Affinage

PCSK6

Proprotein convertase subtilisin/kexin type 6 · UniProt P29122

Length
969 aa
Mass
106.4 kDa
Annotated
2026-06-10
100 papers in source corpus 37 papers cited in narrative 37 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PCSK6 (PACE4/SPC4) is a calcium-dependent subtilisin-like serine endoprotease that matures secreted and membrane precursor proteins by cleaving at paired basic (R-X-X-R) motifs, with substrate selectivity overlapping but distinct from furin (PMID:8468318, PMID:8218226, PMID:10467177). Its biosynthesis requires unimolecular autocatalytic removal of the propeptide in the ER as a prerequisite for export, after which mature enzyme is secreted as a monomer and is not stored in regulated secretory granules (PMID:9032441, PMID:9738469); the CREC-family Ca2+-binding protein RCN-3 transiently associates with the proform and promotes its autoactivation and secretion (PMID:16433634). A C-terminal cysteine-rich domain tethers PCSK6 to the cell surface via TIMP-2 binding and heparan-sulfate interactions, positioning it to process substrates extracellularly and at the plasma membrane (PMID:9234799, PMID:16135528). Through this activity PCSK6 governs developmental axis formation by acting genetically upstream of Nodal/Pitx2/Lefty in left-right and anteroposterior patterning, processing Nodal at the cell surface in complex with Cripto and acting in paracrine fashion to maintain pluripotency and drive endoderm induction (PMID:10809672, PMID:18772886, PMID:21896659). It activates corin at R801 to drive pro-ANP processing, and its loss produces salt-sensitive hypertension in mice (PMID:26259032). In the vasculature and heart PCSK6 activates MT-MMPs including MMP14 to control smooth muscle contractility, migration and arterial remodeling, and acts as a hypoxic cardiomyocyte-secreted factor that activates fibroblast TGF-β/SMAD3 signaling to promote cardiac fibrosis (PMID:31893970, PMID:32100557, PMID:32325687). PCSK6 promotes tumor invasion by processing prostromelysin-3 and MT1/MT2-MMP to activate MMP-2 (PMID:9393739, PMID:16103082), and a DNA-methylation-sensitive alternatively spliced isoform (PACE4-altCT) is retained intracellularly, hyper-autoactivates, processes pro-GDF15, and drives prostate cancer (PMID:28993410). Additional validated substrates include prohepcidin, the insulin receptor B isoform, pro-von Willebrand factor, and the η-secretase MT5-MMP, whose activation by PCSK6 promotes amyloidogenic APP processing in Alzheimer's disease models (PMID:18664504, PMID:25527501, PMID:8218226, PMID:38216110). PCSK6 expression is transcriptionally controlled by E2F factors and Tbx5 (activating) and hASH-1 (repressing) (PMID:17825503, PMID:26744331, PMID:11736660).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1993 Medium

    Establishing PCSK6 as a subtilisin-family endoprotease that cleaves precursors at dibasic sites defined its core biochemical identity and substrate logic.

    Evidence cDNA cloning, sequence analysis, and cotransfection cleavage assays of pro-vWF with cleavage-site mutants

    PMID:8218226 PMID:8262218 PMID:8468318

    Open questions at the time
    • Physiological substrate repertoire not defined
    • No structural basis for substrate selectivity vs furin
  2. 1997 Medium

    Defining propeptide cleavage and secretory itinerary showed how PCSK6 is activated and where it acts, distinguishing it from regulated-pathway convertases.

    Evidence Pulse-chase biosynthesis, subcellular fractionation, and cell-surface/extracellular cleavage assays in transfected and furin-deficient cells

    PMID:9032441 PMID:9234799

    Open questions at the time
    • Mechanism of autocatalysis not yet established
    • Endogenous physiological substrates unproven
  3. 1998 High

    Demonstrating unimolecular autocatalytic propeptide removal in the ER as a prerequisite for export resolved the activation mechanism and oligomeric state.

    Evidence Site-directed mutagenesis of the autocatalytic site, sedimentation velocity, and chemical cross-linking in transfected fibroblasts

    PMID:9738469

    Open questions at the time
    • Chaperones/cofactors of folding and autoactivation not identified at this stage
  4. 1999 High

    Biochemical characterization established PCSK6 as a Ca2+-dependent protease inhibitable by alpha1-PDX yet distinct from furin in inhibitor and substrate profile, clarifying functional redundancy among convertases.

    Evidence In vitro/in vivo acyl-intermediate complex formation, Ca2+/inhibitor enzyme assays, furin-null cell complementation, and antisense knockdown in HepG2

    PMID:10050053 PMID:10215603 PMID:10467177

    Open questions at the time
    • Degree of in vivo redundancy with furin/PC7 tissue-specific
    • Non-redundant substrates not yet defined
  5. 2000 High

    Knockout and epistasis analysis placed PCSK6 genetically upstream of Nodal in axis formation, assigning it a developmental morphogen-processing role.

    Evidence Spc4-null mice, gene expression analysis, and chimeric embryo experiments showing situs ambiguus and craniofacial defects

    PMID:10809672

    Open questions at the time
    • Direct Nodal cleavage by PCSK6 not demonstrated in this study
    • Cell-of-origin for the activity unresolved
  6. 2002 Medium

    Linking PCSK6 overexpression to MMP processing and invasion implicated it in tumor progression through proteolytic activation of MMP zymogens.

    Evidence PACE4 transfection of keratinocytes/SCC cells with prostromelysin-3, MT2-MMP, MMP-2/-9 processing and invasion assays, plus antibody inhibition

    PMID:11917148 PMID:11960907 PMID:9393739

    Open questions at the time
    • Direct vs indirect MMP activation not fully separated
    • P4-arginine specificity rules tested only in vitro
  7. 2005 High

    Identifying the cysteine-rich domain as a TIMP-2-dependent cell-surface anchor explained how PCSK6 is positioned for pericellular substrate processing, and transgenic models confirmed MT-MMP activation drives invasion in vivo.

    Evidence CRD deletion, Co-IP/colocalization with TIMP-2, heparin displacement, TIMP-2-null reconstitution; keratinocyte-targeted transgenic mice with MT1/MT2-MMP processing and carcinogenesis

    PMID:16103082 PMID:16135528

    Open questions at the time
    • Quantitative contribution of TIMP-2 vs heparan-sulfate anchoring in vivo unresolved
  8. 2006 Medium

    RCN-3 was shown to chaperone the PCSK6 precursor and enhance its autoactivation/secretion, adding an ER cofactor to the maturation pathway.

    Evidence Substrate trapping, pulse-chase, Co-IP, and Ca2+-ionophore experiments in GH4C1 cells

    PMID:16433634

    Open questions at the time
    • RCN-3 requirement in vivo not tested
    • Single-lab Co-IP without reciprocal genetic validation
  9. 2008 High

    The Cripto-PACE4/furin complex and cell-surface Nodal processing mechanism explained how PCSK6 spatially restricts Nodal maturation, and paracrine assays extended this to pluripotency and endoderm induction.

    Evidence Co-IP, brefeldin A/density fractionation, antibody-uptake imaging; transgenic reporter live-imaging and conditional knockouts in embryos

    PMID:18772886 PMID:21896659

    Open questions at the time
    • Stoichiometry and structure of the Cripto-convertase-Nodal complex unknown
  10. 2008 High

    Defining preprohepcidin processing at the RRRRR59 site added an iron-homeostasis substrate to the PCSK6 repertoire, again within a redundant convertase group.

    Evidence Cell transfection in Huh-7/LoVo, cleavage-site mutagenesis, and in vitro peptide digestion

    PMID:18664504

    Open questions at the time
    • Relative in vivo contribution of PCSK6 vs furin/PC5/PC7 not established
  11. 2015 High

    Demonstrating that PCSK6 activates corin at R801, with Pcsk6-null mice showing salt-sensitive hypertension and human CORIN variants resistant to PCSK6, established a definitive physiological substrate and disease axis.

    Evidence siRNA, overexpression, purified-protein cleavage with R801A mutant, Pcsk6 knockout mice, and human variant testing

    PMID:26259032 PMID:29180304

    Open questions at the time
    • Whether corin activation occurs at the membrane or in soluble form physiologically partially open
    • Tissue-specific contribution to blood pressure regulation
  12. 2014 Medium

    Showing isoform-selective maturation of insulin receptor B revealed PCSK6 substrate discrimination distinct from furin and tied it to mitogenic signaling.

    Evidence Furin-deficient cell transfection with IRB/IRA processing analysis and pharmacological PACE4 inhibition

    PMID:25527501

    Open questions at the time
    • Physiological relevance of IRB-selective processing in vivo untested
  13. 2017 Medium

    Discovery of the methylation-sensitive PACE4-altCT splice isoform that is intracellularly retained, hyper-autoactivates, and processes pro-GDF15 provided a mechanism for PCSK6-driven prostate cancer.

    Evidence Splicing/methylation analysis, subcellular localization, and pro-GDF15 processing across cancer cell lines

    PMID:23126600 PMID:28993410

    Open questions at the time
    • In vivo tumor dependence on altCT isoform not demonstrated
    • Full altCT substrate set unknown
  14. 2020 High

    Vascular and cardiac studies established PCSK6 as a regulator of SMC contractility/migration via MMP14 activation and as a hypoxic cardiomyocyte-secreted driver of fibroblast TGF-β/SMAD3 signaling and cardiac fibrosis.

    Evidence In situ PLA for MMP2/MMP14 interaction, Pcsk6-/- carotid ligation and remodeling models, secretome analysis, and AAV9 cardiomyocyte overexpression

    PMID:31893970 PMID:32100557 PMID:32325687

    Open questions at the time
    • Direct protease substrate underlying TGF-β activation in fibrosis not pinpointed
    • Whether MMP14 activation is direct cleavage vs indirect
  15. 2024 High

    Identifying MT5-MMP as a PCSK6 substrate (cleaved at RRRNKR) linked PCSK6 to amyloidogenic APP processing and cognitive deficits in Alzheimer's disease models.

    Evidence Cleavage-motif mutagenesis, Co-IP, N2A cleavage assays, and AAV PCSK6 knockdown in APP23/PS45 mice with LTP and spatial memory readouts

    PMID:38216110

    Open questions at the time
    • Human AD relevance not established
    • Contribution relative to other MT5-MMP activators unknown
  16. 2023 Medium

    Non-canonical roles emerged: PCSK6 binds and promotes STAT1 phosphorylation to drive Th1 differentiation and colitis, and is an antigenic target in NSAID-associated membranous nephropathy.

    Evidence Co-IP with STAT1, Pcsk6-KO DSS colitis model, T-cell differentiation assays; laser-microdissection MS/MS and immunofluorescence of glomeruli

    PMID:37119877 PMID:37211384

    Open questions at the time
    • Whether STAT1 regulation requires protease activity untested
    • Mechanistic role of PCSK6 protease activity in nephropathy not tested
    • Single-lab findings

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PCSK6 substrate selectivity is structurally encoded and which substrates it processes non-redundantly in each tissue remain unresolved.
  • No structural model of substrate recognition in the corpus
  • Tissue-specific non-redundant substrate set undefined
  • Mechanism distinguishing protease-dependent vs protease-independent (e.g. STAT1) functions unknown

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:0008092 cytoskeletal protein binding 1
Localization
GO:0005576 extracellular region 3 GO:0005783 endoplasmic reticulum 3 GO:0005886 plasma membrane 3
Pathway
R-HSA-1643685 Disease 4 R-HSA-392499 Metabolism of proteins 4 R-HSA-1266738 Developmental Biology 3 R-HSA-1474244 Extracellular matrix organization 3 R-HSA-162582 Signal Transduction 3
Partners
CRIPTOMMP14MMP2RCN3STAT1TIMP2

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 PC6 (PCSK6) is a subtilisin-like serine endoprotease capable of cleaving precursor proteins at dibasic sites, with a catalytic domain closely related to furin, PC2, PC1/3, PC4, and PACE4, and contains a COOH-terminal Cys-rich region similar to PACE4. Transfection experiments with cleavage assays; cDNA cloning and sequence analysis Journal of biochemistry Medium 8468318
1993 PACE4 (PCSK6) processes pro-von Willebrand factor to its mature form at paired basic residues, with substrate specificity overlapping but not identical to furin; efficient cleavage requires both P4 arginine and P2 lysine, and PACE4 is not inhibited by alpha1-antitrypsin Pittsburgh mutant (unlike furin). Transient DNA cotransfection assay with pro-vWF substrate; inhibitor studies with alpha1-antitrypsin Pittsburgh mutant Biochemistry Medium 8218226
1993 PACE4 processes pro-von Willebrand factor with cleavage site selectivity similar to PC6A but different from furin. Recombinant vaccinia virus-based expression with vWF cleavage site mutants FEBS letters Medium 8262218
1995 PACE4 processes prosomatostatin to generate somatostatin-28 (S-28) and somatostatin-14 (S-14) in constitutive secreting LoVo cells, making it a candidate S-28 and S-14 convertase. Recombinant vaccinia virus coexpression of PACE4 with rat prosomatostatin; HPLC analysis of processed products FEBS letters Medium 7720860
1997 PACE4 biosynthesis involves intracellular cleavage of the propeptide (proPACE4 ~106 kDa to PACE4 ~97 kDa) before secretion; PACE4 is not stored in regulated secretory granules; PACE4 enzyme activity is distinctly sensitive to leupeptin inhibition and relatively insensitive to Ca2+ chelators and dithiothreitol, and is not inhibited by the alpha1-antitrypsin Portland variant that potently inhibits furin. Transfected neuroendocrine and fibroblast cell lines; pulse-chase biosynthesis; enzyme activity assays with various inhibitors The Biochemical journal Medium 9032441
1997 PACE4 can activate anthrax toxin protective antigen (PA) at the cell surface, recognizing the sequences RKKR and RAAR (and to a lesser extent KR); PACE4 is present at the exterior of cells and can activate substrates extracellularly. Furin-deficient CHO cells (FD11) transfected with PACE4; in vitro cleavage assays with iodinated PA and mutant substrates; cytotoxicity assays Infection and immunity Medium 9234799
1997 PACE4 overexpression in squamous cell carcinoma cells results in enhanced invasiveness and processing of prostromelysin-3 (MMP-11) into its active form, implicating PACE4 in tumor progression via MMP activation. PACE4 cDNA transfection in mouse SCC cells; invasion assays; prostromelysin-3 processing assays Cancer research Medium 9393739
1998 SPC4/PACE4 propeptide cleavage occurs mainly through a unimolecular autocatalytic process in the endoplasmic reticulum (ER); propeptide cleavage is a prerequisite for ER export; the precursor exists as both monomer and dimer, while mature SPC4 is only monomeric. Site-directed mutagenesis of autocatalytic site; sedimentation velocity analysis; chemical cross-linking; transfected fibroblast cells FEBS letters High 9738469
1999 PACE4 forms an SDS-stable acyl-intermediate complex (~180 kDa) with alpha1-antitrypsin Portland (alpha1-PDX) both in vivo and in vitro, demonstrating that alpha1-PDX inhibits PACE4. PACE4 is a Ca2+-dependent protease with optimal Ca2+ requirement of 2 mM, highest activity at weakly basic pH, and activity completely inhibited by EDTA and EGTA but not by leupeptin. In vivo and in vitro complex formation assays; immunological characterization of secreted PACE4; enzyme activity measurements with Ca2+ chelators and inhibitors Journal of biochemistry High 10467177
1999 PACE4 rescues processing of LDL receptor-related protein and pro-insulin receptor and pro-von Willebrand factor in furin-null RPE.40 cells; PACE4 activity in vitro is Ca2+-dependent and temperature-sensitive (22–37°C) unlike furin; PACE4 does not process Pseudomonas exotoxin A. Furin-deficient CHO cell complementation; in vitro endoprotease assays; Northern analysis The Biochemical journal Medium 10215603
1999 PACE4, furin, and PC8 are functionally redundant endogenous proalbumin convertases in HepG2 hepatoma cells, each contributing approximately 30% of proalbumin processing activity. Antisense RNA stable expression in HepG2 cells; coexpression studies; Northern blot; ribonuclease protection assay Journal of biochemistry Medium 10050053
2000 SPC4 (PCSK6) is genetically upstream of nodal, pitx2, lefty1, and lefty2 in L/R axis formation; SPC4 acts primarily in the foregut during A/P axis formation as shown by chimeric embryo analysis; SPC4-null embryos develop situs ambiguus and craniofacial defects. Genetic knockout mouse; gene expression analysis; chimeric embryo analysis; genetic interaction studies with nodal Genes & development High 10809672
2002 PACE4 overexpression converts non-tumorigenic keratinocytes to invasive malignant cells; processing of stromelysin-3 (MMP-11), MT2-MMP, MMP-2, and MMP-9 is enhanced by PACE4; inhibition of PACE4 with a specific antibody reduced invasion and MMP processing. Full-length PACE4 cDNA transfection of non-tumorigenic keratinocyte cell lines; in vitro and in vivo invasion assays; antibody inhibition; MMP processing assays Carcinogenesis Medium 11960907
2005 The cysteine-rich domain (CRD) of PACE4 (and PC5A) functions as a cell surface anchor and interacts with TIMP-2; CRD is essential for cell surface tethering and colocalizes/coimmunoprecipitates with full-length and C-terminal domain of TIMP-2; surface-bound PC5A/PACE4 can be displaced by heparin, suramin, heparinases, or excess TIMP-2. Confocal microscopy; coimmunoprecipitation; biochemical fractionation; heparin displacement; TIMP-2 null fibroblasts with reconstitution; CRD deletion analysis Molecular biology of the cell High 16135528
2005 PACE4 overexpression in transgenic mouse basal keratinocytes results in increased processing of MT1-MMP and MT2-MMP, leading to collagenase IV (MMP-2) activation, collagen type IV degradation, basement membrane disruption, and accelerated tumor invasion after chemical carcinogenesis. Transgenic mice with keratinocyte-targeted PACE4 expression; MT-MMP processing assays; collagenase activity assays; histological analysis; chemical carcinogenesis protocol Cancer research High 16103082
2006 Reticulocalbin-3 (RCN-3), a Ca2+-binding protein of the CREC family, transiently associates with the precursor form of PACE4 (proPACE4) but not with mature PACE4; this association occurs in the ER and involves the RXNR target sequences in RCN-3; RCN-3 coexpression increases autoactivation and secretion of PACE4. Alpha1-antitrypsin inhibitor-based substrate trapping in GH4C1 cells; protein sequence analysis; biosynthetic pulse-chase studies; co-immunoprecipitation; Ca2+ ionophore experiments The Biochemical journal Medium 16433634
2007 PACE4 inhibition in MDA-MB-231 breast cancer cells (via ppPACE4 prosegment or alpha1-PDX) increases MMP-9 activity, reduces TIMP-1 secretion, and enhances cell motility, migration, and collagen invasion; in contrast, furin inhibition decreased MMP-9 activity and reduced these functions, demonstrating opposing roles. Stable overexpression of PC inhibitors (alpha1-PDX and ppPACE4) in breast cancer cells; MMP activity assays; TIMP-1 ELISA; migration and invasion assays Cancer research Medium 17909005
2007 E2F1, E2F2, and E2F3 transcription factors upregulate PACE4 expression by binding to two E2F consensus sites (-117/-110 and -86/-79) in the 5'-flanking region of the PACE4 gene; mutation of these sites abolished PACE4 promoter response to E2F1. Promoter luciferase assays; EMSA (electrophoretic mobility-shift assay); site-directed mutagenesis; mRNA expression analysis in tumor vs. normal cells Gene Medium 17825503
2008 Cripto binds the proprotein convertases Furin and PACE4 and localizes Nodal processing at the cell surface; Cripto and uncleaved Nodal associate during secretion; a Cripto-interacting region in the Nodal propeptide potentiates the effect of proteolytic maturation on Nodal signaling; Nodal is exported to the cell surface before entering the TGN/endosomal system. Co-immunoprecipitation; brefeldin A treatment; density fractionation; antibody uptake experiments; GFP-Flotillin colocalization; coexpression studies The EMBO journal High 18772886
2008 PACE4, along with furin, PC5, and PC7, processes preprohepcidin at the RRRRR59DT site to generate mature hepcidin peptides; this processing was confirmed by site-directed mutagenesis of the cleavage site and in vitro digestion of a synthetic peptide mimicking the cleavage site. Cell transfection in Huh-7 and LoVo (PC-deficient) cells; site-directed mutagenesis; in vitro peptide digestion assays; furin inhibitor studies Gut High 18664504
2009 PACE4 is required for skeletal muscle differentiation in C2C12 cells; PACE4 shRNA suppresses myosin light chain (MLC) expression during myogenesis; this effect is rescued by recombinant mature IGF-II; PACE4 expression is induced by a PI3K-dependent positive feedback loop during differentiation. shRNA knockdown of PACE4 in C2C12 cells; MLC expression analysis; IGF-II rescue experiment; PI3K inhibitor (LY294002) treatment Journal of biochemistry Medium 19520771
2011 Furin and Pace4 are released by the extraembryonic microenvironment, cleave a membrane-bound reporter substrate in adjacent epiblast cells in a paracrine manner, and activate Nodal to maintain pluripotency; secreted Pace4 (but not Furin) stimulates endoderm induction. Transgenic reporter substrate live imaging; conditional knockout mouse embryos; paracrine activity assays in embryo culture Genes & development High 21896659
2012 PACE4 inhibition by the Multi-Leu peptide (LLLLRVKR) displays ~20-fold selectivity over furin and significantly reduces proliferation of DU145 and LNCaP prostate cancer cell lines, inducing G0/G1 cell cycle arrest; the peptide must enter cells to inhibit proliferation. Enzyme kinetic assays with recombinant PACE4 and furin; cell proliferation assays; cell cycle analysis; cell penetration studies Journal of medicinal chemistry Medium 23126600
2014 PACE4 selectively supports maturation of insulin receptor isoform B (IRB) at the cell surface when furin-dependent intracellular maturation is inefficient; PACE4 does not preferentially process IRA; selective pharmacological inhibition of PACE4 reduces IRA maturation and mitogenic signaling. Furin-deficient cell transfection; IRB/IRA isoform processing analysis; cell surface receptor assays; PACE4 inhibitor treatment The Journal of biological chemistry Medium 25527501
2015 PCSK6 cleaves and activates corin at the R801 site; PCSK6 siRNA knockdown inhibits corin activation; PCSK6 overexpression enhances corin activation; purified PCSK6 cleaves wild-type corin but not R801A mutant; Pcsk6-knockout mice develop salt-sensitive hypertension with undetectable corin activation and pro-ANP processing activity; CORIN variants associated with hypertension are defective in PCSK6-mediated activation. siRNA knockdown; overexpression in cultured cells; purified protein cleavage assay with site mutant (R801A); Pcsk6 knockout mice with physiological phenotyping; pro-ANP processing assay Nature medicine High 26259032
2015 PC7, Furin, and Pace4 jointly regulate E-cadherin processing during morula compaction and blastocyst inner cell mass formation; differential inhibition reveals all three PCs are active in overlapping but partially non-overlapping compartments (inner and outer cells). PC mutant mouse embryos; live imaging of transgenic reporter substrate; pharmacological inhibition with common inhibitor; E-cadherin processing analysis The Journal of cell biology Medium 26416966
2016 Tbx5 directly regulates Pcsk6 transcription in the posterior second heart field; this was validated by ChIP-qPCR and luciferase reporter assay; Pcsk6 is part of a Tbx5/Osr1/Pcsk6 gene network for atrial septation. ChIP-qPCR; luciferase reporter assay; RNA-seq; immunohistochemistry; human family genotyping Human molecular genetics Medium 26744331
2017 PACE4 pre-mRNA undergoes DNA methylation-sensitive alternative splicing of its terminal exon, generating an oncogenic C-terminally modified isoform (PACE4-altCT) strongly expressed in prostate cancer; PACE4-altCT displays enhanced autoactivating process, is retained intracellularly (not secreted), and dramatically increases processing of pro-GDF15 as its first identified substrate in prostate cancer. Alternative splicing analysis; DNA methylation studies; subcellular localization; pro-GDF15 processing assays; expression in multiple cancer cell lines Cancer research Medium 28993410
2017 Functional analysis reveals that corin lacking the transmembrane domain is activated by PCSK6 in conditioned medium and under cell-free conditions; cell membrane association is not required for PCSK6 to activate corin; soluble corin and PCSK6 are secreted via different intracellular pathways; heparan sulfate/chondroitin sulfate and heparinase/chondroitinase do not alter corin activation by PCSK6; corin pro-peptide domain is dispensable for PCSK6-mediated activation. Corin deletion mutant expression in HEK293 cells; cell-free cleavage assay; monensin blockade; immunostaining; glycosaminoglycan treatment and enzyme treatment The international journal of biochemistry & cell biology Medium 29180304
2020 PCSK6 cointeracts with MMP2 and MMP14 in smooth muscle cells (demonstrated by in situ proximity ligation assay); Pcsk6-/- mice show reduced MMP14 activation and decreased intimal hyperplasia after carotid ligation; PCSK6 overexpression increases PDGFBB-induced SMC migration; PCSK6 silencing downregulates contractile SMC markers and increases MMP2 expression. In situ proximity ligation assay for protein interaction; Pcsk6-/- mouse carotid ligation model; aortic ring SMC outgrowth assay; siRNA knockdown in human SMCs; PCSK6 overexpression migration assays; Affymetrix microarrays Circulation research High 31893970
2020 PCSK6 secreted from hypoxic cardiomyocytes activates TGF-β signaling and SMAD3 translocation in fibroblasts; cardiomyocyte-specific AAV9-mediated PCSK6 overexpression in mice increases collagen I and III expression, cardiac fibrosis, and decreases LV function after MI; PCSK6-depleted cardiomyocyte secretome reduces collagen expression in fibroblasts. Stable isotope labeling secretome analysis; siRNA knockdown; AAV9 cardiomyocyte-specific overexpression in mice; SMAD3 translocation assay; collagen expression analysis; left anterior descending coronary artery ligation model Circulation High 32100557
2024 PCSK6 cleaves and activates MT5-MMP (η-secretase) by recognizing the RRRNKR sequence in its N-terminal propeptide domain; mutation or knockout of this cleavage motif prevents PCSK6 from interacting with and cleaving MT5-MMP; PCSK6 knockdown reduces amyloidogenic APP processing (Aβ production) and ameliorates hippocampal LTP and spatial memory in AD model mice. Site-directed mutagenesis of MT5-MMP cleavage motif; Co-IP; N2A cell cleavage assays; AAV-mediated PCSK6 knockdown in APP23/PS45 transgenic mice; LTP electrophysiology; spatial memory testing Experimental neurology High 38216110
2023 PCSK6 is identified as a likely antigenic target in membranous nephropathy associated with NSAID use; IgG from affected patients binds to PCSK6 along the glomerular basement membrane, co-localizing with IgG deposits. Laser microdissection of glomeruli followed by mass spectrometry (MS/MS); protein G immunoprecipitation; immunofluorescence; confocal microscopy; western blot of tissue eluates Kidney international Medium 37119877
2001 hASH-1 (and MASH-1) transcription factors downregulate PACE4 gene expression by binding to an E-box cluster (E4-E9) in the 5'-flanking region; this effect is specific to PACE4 and does not affect furin, PC5/6, or PC7/8; other neural bHLH factors tested did not affect PACE4 expression. Luciferase reporter assay; EMSA with hASH-1 binding to E-box cluster; overexpression of hASH-1/MASH-1 in neuroblastoma cell lines; mRNA expression analysis The Biochemical journal Medium 11736660
2002 The P4 arginine residue is crucial for PACE4 inhibition by alpha1-antitrypsin variants; an AVRR variant inhibited furin and PC6 but not PACE4; the RVRR variant inhibited both PACE4 and furin but required 600-fold higher concentration to inhibit PC6; these variants form SDS-stable complexes with their respective targets. In vitro enzyme inhibition assays with fluorogenic substrate; SDS-stable complex formation assays ex vivo; inhibition of pro-complement C3 processing Protein engineering Medium 11917148
2020 Pcsk6-/- mice display increased flow-mediated outward arterial remodeling; absence of PCSK6 increases lumen circumference and reduces medial contractility (decreased active tension) and SMC contractile markers (SMA, MYH11, LMOD1) in response to increased blood flow. Pcsk6-/- mouse carotid ligation model; ultrasound biomicroscopy; wire myography; immunohistochemistry; transmission electron microscopy Cells Medium 32325687
2023 PCSK6 binds to STAT1 and promotes STAT1 phosphorylation, thereby regulating Th1 cell differentiation; PCSK6 overexpression promotes Th0-to-Th1 conversion, while PCSK6 silencing suppresses it; PCSK6 knockdown in Pcsk6-KO mice ameliorates DSS-induced colitis with decreased Th1 and M1 macrophage proportions. Co-IP (COPI assay) demonstrating PCSK6-STAT1 binding; Pcsk6 KO mouse DSS colitis model; STAT1 inhibitor studies; in vitro T cell differentiation assays Aging Medium 37211384

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1993 Identification and functional expression of a new member of the mammalian Kex2-like processing endoprotease family: its striking structural similarity to PACE4. Journal of biochemistry 201 8468318
2000 SPC4/PACE4 regulates a TGFbeta signaling network during axis formation. Genes & development 136 10809672
2015 PCSK6-mediated corin activation is essential for normal blood pressure. Nature medicine 109 26259032
1997 Comparative analysis of expression of the proprotein convertases furin, PACE4, PC1 and PC2 in human lung tumours. British journal of cancer 108 9166946
2010 PCSK6 is associated with handedness in individuals with dyslexia. Human molecular genetics 94 21051773
1996 SPC4, SPC6, and the novel protease SPC7 are coexpressed with bone morphogenetic proteins at distinct sites during embryogenesis. The Journal of cell biology 85 8698813
2013 Profiling of atherosclerotic lesions by gene and tissue microarrays reveals PCSK6 as a novel protease in unstable carotid atherosclerosis. Arteriosclerosis, thrombosis, and vascular biology 78 23908247
1995 Distinct mRNA expression of the highly homologous convertases PC5 and PACE4 in the rat brain and pituitary. The Journal of neuroscience : the official journal of the Society for Neuroscience 78 7891135
2005 The cysteine-rich domain of the secreted proprotein convertases PC5A and PACE4 functions as a cell surface anchor and interacts with tissue inhibitors of metalloproteinases. Molecular biology of the cell 75 16135528
2008 Cripto recruits Furin and PACE4 and controls Nodal trafficking during proteolytic maturation. The EMBO journal 69 18772886
2000 The proprotein convertases furin and PACE4 play a significant role in tumor progression. Molecular carcinogenesis 69 10900462
1995 Comparative proteolytic processing of rat prosomatostatin by the convertases PC1, PC2, furin, PACE4 and PC5 in constitutive and regulated secretory pathways. FEBS letters 65 7720860
2020 Secretome Analysis of Cardiomyocytes Identifies PCSK6 (Proprotein Convertase Subtilisin/Kexin Type 6) as a Novel Player in Cardiac Remodeling After Myocardial Infarction. Circulation 64 32100557
2011 Molecular Validation of PACE4 as a Target in Prostate Cancer. Translational oncology 59 21633671
1993 PACE4 is a member of the mammalian propeptidase family that has overlapping but not identical substrate specificity to PACE. Biochemistry 59 8218226
1997 PACE4: a subtilisin-like endoprotease with unique properties. The Biochemical journal 57 9032441
2007 Opposing function of the proprotein convertases furin and PACE4 on breast cancer cells' malignant phenotypes: role of tissue inhibitors of metalloproteinase-1. Cancer research 55 17909005
1997 Expression of PACE4 in chemically induced carcinomas is associated with spindle cell tumor conversion and increased invasive ability. Cancer research 46 9393739
2020 PCSK6 Is a Key Protease in the Control of Smooth Muscle Cell Function in Vascular Remodeling. Circulation research 45 31893970
2005 PACE4 expression in mouse basal keratinocytes results in basement membrane disruption and acceleration of tumor progression. Cancer research 44 16103082
2002 Malignant conversion of non-tumorigenic murine skin keratinocytes overexpressing PACE4. Carcinogenesis 44 11960907
1999 Inactivation of proprotein convertase, PACE4, by alpha1-antitrypsin Portland (alpha1-PDX), a blocker of proteolytic activation of bone morphogenetic protein during embryogenesis: evidence that PACE4 is able to form an SDS-stable acyl intermediate with alpha1-PDX. Journal of biochemistry 44 10467177
1994 PACE4: a subtilisin-like endoprotease prevalent in the anterior pituitary and regulated by thyroid status. Endocrinology 44 8070361
2012 A role for PACE4 in osteoarthritis pain: evidence from human genetic association and null mutant phenotype. Annals of the rheumatic diseases 43 22440827
2012 The Multi-Leu peptide inhibitor discriminates between PACE4 and furin and exhibits antiproliferative effects on prostate cancer cells. Journal of medicinal chemistry 43 23126600
2006 A proteomic approach reveals transient association of reticulocalbin-3, a novel member of the CREC family, with the precursor of subtilisin-like proprotein convertase, PACE4. The Biochemical journal 42 16433634
1997 A role for PACE4 in the proteolytic activation of anthrax toxin protective antigen. Infection and immunity 42 9234799
2012 Identification and functional validation of CDH11, PCSK6 and SH3GL3 as novel glioma invasion-associated candidate genes. Neuropathology and applied neurobiology 40 21722156
1993 Proprotein processing activity and cleavage site selectivity of the Kex2-like endoprotease PACE4. FEBS letters 40 8262218
2019 Aerobic degradation of 3,3',4,4'-tetrachlorobiphenyl by a resuscitated strain Castellaniella sp. SPC4: Kinetics model and pathway for biodegradation. The Science of the total environment 38 31726573
1997 Endoprotease activities other than furin and PACE4 with a role in processing of HIV-I gp160 glycoproteins in CHO-K1 cells. The Journal of biological chemistry 38 8995442
1997 The developmental expression in the rat CNS and peripheral tissues of proteases PC5 and PACE4 mRNAs: comparison with other proprotein processing enzymes. Developmental biology 38 9013936
2023 Proprotein convertase subtilisin/kexin type 6 (PCSK6) is a likely antigenic target in membranous nephropathy and nonsteroidal anti-inflammatory drug use. Kidney international 36 37119877
2017 PACE4 Undergoes an Oncogenic Alternative Splicing Switch in Cancer. Cancer research 36 28993410
2011 The microenvironment patterns the pluripotent mouse epiblast through paracrine Furin and Pace4 proteolytic activities. Genes & development 36 21896659
1994 Identification of novel cDNAs encoding human kexin-like protease, PACE4 isoforms. Biochemical and biophysical research communications 36 8179631
2023 PCSK6 and Survival in Idiopathic Pulmonary Fibrosis. American journal of respiratory and critical care medicine 35 36780644
2015 PACE4 inhibitors and their peptidomimetic analogs block prostate cancer tumor progression through quiescence induction, increased apoptosis and impaired neovascularisation. Oncotarget 32 25682874
1997 Genomic organization and alternative splicing of human PACE4 (SPC4), kexin-like processing endoprotease. Journal of biochemistry 32 9378725
2022 AKAP12 ameliorates liver injury via targeting PI3K/AKT/PCSK6 pathway. Redox biology 31 35576690
1999 Subtilisin-like proprotein convertases, PACE4 and PC8, as well as furin, are endogenous proalbumin convertases in HepG2 cells. Journal of biochemistry 29 10050053
1998 Biosynthetic processing and quaternary interactions of proprotein convertase SPC4 (PACE4). FEBS letters 29 9738469
2016 Gene network and familial analyses uncover a gene network involving Tbx5/Osr1/Pcsk6 interaction in the second heart field for atrial septation. Human molecular genetics 28 26744331
2014 Implications of Proprotein Convertases in Ovarian Cancer Cell Proliferation and Tumor Progression: Insights for PACE4 as a Therapeutic Target. Translational oncology 27 24818756
2008 Regulation of prohepcidin processing and activity by the subtilisin-like proprotein convertases Furin, PC5, PACE4 and PC7. Gut 27 18664504
2014 miR-124 exhibits antiproliferative and antiaggressive effects on prostate cancer cells through PACE4 pathway. The Prostate 26 24913567
1997 A novel human PACE4 isoform, PACE4E is an active processing protease containing a hydrophobic cluster at the carboxy terminus. Journal of biochemistry 26 9192737
1996 Functional analysis of human PACE4-A and PACE4-C isoforms: identification of a new PACE4-CS isoform. FEBS letters 25 8906861
2002 Development of selectivity of alpha1-antitrypsin variant by mutagenesis in its reactive site loop against proprotein convertase. A crucial role of the P4 arginine in PACE4 inhibition. Protein engineering 24 11917148
2014 The paired basic amino acid-cleaving enzyme 4 (PACE4) is involved in the maturation of insulin receptor isoform B: an opportunity to reduce the specific insulin receptor-dependent effects of insulin-like growth factor 2 (IGF2). The Journal of biological chemistry 21 25527501
1999 Endoprotease PACE4 is Ca2+-dependent and temperature-sensitive and can partly rescue the phenotype of a furin-deficient cell strain. The Biochemical journal 21 10215603
2021 Up-regulation of PCSK6 by lipid oxidation products: A possible role in atherosclerosis. Biochimie 20 33359561
2021 Up-regulation of microRNA-135 or silencing of PCSK6 attenuates inflammatory response in preeclampsia by restricting NLRP3 inflammasome. Molecular medicine (Cambridge, Mass.) 20 34301174
2014 Inhibition of PCSK6 may play a protective role in the development of rheumatoid arthritis. The Journal of rheumatology 20 25433529
2015 PC7 and the related proteases Furin and Pace4 regulate E-cadherin function during blastocyst formation. The Journal of cell biology 19 26416966
2009 Subtilisin-like proprotein convertase PACE4 is required for skeletal muscle differentiation. Journal of biochemistry 19 19520771
2000 Highly regulated expression of subtilisin-like proprotein convertase PACE4 (SPC4) during dentinogenesis. Biochemical and biophysical research communications 18 10833428
2016 The PCSK6 gene is associated with handedness, the autism spectrum, and magical ideation in a non-clinical population. Neuropsychologia 17 26921480
1994 The tissue distribution of mRNAs for the PACE4 isoforms, kexin-like processing protease: PACE4C and PACE4D mRNAs are major transcripts among PACE4 isoforms. Biochemical and biophysical research communications 17 8060295
2023 PCSK6 attenuates cardiac dysfunction in doxorubicin-induced cardiotoxicity by regulating autophagy. Free radical biology & medicine 16 37061139
2014 Estrogen stimuli promote osteoblastic differentiation via the subtilisin-like proprotein convertase PACE4 in MC3T3-E1 cells. Journal of bone and mineral metabolism 16 24557631
2014 PACE4 regulates proliferation, migration and invasion in human breast cancer MDA-MB-231 cells. Molecular medicine reports 16 25333574
2007 Transcriptional regulation of subtilisin-like proprotein convertase PACE4 by E2F: possible role of E2F-mediated upregulation of PACE4 in tumor progression. Gene 16 17825503
2007 Regulation of Pcsk6 expression during the preantral to antral follicle transition in mice: opposing roles of FSH and oocytes. Biology of reproduction 16 17914070
1994 Correlation of proteolytic cleavage of F protein precursors in paramyxoviruses with expression of the fur, PACE4 and PC6 genes in mammalian cells. The Journal of general virology 16 7931173
2017 PACE4 is an important driver of ZR-75-1 estrogen receptor-positive breast cancer proliferation and tumor progression. European journal of cell biology 15 28347547
2017 Functional analysis of corin protein domains required for PCSK6-mediated activation. The international journal of biochemistry & cell biology 15 29180304
2014 PCSK6 regulated by LH inhibits the apoptosis of human granulosa cells via activin A and TGFβ2. The Journal of endocrinology 15 24860148
2001 Proprotein convertase PACE4 is down-regulated by the basic helix-loop-helix transcription factor hASH-1 and MASH-1. The Biochemical journal 15 11736660
1999 Subtilisin-like proprotein convertase PACE4 (SPC4) is a candidate processing enzyme of bone morphogenetic proteins during tooth formation. Developmental dynamics : an official publication of the American Association of Anatomists 15 10633867
2022 Pcsk6 Deficiency Promotes Cardiomyocyte Senescence by Modulating Ddit3-Mediated ER Stress. Genes 14 35456517
2016 Novel Insights into Structure-Activity Relationships of N-Terminally Modified PACE4 Inhibitors. ChemMedChem 13 26751825
2014 PACE4-based molecular targeting of prostate cancer using an engineered ⁶⁴Cu-radiolabeled peptide inhibitor. Neoplasia (New York, N.Y.) 13 25220591
2015 PACE4 regulates apoptosis in human prostate cancer cells via endoplasmic reticulum stress and mitochondrial signaling pathways. Drug design, development and therapy 11 26604689
2017 Positional Scanning Identifies the Molecular Determinants of a High Affinity Multi-Leucine Inhibitor for Furin and PACE4. Journal of medicinal chemistry 10 28287731
2007 Engineering of alpha1-antitrypsin variants selective for subtilisin-like proprotein convertases PACE4 and PC6: importance of the P2' residue in stable complex formation of the serpin with proprotein convertase. Protein engineering, design & selection : PEDS 10 17351018
2003 The expression of proprotein convertase PACE4 is highly regulated by Hash-2 in placenta: possible role of placenta-specific basic helix-loop-helix transcription factor, human achaete-scute homologue-2. Journal of biochemistry 10 14561729
2022 Identification of Genes Associated with Liver Metastasis in Pancreatic Cancer Reveals PCSK6 as a Crucial Mediator. Cancers 9 36612240
2019 Serum PCSK6 and corin levels are not associated with cardiovascular outcomes in patients undergoing coronary angiography. PloS one 9 31825978
2008 Inhibition and transcriptional silencing of a subtilisin-like proprotein convertase, PACE4/SPC4, reduces the branching morphogenesis of and AQP5 expression in rat embryonic submandibular gland. Developmental biology 9 19013448
2023 Circ_0002984 promotes proliferation, migration and inflammatory cytokine secretion and inhibits apoptosis of rheumatoid arthritis fibroblast-like synoviocytes by inducing PCSK6 through miR-543. Journal of orthopaedic surgery and research 8 37149637
2020 Paired Basic Amino Acid-cleaving Enzyme 4 (PCSK6): An Emerging New Target Molecule in Human Melanoma. Acta dermato-venereologica 8 32449780
2019 Enhanced anti-tumor activity of the Multi-Leu peptide PACE4 inhibitor transformed into an albumin-bound tumor-targeting prodrug. Scientific reports 8 30765725
2023 PCSK6 mediates Th1 differentiation and promotes chronic colitis progression and mucosal barrier injury via STAT1. Aging 7 37211384
2020 Lack of PCSK6 Increases Flow-Mediated Outward Arterial Remodeling in Mice. Cells 7 32325687
2017 Macrocyclization of a potent PACE4 inhibitor: Benefits and limitations. European journal of cell biology 7 28483279
2014 Enhanced aggressiveness of benzopyrene-induced squamous carcinomas in transgenic mice overexpressing the proprotein convertase PACE4 (PCSK6). Molecular carcinogenesis 7 24845697
2019 Structural Asymmetry in the Frontal and Temporal Lobes Is Associated with PCSK6 VNTR Polymorphism. Molecular neurobiology 6 31115778
2018 Evaluation of PACE4 isoforms as biomarkers in thyroid cancer. Journal of otolaryngology - head & neck surgery = Le Journal d'oto-rhino-laryngologie et de chirurgie cervico-faciale 6 30340539
2023 Bone Mesenchymal Stem Cell-Derived Small Extracellular Vesicles Ameliorated Lipopolysaccharide-Induced Lung Injury Via the miR-21-5p/PCSK6 Pathway. Journal of immunology research 5 37937296
2022 PACE4-altCT isoform of proprotein convertase PACE4 as tissue and plasmatic biomarker for prostate cancer. Scientific reports 5 35410344
2020 Aberrant corin and PCSK6 in placentas of the maternal hyperinsulinemia IUGR rat model. Pregnancy hypertension 5 32442927
2016 The handedness-associated PCSK6 locus spans an intronic promoter regulating novel transcripts. Human molecular genetics 5 26908617
2015 Multi-Leu PACE4 Inhibitor Retention within Cells Is PACE4 Dependent and a Prerequisite for Antiproliferative Activity. BioMed research international 5 26114115
2024 PCSK6 exacerbates Alzheimer's disease pathogenesis by promoting MT5-MMP maturation. Experimental neurology 4 38216110
2023 Enhancing the Drug-Like Profile of a Potent Peptide PACE4 Inhibitor by the Formation of a Host-Guest Inclusion Complex with β-Cyclodextrin. Molecular pharmaceutics 3 37555521
2020 Upregulation of PACE4 in prostate cancer is not dependent on E2F transcription factors. Canadian journal of physiology and pharmacology 3 32119574
2018 Improving the Selectivity of PACE4 Inhibitors through Modifications of the P1 Residue. Journal of medicinal chemistry 3 30501188
2016 PACE4 regulates apoptosis in human pancreatic cancer Panc‑1 cells via the mitochondrial signaling pathway. Molecular medicine reports 3 27779720
2007 Temporospatially regulated expression of subtilisin-like proprotein convertase PACE4 (SPC4) during development of the rat submandibular gland. Developmental dynamics : an official publication of the American Association of Anatomists 3 17083113

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