK-independent mechanisms. Stable transfection with KLK4-7 plasmids, quantitative gene and protein expression, confocal microscopy, cell adhesion assays, chemosensitivity assays, MEK1/2 inhibitor (U0126) treatment Gynecologic oncology Low 22964375
2017 KLK4 silencing in OSCC cells inhibits proliferation, causes cell cycle arrest, induces apoptosis (increased cleaved PARP, cleaved caspase-3, Bax; decreased Bcl-2), and suppresses the Wnt/β-catenin signaling pathway (decreased Wnt1, β-catenin, GSK-3β phosphorylation, cyclin D1, c-myc); Wnt/β-catenin activator reverses these effects. siRNA-mediated KLK4 knockdown in OSCC cells, Western blotting, proliferation and colony formation assays, flow cytometry, Wnt activator rescue experiment Cell biology international Medium 28150891

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Functions of KLK4 and MMP-20 in dental enamel formation. Biological chemistry 196 18627287
1988 Regulation of the phosphate regulon of Escherichia coli. Activation of pstS transcription by PhoB protein in vitro. Journal of molecular biology 164 3054125
2008 Kallikrein-related peptidase 4 (KLK4) initiates intracellular signaling via protease-activated receptors (PARs). KLK4 and PAR-2 are co-expressed during prostate cancer progression. The Journal of biological chemistry 118 18308730
2009 Hypomaturation enamel defects in Klk4 knockout/LacZ knockin mice. The Journal of biological chemistry 117 19578120
1999 Prostase/KLK-L1 is a new member of the human kallikrein gene family, is expressed in prostate and breast tissues, and is hormonally regulated. Cancer research 111 10485467
2009 Cross-talk between two global regulators in Streptomyces: PhoP and AfsR interact in the control of afsS, pstS and phoRP transcription. Molecular microbiology 100 19220751
2001 Human kallikrein 4 (KLK4) is highly expressed in serous ovarian carcinomas. Clinical cancer research : an official journal of the American Association for Cancer Research 99 11489814
1999 Localization of a new prostate-specific antigen-related serine protease gene, KLK4, is evidence for an expanded human kallikrein gene family cluster on chromosome 19q13.3-13.4. The Journal of biological chemistry 87 10438493
2009 Mmp-20 and Klk4 cleavage site preferences for amelogenin sequences. Journal of dental research 82 19767579
2005 Substrates of the prostate-specific serine protease prostase/KLK4 defined by positional-scanning peptide libraries. The Prostate 76 15389820
2006 Overexpression of the human tissue kallikrein genes KLK4, 5, 6, and 7 increases the malignant phenotype of ovarian cancer cells. Biological chemistry 75 16800744
2008 Human and mouse enamel phenotypes resulting from mutation or altered expression of AMEL, ENAM, MMP20 and KLK4. Cells, tissues, organs 71 18714142
2000 Characterization of the mouse and human PRSS17 genes, their relationship to other serine proteases, and the expression of PRSS17 in developing mouse incisors. Gene 66 10863090
2019 Circular RNA (hsa_circ_0051240) promotes cell proliferation, migration and invasion in ovarian cancer through miR-637/KLK4 axis. Artificial cells, nanomedicine, and biotechnology 65 30945557
2010 Analyzing the protease web in skin: meprin metalloproteases are activated specifically by KLK4, 5 and 8 vice versa leading to processing of proKLK7 thereby triggering its activation. Biological chemistry 65 20128684
2008 Structure-function aspects of PstS in multi-drug-resistant Pseudomonas aeruginosa. PLoS pathogens 63 18282104
2013 Molecular circuit involving KLK4 integrates androgen and mTOR signaling in prostate cancer. Proceedings of the National Academy of Sciences of the United States of America 60 23798432
1989 Regulation of the phosphate regulon of Escherichia coli: characterization of the promoter of the pstS gene. Molecular & general genetics : MGG 54 2651888
2015 PstS-1, the 38-kDa Mycobacterium tuberculosis glycoprotein, is an adhesin, which binds the macrophage mannose receptor and promotes phagocytosis. Scandinavian journal of immunology 51 25359607
2005 The high-affinity phosphate-binding protein PstS is accumulated under high fructose concentrations and mutation of the corresponding gene affects differentiation in Streptomyces lividans. Microbiology (Reading, England) 49 16079337
2013 Novel KLK4 and MMP20 mutations discovered by whole-exome sequencing. Journal of dental research 47 23355523
2008 Glycosylation of the phosphate binding protein, PstS, in Streptomyces coelicolor by a pathway that resembles protein O-mannosylation in eukaryotes. Molecular microbiology 47 19017269
2000 Localization of EMSP1 expression during tooth formation and cloning of mouse cDNA. Journal of dental research 47 10690663
2014 Fluoride affects enamel protein content via TGF-β1-mediated KLK4 inhibition. Journal of dental research 46 25074495
2009 Establishment and characterization of three novel cell lines - P-STS, L-STS, H-STS - derived from a human metastatic midgut carcinoid. Anticancer research 46 19528452
2005 Compartmentalized expression of kallikrein 4 (KLK4/hK4) isoforms in prostate cancer: nuclear, cytoplasmic and secreted forms. Endocrine-related cancer 45 16322328
2001 Kallikrein 4 (KLK4), a new member of the human kallikrein gene family is up-regulated by estrogen and progesterone in the human endometrial cancer cell line, KLE. The Journal of clinical endocrinology and metabolism 43 11344246
2005 A proteomic analysis of penicillin resistance in Streptococcus pneumoniae reveals a novel role for PstS, a subunit of the phosphate ABC transporter. Molecular microbiology 42 16313627
2015 MMP20, KLK4, and MMP20/KLK4 double null mice define roles for matrix proteases during dental enamel formation. Molecular genetics & genomic medicine 38 27066511
2012 Combined expression of KLK4, KLK5, KLK6, and KLK7 by ovarian cancer cells leads to decreased adhesion and paclitaxel-induced chemoresistance. Gynecologic oncology 38 22964375
2014 Preferential and selective degradation and removal of amelogenin adsorbed on hydroxyapatites by MMP20 and KLK4 in vitro. Frontiers in physiology 37 25104939
2010 A variant of the KLK4 gene is expressed as a cis sense-antisense chimeric transcript in prostate cancer cells. RNA (New York, N.Y.) 35 20406994
2001 Distinctly different gene structure of KLK4/KLK-L1/prostase/ARM1 compared with other members of the kallikrein family: intracellular localization, alternative cDNA forms, and Regulation by multiple hormones. DNA and cell biology 35 11506707
2012 Reversible inactivation of pSTS suppresses social gaze following in the macaque (Macaca mulatta). Social cognitive and affective neuroscience 34 23171617
2012 Kallikrein-related peptidase 4 (KLK4) mRNA predicts short-term relapse in colorectal adenocarcinoma patients. Cancer letters 34 23201139
2010 Polyclonal antibodies against kallikrein-related peptidase 4 (KLK4): immunohistochemical assessment of KLK4 expression in healthy tissues and prostate cancer. Biological chemistry 33 20180634
2019 Long non-coding RNA LINC01314 represses cell migration, invasion, and angiogenesis in gastric cancer via the Wnt/β-catenin signaling pathway by down-regulating KLK4. Cancer cell international 32 31007611
2014 Kallikrein-related peptidase-4 (KLK4): role in enamel formation and revelations from ablated mice. Frontiers in physiology 32 25071586
2013 TGF-ß regulates enamel mineralization and maturation through KLK4 expression. PloS one 32 24278477
2014 Loss of miR-378 in prostate cancer, a common regulator of KLK2 and KLK4, correlates with aggressive disease phenotype and predicts the short-term relapse of the patients. Biological chemistry 31 25153390
2014 The Pseudomonas aeruginosa phosphate transport protein PstS plays a phosphate-independent role in biofilm formation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 30 25223609
2011 Kallikrein-related peptidase 4 gene (KLK4) in prostate tumors: quantitative expression analysis and evaluation of its clinical significance. The Prostate 30 21520157
2009 Comparative determination of paralytic shellfish toxins (PSTs) using five different toxin detection methods in shellfish species collected in the Aleutian Islands, Alaska. Toxicon : official journal of the International Society on Toxinology 29 19450616
2006 Immunogenicity and protective efficacy of tuberculosis DNA vaccines combining mycolyl-transferase Ag85A and phosphate transport receptor PstS-3. Immunology 28 16827893
2002 Characterization of KLK4 expression and detection of KLK4-specific antibody in prostate cancer patient sera. Oncogene 28 12370833
2016 Direct and indirect mechanisms of KLK4 inhibition revealed by structure and dynamics. Scientific reports 26 27767076
2011 Why does enamel in Klk4-null mice break above the dentino-enamel junction? Cells, tissues, organs 24 21546759
2016 Abrogation of epithelial BMP2 and BMP4 causes Amelogenesis Imperfecta by reducing MMP20 and KLK4 expression. Scientific reports 22 27146352
2010 Effect of PstS sub-units or PknD deficiency on the survival of Mycobacterium tuberculosis. Tuberculosis (Edinburgh, Scotland) 22 20933472
2009 Expression analysis and study of KLK4 in benign and malignant breast tumours. Thrombosis and haemostasis 22 19190825
2009 DPPI may activate KLK4 during enamel formation. Journal of dental research 22 19407151
2020 Mesorhizobium alexandrii sp. nov., isolated from phycosphere microbiota of PSTs-producing marine dinoflagellate Alexandrium minutum amtk4. Antonie van Leeuwenhoek 21 32193664
2019 Multiple biomarkers response in a Neotropical fish exposed to paralytic shellfish toxins (PSTs). Chemosphere 21 31466003
2019 MiR-378a-5p inhibits angiogenesis of oral squamous cell carcinoma by targeting KLK4. Neoplasma 21 31829025
2001 Molecular analysis of Mycobacterium tuberculosis phosphate specific transport system in Mycobacterium smegmatis. Characterization of recombinant 38 kDa (PstS-1). Microbial pathogenesis 21 11373123
2015 Expression of human kallikrein 1-related peptidase 4 (KLK4) and MET phosphorylation in prostate cancer tissue: immunohistochemical analysis. Human cell 20 25862631
2013 MMP20 and KLK4 activation and inactivation interactions in vitro. Archives of oral biology 20 24112721
2007 Structures of OppA and PstS from Yersinia pestis indicate variability of interactions with transmembrane domains. Acta crystallographica. Section D, Biological crystallography 20 18007034
2002 Odontoblasts enhance the maturation of enamel crystals by secreting EMSP1 at the enamel-dentin junction. Journal of dental research 20 12351663
2017 A Fourth KLK4 Mutation Is Associated with Enamel Hypomineralisation and Structural Abnormalities. Frontiers in physiology 19 28611678
2017 Tissue kallikrein-related peptidase 4 (KLK4), a novel biomarker in triple-negative breast cancer. Biological chemistry 19 28755528
2012 Genetic association of the KLK4 locus with risk of prostate cancer. PloS one 19 22970239
2008 Expression of the pstS gene of Streptomyces lividans is regulated by the carbon source and is partially independent of the PhoP regulator. BMC microbiology 18 19019225
2001 Streptococcus pneumoniae PstS production is phosphate responsive and enhanced during growth in the murine peritoneal cavity. Infection and immunity 18 11705934
2021 LncRNA RP11-465B22.8 triggers esophageal cancer progression by targeting miR-765/KLK4 axis. Cell death discovery 17 34561425
2020 Circular RNA Circ_0025033 Promotes the Evolvement of Ovarian Cancer Through the Regulation of miR-330-5p/KLK4 Axis. Cancer management and research 17 32425594
2014 Evolution of Klk4 and enamel maturation in eutherians. Biological chemistry 17 25153384
2003 B- and T-cell responses to the mycobacterium surface antigen PstS-1 in the respiratory tract and adjacent tissues. Role of adjuvants and routes of immunization. Vaccine 17 12531644
2019 Use of the high-affinity phosphate transporter gene, pstS, as an indicator for phosphorus stress in the marine diazotroph Crocosphaera watsonii (Chroococcales, Cyanobacteria). Journal of phycology 16 30929262
2005 Evaluation of the immunogenicity of pBudCE4.1 plasmids encoding mycolyl-transferase Ag85A and phosphate transport receptor PstS-3 from Mycobacterium tuberculosis. Vaccine 16 16169132
2019 Characterization of kallikrein-related peptidase 4 (KLK4) mRNA expression in tumor tissue of advanced high-grade serous ovarian cancer patients. PloS one 15 30811511
2015 Functional characterization of BC039389-GATM and KLK4-KRSP1 chimeric read-through transcripts which are up-regulated in renal cell cancer. BMC genomics 15 25888189
2013 Sequence, biophysical, and structural analyses of the PstS lipoprotein (BB0215) from Borrelia burgdorferi reveal a likely binding component of an ABC-type phosphate transporter. Protein science : a publication of the Protein Society 15 24318969
2019 Emergence of an Australian-like pstS-null vancomycin resistant Enterococcus faecium clone in Scotland. PloS one 14 31194809
2021 Potent allelopathy and non-PSTs, non-spirolides toxicity of the dinoflagellate Alexandrium leei to phytoplankton, finfish and zooplankton observed from laboratory bioassays. The Science of the total environment 13 33774286
2021 lncRNA IGF2-AS promotes the osteogenic differentiation of bone marrow mesenchymal stem cells by sponging miR-3,126-5p to upregulate KLK4. The journal of gene medicine 13 34101307
2020 Emergence of vancomycin-resistant Enterococcus faecium ST1421 lacking the pstS gene in Korea. European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology 13 32128641
2017 KLK4 silencing inhibits the growth of oral squamous cell carcinoma through Wnt/β-catenin signaling pathway. Cell biology international 13 28150891
2017 Fluoride Alters Klk4 Expression in Maturation Ameloblasts through Androgen and Progesterone Receptor Signaling. Frontiers in physiology 13 29249975
2020 Cell surface-expression of the phosphate-binding protein PstS: System development, characterization, and evaluation for phosphorus removal and recovery. Journal of environmental sciences (China) 11 32430116
2014 Evaluation of gamma interferon immune response elicited by the newly constructed PstS-1(285-374):CFP10 fusion protein to detect Mycobacterium tuberculosis infection. Clinical and vaccine immunology : CVI 11 24521785
2008 Stability of the pstS transcript of Escherichia coli. Archives of microbiology 11 18820899
2020 Role of PstS in the Pathogenesis of Acinetobacter baumannii Under Microaerobiosis and Normoxia. The Journal of infectious diseases 10 32324853
2015 Sublingual immunization with the phosphate-binding-protein (PstS) reduces oral colonization by Streptococcus mutans. Molecular oral microbiology 10 26462737
2019 Recombinant O-mannosylated protein production (PstS-1) from Mycobacterium tuberculosis in Pichia pastoris (Komagataella phaffii) as a tool to study tuberculosis infection. Microbial cell factories 9 30660186
2019 MicroRNA-378-3p/5p suppresses the migration and invasiveness of oral squamous carcinoma cells by inhibiting KLK4 expression. Biochemistry and cell biology = Biochimie et biologie cellulaire 9 31265790
2017 Activation of the ileal neuroendocrine tumor cell line P-STS by acetylcholine is amplified by histamine: role of H3R and H4R. Scientific reports 9 28465562
2014 Localization of DING proteins on PstS-containing outer-surface appendages of Pseudomonas aeruginosa. FEMS microbiology letters 9 24372739
2012 Significant alterations in the expression pattern of kallikrein-related peptidase genes KLK4, KLK5 and KLK14 after treatment of breast cancer cells with the chemotherapeutic agents epirubicin, docetaxel and methotrexate. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 9 23086576
2017 KLK4 Gene and Dental Decay: Replication in a South Brazilian Population. Caries research 8 28445870
2004 Engineering of Escherichia coli to improve the purification of periplasmic Fab' fragments: changing the pI of the chromosomally encoded PhoS/PstS protein. Protein expression and purification 8 15294288
2023 Deficiency of G protein-coupled receptor Gpr111/Adgrf2 causes enamel hypomineralization in mice by alteration of the expression of kallikrein-related peptidase 4 (Klk4) during pH cycling process. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 7 36929047
2020 MicroRNA-378-3p/5p represses proliferation and induces apoptosis of oral squamous carcinoma cells via targeting KLK4. Clinical and experimental pharmacology & physiology 7 31868942
2000 Evaluation of phosphate removal from water by immobilized phosphate-binding protein PstS. Journal of bioscience and bioengineering 7 16232935
2022 Mechanisms Underlying the Virulence Regulation of Vibrio alginolyticus ND-01 pstS and pstB with a Transcriptomic Analysis. Microorganisms 6 36363689
2017 Direct evidence that KLK4 is a hydroxyapatite-binding protein. Biochemical and biophysical research communications 6 29229389
2014 Expression, purification and crystallization of the phosphate-binding PstS protein from Pseudomonas aeruginosa. Acta crystallographica. Section F, Structural biology communications 6 25005086
2022 Novel KLK4 Mutations Cause Hypomaturation Amelogenesis Imperfecta. Journal of personalized medicine 5 35207639
2021 NaF reduces KLK4 expression by decreasing Foxo1/Runx2 expression in LS8 cells. Archives of oral biology 5 34781073
2017 Aberrant KLK4 gene promoter hypomethylation in pediatric hepatoblastomas. Oncology letters 5 28454262

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