Affinage

PCSK5

Proprotein convertase subtilisin/kexin type 5 · UniProt Q92824

Length
1860 aa
Mass
206.9 kDa
Annotated
2026-06-10
100 papers in source corpus 30 papers cited in narrative 29 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

PCSK5 (PC5/6) is a subtilisin/kexin-like proprotein convertase that activates a broad set of secreted precursors by endoproteolytic cleavage at multibasic motifs, with a strong active-site preference for polybasic (poly-Arg) sequences (PMID:8341687, PMID:17012622). It is expressed as two alternatively sorted isoforms—soluble PC5/6A, which is routed to dense-core regulated secretory granules through a C-terminal alpha-helical sorting signal in its unique 38-residue tail, and membrane-bound PC5/6B, which is retained in the Golgi (PMID:8947550, PMID:17645548); PC5/6A acts in early compartments of the regulated secretory pathway and is not released with its substrates (PMID:10408612). Its catalytic activity depends on the active-site serine and on correct folding of the P domain, where the C470R mutation disrupts a disulfide bond, blocks ER export, and abolishes convertase function (PMID:8620001, PMID:18378898, PMID:18519639). Through this activity PCSK5 governs vertebrate developmental patterning, principally by cleaving and activating the TGF-beta superfamily ligand GDF11 (with selectivity conferred by the P1' Asn of the RSRR↓N motif), as well as BMP-4; epiblast-specific deletion produces GDF11-related anteroposterior patterning, vertebral, and kidney-agenesis phenotypes (PMID:18378898, PMID:18519639, PMID:9707432). PCSK5 also processes prorenin, proVEGF-C, PCSK9, pro-TGF-beta, osteopontin, pro-neurotensin, pro-CCK, prohepcidin, and inhibin subunits, linking it to cardiovascular signaling, lipid metabolism, bone mineralization, neuroendocrine peptide production, iron homeostasis, and reproduction (PMID:8901832, PMID:12782675, PMID:16912035, PMID:38972101, PMID:29126984, PMID:9738000, PMID:16266771, PMID:18664504, PMID:21408162). In the vasculature it activates alphav integrin to drive smooth-muscle adhesion, migration, and FAK/Akt signaling (PMID:14970114), and it cleaves alpha-dystroglycan and is required for embryo implantation (PMID:26077903, PMID:15601911). PCSK5 additionally activates the hemagglutinin of virulent influenza viruses (PMID:8057485) and is protective against intestinal tumorigenesis (PMID:19737405).

Mechanistic history

Synthesis pass · year-by-year structured walk · 23 steps
  1. 1993 Medium

    Establishing PCSK5 as a distinct subtilisin/kexin-like convertase defined a new candidate proteolytic activator of secretory precursors and placed it within the PACE4-related branch of the family.

    Evidence RT-PCR cloning, cDNA sequencing, Northern blot and in situ hybridization across tissues

    PMID:8341687

    Open questions at the time
    • No substrate identified at cloning stage
    • ACTH/cAMP regulation shown only in Y1 cells
  2. 1996 High

    Discovery of two isoforms with distinct sorting (soluble PC5/6A to dense-core granules, membrane-bound PC5/6B to Golgi) revealed that PCSK5 can act in both regulated and constitutive secretory compartments.

    Evidence Stable AtT-20 transfection, deletion mutagenesis, immunofluorescence, immunogold EM in pancreatic cells

    PMID:8947550

    Open questions at the time
    • Functional substrates of each isoform not yet mapped
    • Molecular sorting receptor for PC5/6A not identified
  3. 1996 High

    Demonstrating that PC5 cleaves RPTPmu only when its active-site serine is intact established the catalytic, sequence-specific nature of PCSK5 proteolysis and linked it to endothelial confluence.

    Evidence COS cotransfection, active-site Ser-to-Ala mutagenesis, immunoblot, RNA blot in HUVECs

    PMID:8620001

    Open questions at the time
    • Physiological consequence of RPTPmu cleavage not defined
  4. 1994 High

    Showing PC6 restores influenza HA cleavage in furin-deficient cells established PCSK5 as a furin-like activator of viral fusion proteins relevant to pathogenicity.

    Evidence Vaccinia expression in LoVo cells, viral replication assay, mutant HA panel

    PMID:8057485

    Open questions at the time
    • Relative contribution of PC5 vs furin in natural infection unresolved
  5. 1996 Medium

    Cell-based activation of prorenin and a candidate role in HIV gp160 processing extended PCSK5 substrate range toward blood-pressure regulation and viral envelope maturation.

    Evidence Cotransfection in GH4C1 cells with prorenin site mutagenesis and IHC; expression inference in CD4+ T cells

    PMID:8755538 PMID:8901832

    Open questions at the time
    • gp160 cleavage by PC6 inferred from expression only, no direct cleavage assay
    • Prorenin activation shown in cell lines, not in vivo kidney
  6. 1998 High

    Demonstrating PC6B-mediated BMP-4 activation in vitro and phenocopy by alpha1-PDX in embryos gave the first in vivo evidence that PCSK5 contributes to morphogen activation during vertebrate development.

    Evidence In vitro digestion, Xenopus oocyte translation, alpha1-PDX misexpression and BMP epistasis

    PMID:9707432

    Open questions at the time
    • alpha1-PDX does not distinguish furin from PC6
    • Endogenous convertase identity at each site unresolved
  7. 1995 Medium

    The inability of PC5 to process prosomatostatin established that PCSK5 has a restricted substrate repertoire rather than indiscriminate multibasic cleavage.

    Evidence Vaccinia coexpression in LoVo and AtT-20 cells, HPLC product analysis

    PMID:7720860

    Open questions at the time
    • Structural basis of substrate exclusion not defined
  8. 1998 High

    Localization of PC5/6A to regulated secretory granules where it processes pro-neurotensin/neuromedin N established its role as a bona fide prohormone convertase distinct from PC1/PC2.

    Evidence Stable PC12 transfection, metabolic labeling, fractionation, HPLC of products

    PMID:9738000

    Open questions at the time
    • In vivo requirement for neurotensin processing not tested
  9. 1999 Medium

    Mapping PC5/6A to neuronal Golgi and perikaryal vesicles but not axon terminals refined the model that PCSK5 acts in early secretory compartments and is not co-released with peptides.

    Evidence Immunohistochemistry with Golgi, synaptic, and glial markers in rat brain

    PMID:10408612

    Open questions at the time
    • Single-marker dynamin-1 negative used to infer terminal exclusion
  10. 2001 Medium

    Identifying PC5 as a pro-CCK convertase in cells lacking PC1/PC2 showed PCSK5 generates distinct CCK products, broadening its neuroendocrine processing role.

    Evidence Stable transfection of GT1-7/SK-N cells, RIA, carboxypeptidase B treatment, gel filtration

    PMID:11457520

    Open questions at the time
    • Endogenous contribution to CCK biosynthesis not isolated
  11. 2004 High

    Loss-of-function in vascular smooth muscle linked PCSK5-mediated alphav integrin activation to adhesion, migration, and FAK/Akt signaling, defining a vascular signaling axis.

    Evidence Antisense knockdown and dec-CMK inhibition, adhesion/migration assays, FAK/Akt blots, plaque IHC; in vivo balloon injury

    PMID:12649739 PMID:14970114

    Open questions at the time
    • dec-CMK not PC5-selective
    • Direct cleavage of alphav not reconstituted in vitro
  12. 2003 High

    Demonstrating proVEGF-C cleavage by PC5 and others, with functional angio/lymphangiogenesis from mature ligand, connected PCSK5 to vascular growth-factor activation.

    Evidence LoVo cotransfection, fluorogenic peptide assay, cleavage-site mutagenesis, nude mouse assay

    PMID:12782675

    Open questions at the time
    • Redundancy with furin/PC7 leaves in vivo PC5 contribution unclear
  13. 2006 High

    Establishing that furin/PC5/6A cleave PCSK9 at RFHR218 and that hypercholesterolemia mutations block this cleavage linked PCSK5 activity to LDL-receptor regulation.

    Evidence Cell processing assays, PCSK9 site mutagenesis, human plasma analysis

    PMID:16912035

    Open questions at the time
    • Quantitative role of PC5 vs furin in vivo plasma PCSK9 processing not separated
  14. 2008 High

    Identifying GDF11 as a PCSK5 substrate with P1'-Asn selectivity, plus epiblast-specific knockout phenotypes and a catalytically inactivating C470R mutation, established PCSK5 as a key activator in anteroposterior patterning and kidney development.

    Evidence In vitro cleavage with substrate mutagenesis, conditional knockout, ENU mutagenesis, ER export assay

    PMID:18378898 PMID:18519639

    Open questions at the time
    • GDF11-independent knockout phenotypes have undefined substrates
  15. 2008 Medium

    Showing prohepcidin processing by furin/PACE4/PC5/PC7 connected PCSK5 to iron homeostasis through generation of active hepcidin.

    Evidence LoVo rescue, fluorogenic peptide assay, cleavage-site mutagenesis

    PMID:18664504

    Open questions at the time
    • Redundancy obscures in vivo PC5 contribution
    • No knockout validation of hepcidin defect
  16. 2009 High

    Site-resolved analysis of pro-BMP4 cleavage showed furin and PC6 act redundantly on S1/S2 in oocytes but that an additional S1-specific convertase operates in embryos, refining the developmental processing model.

    Evidence Xenopus oocyte/embryo antisense knockdown, alpha1-PDX and engineered variants

    PMID:19651771

    Open questions at the time
    • Identity of the embryonic S1-site convertase unresolved
  17. 2009 Medium

    Enterocyte-specific Pcsk5 knockout increasing intestinal tumors on the ApcMin background, with downregulation in human tumors, established a tumor-protective role.

    Evidence Conditional knockout in ApcMin mice, tumor counts, survival, human expression analysis

    PMID:19737405

    Open questions at the time
    • Substrate mediating tumor protection not identified
  18. 2011 Medium

    Demonstrating inhibin subunit maturation by PC5/6 and activin-driven PCSK5 induction linked the convertase to follicular development.

    Evidence LoVo overexpression, dec-CMK inhibition in granulosa cells, qRT-PCR, Western blot

    PMID:21408162

    Open questions at the time
    • No in vivo ovarian knockout validation
    • Inhibitor not PC5-selective
  19. 2004 High

    Showing PC6 induction at the implantation site and complete block of implantation upon uterine knockdown established PCSK5 as essential for endometrial receptivity, later mechanistically tied to alpha-dystroglycan cleavage.

    Evidence Uterine morpholino knockdown in vivo, IHC across mouse/primate; in vitro peptide cleavage, siRNA, substrate-site mutagenesis, blastocyst adhesion assay

    PMID:15601911 PMID:26077903

    Open questions at the time
    • Full set of implantation substrates beyond alpha-DG not enumerated
  20. 2017 High

    Identifying osteopontin as a substrate with MS-mapped sites and reduced bone mineralization in knockout embryos, plus a stage-specific cranio-cardiac mesoderm requirement, broadened PCSK5 roles into bone and heart development.

    Evidence In silico prediction, cotransfection, cell-free assay, mass spectrometry, micro-CT and Cre-conditional knockouts, MRI

    PMID:28446132 PMID:29126984

    Open questions at the time
    • Cardiac substrate(s) in cranio-cardiac mesoderm not identified
    • OPN-processing consequence for mineralization mechanism not fully defined
  21. 2006 Medium

    Defining the polybasic active-site preference and potent nona-Arg inhibitors provided the biochemical basis for PCSK5 substrate selectivity and pharmacological targeting.

    Evidence Positional-scanning combinatorial peptide library screening, Ki kinetic assays

    PMID:17012622

    Open questions at the time
    • Inhibitors not selective over PC7
  22. 2024 Medium

    Demonstrating direct PCSK5 binding and cleavage of pro-TGF-beta driving SMAD2/3 and ECM responses, disruptable by leflunomide, implicated PCSK5 in adventitial fibroblast signaling and vascular inflammation.

    Evidence Co-IP, fibroblast overexpression, SMAD2/3 blots, leflunomide inhibition, patient tissue IHC

    PMID:38972101

    Open questions at the time
    • Single Co-IP without reciprocal validation
    • In vivo requirement not tested
  23. 2025 Medium

    Characterizing the M452I allele as a hypomorph with reduced GDF11 maturation and defects in transport, 3D organization, and xenograft growth refined genotype-function relationships for PCSK5 catalytic capacity.

    Evidence In-cell GDF11 maturation assay, null-background allelic reconstitution, 3D matrigel and intraductal xenograft assays (preprint)

    PMID:40093128

    Open questions at the time
    • Preprint, not yet peer-reviewed
    • Clinical/genetic disease association not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • The full in vivo substrate hierarchy of PCSK5 versus furin and PACE4 at shared multibasic sites, and the identity of substrates underlying its GDF11-independent developmental and tumor-protective roles, remain unresolved.
  • Redundancy with other convertases prevents isoform-specific substrate attribution in vivo
  • GDF11-independent knockout phenotypes lack identified substrates
  • No human Mendelian disease causation established in this corpus

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 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005794 Golgi apparatus 3 GO:0031410 cytoplasmic vesicle 3
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-392499 Metabolism of proteins 4 R-HSA-1474165 Reproduction 3 R-HSA-162582 Signal Transduction 3
Partners
BMP4DAG1GDF11ITGAVPCSK9RENTGFB1VEGFC

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 PC5 (PCSK5) was identified as a subtilisin/kexin-like proprotein convertase with a C-terminal cysteine-rich domain (5 repeats of a consensus Cys motif), most closely homologous to PACE4; its mRNA is most abundant in adrenal and gut tissues, and its expression in adrenocortical Y1 cells is upregulated by ACTH/cAMP. Reverse transcriptase/PCR cloning, cDNA sequencing, Northern blotting, in situ hybridization Proceedings of the National Academy of Sciences of the United States of America Medium 8341687
1996 PC5 (PCSK5) generates two COOH-terminal isoforms (PC5-A, 915 aa, soluble; PC5-B, 1877 aa, membrane-bound) with distinct subcellular localizations: PC5-A is sorted to regulated secretory granules via a sorting signal in its unique C-terminal 38 amino acids, while PC5-B localizes to the Golgi. Immunoelectron microscopy confirmed PC5 in glucagon-containing dense core granules of pancreatic cells. Stable transfection of AtT-20 cells, biosynthetic analysis, immunofluorescence, deletion mutagenesis, electron microscopy/immunogold labeling The Journal of cell biology High 8947550
1994 PC6 (PCSK5) can proteolytically activate the hemagglutinin of virulent avian influenza viruses at the authentic multibasic cleavage site, functioning similarly to furin; expression of PC6 in furin-deficient LoVo cells restored HA cleavage and supported multiple cycles of viral replication. Vaccinia virus expression in LoVo (furin-deficient) cells, viral replication assay, site-directed mutant HA panel Journal of virology High 8057485
1998 Furin and PC6B (but not PACE4 or PC5-A) can cleave and proteolytically activate BMP-4 precursor in vitro; in Xenopus oocytes, alpha1-PDX (a furin/PC6-selective inhibitor) blocks BMP-4 processing, and ectopic expression of alpha1-PDX in embryos phenocopies BMP-4 blockade, providing the first in vivo evidence that furin and/or PC6 activate BMP-4 during vertebrate embryogenesis. In vitro digestion assay, Xenopus oocyte translation assay, alpha1-PDX inhibitor misexpression in embryos, epistasis with downstream BMP signaling components The EMBO journal High 9707432
1996 PC5 (but not PACE4) cleaves the receptor protein tyrosine phosphatase RPTPmu at its dibasic motif (RXK/RR); cleavage was abolished when the active-site serine of PC5 was mutated to alanine, demonstrating catalytic requirement. PC5 mRNA is upregulated >30-fold in human umbilical vein endothelial cells as they approach confluence, correlating with increased RPTPmu processing. COS cell cotransfection, active-site serine-to-alanine mutagenesis, immunoblotting, RNA blot analysis Biochemistry High 8620001
1996 Human PC6 (PCSK5) is expressed as two isoforms (hPC6A and hPC6B) in human CD4+ T lymphocytes and is the most likely candidate host cell protease responsible for HIV-1 gp160 processing in T cells, based on its expression pattern in furin-deficient LoVo cells that remain competent for HIV virion production. RT-PCR, Northern blot analysis, comparison with furin-deficient LoVo cells Proceedings of the National Academy of Sciences of the United States of America Low 8755538
1996 PC5 (PCSK5) cleaves and activates human prorenin in cells containing dense core secretory granules (GH4C1 cells); activation depended on the paired basic amino acids at positions 42 and 43 of the prorenin prosegment, and PC5 co-localizes with renin in the zona glomerulosa of the human adrenal gland. Co-transfection of PC5 and prorenin in GH4C1 cells, site-directed mutagenesis of prorenin cleavage site, immunohistochemistry Hypertension Medium 8901832
1998 PC5-A functions as a prohormone convertase in the regulated secretory pathway: in stably transfected PC12 cells, PC5-A is sorted to early compartments of regulated secretory granules where it co-localizes with neurotensin and processes pro-neurotensin/neuromedin N (pro-NT/NN) into active peptides with a pattern distinct from PC1 and PC2, resembling processing in the adrenal medulla. Stable transfection of PC12 cells, metabolic labeling, immunochemistry, subcellular fractionation, HPLC analysis of cleavage products The Journal of biological chemistry High 9738000
2003 Furin, PC5, and PC7 cleave proVEGF-C at the dibasic motif HSIIRR(227)SL to generate mature VEGF-C; this processing was demonstrated by cotransfection in LoVo cells and by in vitro digestion of a fluorogenic peptide mimicking the cleavage site. Processing is blocked by prosegment inhibitors of furin/PC5/PACE4. Mature VEGF-C, but not processing-site mutant proVEGF-C, promotes angiogenesis and lymphangiogenesis in nude mice. Cotransfection in LoVo (furin-deficient) cells, in vitro fluorogenic peptide cleavage assay, site-directed mutagenesis of cleavage site, nude mouse xenograft assay The Journal of clinical investigation High 12782675
2004 PC5 (PCSK5) endoproteolytically activates alphav integrin in vascular smooth muscle cells (VSMCs); PC5-specific antisense oligonucleotides and the pharmacological PC inhibitor dec-CMK inhibited alphav cleavage, VSMC adhesion to vitronectin, VSMC migration, and focal adhesion kinase (FAK Y397) autophosphorylation and Akt activation, but not ERK1/2 phosphorylation. PC5 co-localizes with alphav integrin in human carotid atherosclerotic plaques. Antisense oligonucleotide knockdown, pharmacological inhibition (dec-CMK), immunoblotting, adhesion and migration assays, FAK/Akt signaling assays, immunohistochemistry of human tissue Circulation High 14970114
2003 PC5A is the major convertase for alphav integrin activation in vascular smooth muscle cells in vivo: PC5A mRNA (but not furin) is upregulated during neointima formation after balloon injury, alphav integrin is upregulated in PCNA-positive VSMCs, and brefeldin A blocks alphav maturation indicating cleavage occurs in the trans-Golgi network where PC5 resides. Balloon injury in vivo model, Northern blot, immunocytochemistry, brefeldin A treatment, in situ hybridization Histochemistry and cell biology Medium 12649739
2004 PC6 (PCSK5) is essential for embryo implantation: PC6 protein is specifically induced in uterine stromal cells at the site of embryo attachment in mice, and morpholino antisense knockdown of uterine PC6 completely blocked implantation. PC6 is dramatically upregulated in primate endometrium during uterine receptivity and decidualization. Morpholino antisense oligonucleotide knockdown in vivo (mouse uterus), immunohistochemistry, in situ localization during early pregnancy in mouse and primates Biology of reproduction High 15601911
2006 PCSK9 is cleaved and inactivated by furin and/or PC5/6A at the motif RFHR218; natural gain-of-function hypercholesterolemia mutations (R218S, F216L, D374Y) cause total or partial loss of furin/PC5/6A processing at this site. Processed (cleaved) PCSK9 has reduced ability to degrade the LDL receptor. Cell-based processing assays, site-directed mutagenesis of PCSK9 cleavage site, immunoblotting, analysis of circulating PCSK9 forms in human plasma The Journal of biological chemistry High 16912035
2007 A predicted alpha-helix in the C-terminus of PC5/6A is required for targeting to dense core secretory granules; this helix can redirect a constitutively secreted protein to the regulated secretory pathway of AtT-20 cells, analogous to sorting helices in PC1/3 and PC2. Fusion protein analysis, deletion mutagenesis of C-terminal domain, subcellular distribution assay in AtT-20 cells, structural prediction The FEBS journal Medium 17645548
2008 PCSK5 (PC5/6A) cleaves and activates GDF11 in vitro and ex vivo; the selectivity for GDF11 resides in the P1' Asn in the RSRR↓N cleavage motif. In vivo, epiblast-specific conditional deletion of Pcsk5 causes GDF11-related phenotypes (altered anteroposterior patterning, extra vertebrae, kidney agenesis) and GDF11-independent phenotypes. The C470R ENU mutation ablates a disulfide bond in the P domain, blocking ER export and convertase activity. In vitro cleavage assay, ex vivo analysis, conditional epiblast-specific Pcsk5 knockout, ENU mutagenesis with compound mutant analysis, site-directed mutagenesis (C470R), ER export assay Proceedings of the National Academy of Sciences of the United States of America / Genes & development High 18378898 18519639
2009 In Xenopus oocytes, furin and PC6 function redundantly to cleave both the S1 and S2 sites of pro-BMP4; antisense-mediated knockdown and alpha1-PDX inhibitor block both cleavages. In embryos, alpha1-PDX blocks S2 but not S1 site cleavage of pro-BMP4, suggesting a developmentally regulated S1-site-specific convertase distinct from furin/PC6. Xenopus oocyte antisense knockdown, alpha1-PDX inhibitor (furin/PC6-selective), engineered alpha1-PDX variant targeting PC7, in vivo cleavage assays in embryos The Journal of biological chemistry High 19651771
2008 Furin, PACE4, PC5, and PC7 process preprohepcidin at the RRRRR(59)DT motif to generate mature hepcidins; this was demonstrated by restoration of processing in PC-activity-deficient LoVo cells by each convertase, confirmed by in vitro fluorogenic peptide digestion. Site-directed mutagenesis of the cleavage site (RRRRR→SSSSS) abrogates processing and biological activity (inability to degrade ferroportin). Cell transfection in LoVo cells, in vitro fluorogenic peptide cleavage assay, site-directed mutagenesis, furin inhibitor (alpha1-PDX, ppFurin) Gut Medium 18664504
2009 PC5/6 is protective against intestinal tumorigenesis: enterocyte-specific conditional Pcsk5 knockout mice on the ApcMin/+ background showed significantly higher tumor number in the duodenum and premature mortality compared to ApcMin/+ controls with normal PC5/6. Human intestinal tumors systematically downregulate PC5/6 expression. Conditional enterocyte-specific Pcsk5 knockout in ApcMin/+ mouse model, tumor counting, survival analysis, human tumor expression analysis Molecular cancer Medium 19737405
2011 PCSK5 processes the inhibin alpha- and beta-subunits in ovarian follicles: overexpression of PC5/6 in furin-deficient LoVo cells increased inhibin alpha- and betaB-subunit maturation; PC convertase inhibitor dec-CMK blocked inhibin subunit maturation in granulosa cells; activin A selectively elevated PCSK5 mRNA at the two-layer secondary to pre-antral follicle transition. Overexpression in furin-deficient LoVo cells, pharmacological inhibition (dec-CMK) in granulosa cells, quantitative RT-PCR, Western blotting PloS one Medium 21408162
2015 PC6 (PCSK5) cleaves alpha-dystroglycan at a specific site near its N-terminus (alpha-DG-N), removing the obstructing N-terminal domain from the endometrial epithelial cell surface to enable DG-mediated adhesion and blastocyst attachment. PC6 knockdown reduced alpha-DG-N removal and blastocyst adhesion; mutation of the PC6 cleavage site prevented alpha-DG-N shedding and caused retention of full-length alpha-DG with loss of adhesiveness. In vitro peptide cleavage assay (PC6 cleavage site peptide), siRNA knockdown, site-directed mutagenesis of PC6 cleavage site in alpha-DG, blastocyst adhesion assay, in vivo uterine tissue analysis FASEB journal High 26077903
2001 PC5 (PCSK5) processes pro-CCK in neuronal cell lines: GT1-7 and SK-N-MC/SK-N-SH cells that express PC5 but not PC1 or PC2 produce glycine-extended CCK 12 and CCK 22 from stably overexpressed pro-CCK, demonstrating PC5's ability to cleave pro-CCK at specific sites distinct from those used by PC1/PC2. Stable transfection, radioimmunoassay, carboxypeptidase B treatment, gel filtration chromatography, RT-PCR, Western blot Peptides Medium 11457520
2005 siRNA knockdown of PC5 in STC-1 intestinal cells reduced CCK secretion (particularly CCK 22) and decreased PC5 protein by ~50%; PC5 knockdown was accompanied by a 3-fold compensatory increase in PC2 mRNA and protein, providing the first direct evidence that PC5 is involved in CCK processing. Stable siRNA transfection, quantitative RT-PCR, Western blot, CCK radioimmunoassay Peptides Medium 16266771
2017 Osteopontin (OPN) is a substrate of PC5/6 in bone: in silico analysis identified four potential PC5/6 cleavage sites in human OPN; ex vivo co-transfections showed complete OPN cleavage by PC5/6; direct cleavage was confirmed by cell-free enzyme-substrate assays and mass spectrometry identification of cleavage sites. PC5/6-knockout embryos show reduced bone mineralization and altered OPN processing patterns in bone extracts. In silico site prediction, co-transfection (ex vivo), cell-free enzyme-substrate assay, mass spectrometry, micro-CT of knockout embryos, in situ hybridization, immunoblotting Bone High 29126984
2017 Pcsk5 is required specifically in early cranio-cardiac mesoderm for heart development: conditional deletion of Pcsk5 in Nkx2.5-expressing cardiogenic progenitors or pharyngeal mesodermal progenitors did not affect heart development, but deletion in earlier cranio-cardiac mesodermal precursors caused cardiac malformations; neural crest deletion had no effect on conotruncal septation. Conditional tissue-specific Pcsk5 knockout (multiple Cre drivers), magnetic resonance imaging of embryonic hearts BMC developmental biology Medium 28446132
2024 PCSK5 activates precursor TGF-beta (pro-TGF-beta) by binding to and cleaving at the pro-TGF-beta cleavage site, activating downstream SMAD2/3 signaling and ECM expression in aortic adventitial fibroblasts; this was demonstrated by co-immunoprecipitation (PCSK5 interacts with pro-TGF-beta), overexpression studies, and pharmacological disruption of the PCSK5/pro-TGF-beta interaction by leflunomide. Co-immunoprecipitation, overexpression in adventitial fibroblasts, Western blotting for SMAD2/3 activation, pharmacological inhibition (leflunomide), immunohistochemistry in TAK patient tissue Journal of autoimmunity Medium 38972101
2025 PCSK5 M452I is a recessive hypomorphic allele: overexpressed PCSK5M452I retains measurable but reduced GDF11 maturation activity compared to wildtype; in a PCSK5-null MCF10DCIS.com background, PCSK5M452I addback showed mildly defective anterograde transport and significantly less compact multicellular organization in 3D matrigel cultures and impaired xenograft growth. No gain-of-function was observed. In-cell GDF11 maturation assay, reconstitution of PCSK5-null cells with different alleles, 3D matrigel culture, intraductal xenograft assay, anterograde transport assay bioRxivpreprint Medium 40093128
1995 PC5 (PCSK5) is unable to process rat prosomatostatin in either constitutive (LoVo) or regulated (AtT-20) secretory cell lines, in contrast to PC1, furin, PACE4, and (in AtT-20) PC2, demonstrating a substrate specificity that excludes prosomatostatin. Recombinant vaccinia virus co-expression, gel-permeation HPLC analysis of processing products FEBS letters Medium 7720860
1999 PC5-A immunoreactivity in rat brain neurons is concentrated in the Golgi apparatus and small vesicular elements in perikarya and dendrites, but is absent from axons and synaptic terminals (no co-localization with dynamin-1), suggesting PC5-A acts in early compartments of the regulated secretory pathway and is not released with its processed substrates. Immunohistochemistry with N-terminal-directed antibody, co-localization with Golgi marker MG-160 and synaptic marker dynamin-1, glial marker S-100alpha Neuroscience Medium 10408612
2006 PC5/6A and PC7 have a strong preference for polybasic (poly-Arg) sequences at all six positions of their active site; nona-L-Arg is a potent nanomolar inhibitor of PC5/6A (Ki ~150 nM), and nona-D-Arg is even more potent (Ki ~19 nM), as established by positional scanning-synthetic peptide combinatorial library (PS-SPCL) screening. Positional scanning synthetic peptide combinatorial library (PS-SPCL) screening, enzyme kinetic assays (Ki determination) Molecular pharmacology Medium 17012622

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 Mitochondrial depolarization accompanies cytochrome c release during apoptosis in PC6 cells. The Journal of biological chemistry 299 10026183
1993 cDNA structure of the mouse and rat subtilisin/kexin-like PC5: a candidate proprotein convertase expressed in endocrine and nonendocrine cells. Proceedings of the National Academy of Sciences of the United States of America 247 8341687
2006 The proprotein convertase (PC) PCSK9 is inactivated by furin and/or PC5/6A: functional consequences of natural mutations and post-translational modifications. The Journal of biological chemistry 236 16912035
1998 BMP-4 is proteolytically activated by furin and/or PC6 during vertebrate embryonic development. The EMBO journal 191 9707432
1994 Proprotein-processing endoproteases PC6 and furin both activate hemagglutinin of virulent avian influenza viruses. Journal of virology 183 8057485
2003 The secretory proprotein convertases furin, PC5, and PC7 activate VEGF-C to induce tumorigenesis. The Journal of clinical investigation 175 12782675
1996 The isoforms of proprotein convertase PC5 are sorted to different subcellular compartments. The Journal of cell biology 137 8947550
2008 VACTERL/caudal regression/Currarino syndrome-like malformations in mice with mutation in the proprotein convertase Pcsk5. Genes & development 106 18519639
2008 In vivo functions of the proprotein convertase PC5/6 during mouse development: Gdf11 is a likely substrate. Proceedings of the National Academy of Sciences of the United States of America 85 18378898
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
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
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
2009 Site-specific cleavage of BMP4 by furin, PC6, and PC7. The Journal of biological chemistry 60 19651771
1996 Increased proteolytic processing of protein tyrosine phosphatase mu in confluent vascular endothelial cells: the role of PC5, a member of the subtilisin family. Biochemistry 57 8620001
2000 Growth inhibitory effect of a new camptothecin analog, DX-8951f, on various drug-resistant sublines including BCRP-mediated camptothecin derivative-resistant variants derived from the human lung cancer cell line PC-6. Anti-cancer drugs 54 10912951
1996 Isolation of the human PC6 gene encoding the putative host protease for HIV-1 gp160 processing in CD4+ T lymphocytes. Proceedings of the National Academy of Sciences of the United States of America 50 8755538
2006 Short polybasic peptide sequences are potent inhibitors of PC5/6 and PC7: Use of positional scanning-synthetic peptide combinatorial libraries as a tool for the optimization of inhibitory sequences. Molecular pharmacology 47 17012622
1998 PC5-A-mediated processing of pro-neurotensin in early compartments of the regulated secretory pathway of PC5-transfected PC12 cells. The Journal of biological chemistry 46 9738000
2005 Proprotein convertases furin and PC5: targeting atherosclerosis and restenosis at multiple levels. Journal of molecular medicine (Berlin, Germany) 42 16244876
2010 Resveratrol reduces oxidative stress and cell death and increases mitochondrial antioxidants and XIAP in PC6.3-cells. Neuroscience letters 41 21094207
2004 Inhibiting uterine PC6 blocks embryo implantation: an obligatory role for a proprotein convertase in fertility. Biology of reproduction 41 15601911
2009 The effects of acupuncture stimulation at PC6 (Neiguan) on chronic mild stress-induced biochemical and behavioral responses. Neuroscience letters 40 19427367
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
2012 The influence of PC6 on cardiovascular disorders: a review of central neural mechanisms. Acupuncture in medicine : journal of the British Medical Acupuncture Society 37 22378585
2013 Enzymatic conversion of D-galactose to D-tagatose: cloning, overexpression and characterization of L-arabinose isomerase from Pediococcus pentosaceus PC-5. Microbiological research 35 23948501
2004 Endoproteolytic activation of alpha(v) integrin by proprotein convertase PC5 is required for vascular smooth muscle cell adhesion to vitronectin and integrin-dependent signaling. Circulation 33 14970114
2011 PC6 levels in uterine lavage are closely associated with uterine receptivity and significantly lower in a subgroup of women with unexplained infertility. Human reproduction (Oxford, England) 30 21273245
2007 Effects and mechanisms of electroacupuncture at PC6 on frequency of transient lower esophageal sphincter relaxation in cats. World journal of gastroenterology 30 17828819
1996 Prohormone convertase PC5 is a candidate processing enzyme for prorenin in the human adrenal cortex. Hypertension (Dallas, Tex. : 1979) 29 8901832
1997 Murine subtilisin-like proteinase SPC6 is expressed during embryonic implantation, somitogenesis, and skeletal formation. Developmental genetics 28 9291583
2008 Regulation of prohepcidin processing and activity by the subtilisin-like proprotein convertases Furin, PC5, PACE4 and PC7. Gut 27 18664504
2001 Selective expression of the proprotein convertases furin, pc5, and pc7 in proliferating vascular smooth muscle cells of the rat aorta in vitro. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 27 11181735
1995 Chromosomal assignment of the genes for proprotein convertases PC4, PC5, and PACE 4 in mouse and human. Genomics 27 7782070
2002 Proprotein convertase PC5 regulation by PDGF-BB involves PI3-kinase/p70(s6)-kinase activation in vascular smooth muscle cells. Hypertension (Dallas, Tex. : 1979) 26 11882580
1998 The pro-protein convertase PC1 is induced in the transected sciatic nerve and is present in cultured Schwann cells: comparison with PC5, furin and PC7, implication in pro-BDNF processing. Brain research. Molecular brain research 26 9729404
2007 Pro-protein convertases (PCs) other than PC6 are not tightly regulated for implantation in the human endometrium. Reproduction (Cambridge, England) 24 17636173
2023 Electroacupuncture at Neiguan (PC6) attenuates cardiac dysfunction caused by cecal ligation and puncture via the vagus nerve. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 23 36996679
2001 Growth and differentiation of PC6 cells: the effects of pulsed electromagnetic fields (PEMF). Bioelectromagnetics 23 11298388
2011 Role of PCSK5 expression in mouse ovarian follicle development: identification of the inhibin α- and β-subunits as candidate substrates. PloS one 22 21408162
2009 The proprotein convertase PC5/6 is protective against intestinal tumorigenesis: in vivo mouse model. Molecular cancer 22 19737405
1999 Immunohistochemical distribution of the prohormone convertase PC5-A in rat brain. Neuroscience 22 10408612
2001 Neuronal cell lines expressing PC5, but not PC1 or PC2, process Pro-CCK into glycine-extended CCK 12 and 22. Peptides 21 11457520
2011 The nonstructural protein pC6 of rice grassy stunt virus trans-complements the cell-to-cell spread of a movement-defective tomato mosaic virus. Archives of virology 20 21327784
2011 PCSK5 and GDF11 expression in the hindgut region of mouse embryos with anorectal malformations. European journal of pediatric surgery : official journal of Austrian Association of Pediatric Surgery ... [et al] = Zeitschrift fur Kinderchirurgie 20 21480163
2015 Posttranslational removal of α-dystroglycan N terminus by PC5/6 cleavage is important for uterine preparation for embryo implantation in women. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 19 26077903
2011 Electroacupuncture at PC6 (Neiguan) Improves Extracellular Signal-Regulated Kinase Signaling Pathways Through the Regulation of Neuroendocrine Cytokines in Myocardial Hypertrophic Rats. Evidence-based complementary and alternative medicine : eCAM 19 21876715
2021 Electroacupuncture Pretreatment at Neiguan (PC6) attenuates autophagy in rats with myocardial ischemia reperfusion through the phosphatidylinositol 3-kinase-Akt-mammalian target of rapamycin pathway. Journal of traditional Chinese medicine = Chung i tsa chih ying wen pan 18 34114404
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 Antihypertensive and Antihypertrophic Effects of Acupuncture at PC6 Acupoints in Spontaneously Hypertensive Rats and the Underlying Mechanisms. Evidence-based complementary and alternative medicine : eCAM 15 28293268
2010 Molecular cloning and embryonic expression of zebrafish PCSK5 co-orthologues: functional assessment during lateral line development. Developmental dynamics : an official publication of the American Association of Anatomists 15 20882679
2007 PC1/3, PC2 and PC5/6A are targeted to dense core secretory granules by a common mechanism. The FEBS journal 15 17645548
2003 Coordinated regulation and colocalization of alphav integrin and its activating enzyme proprotein convertase PC5 in vivo. Histochemistry and cell biology 15 12649739
2019 Acupuncture at PC6 prevents cardiac hypertrophy in isoproterenol-treated mice. Acupuncture in medicine : journal of the British Medical Acupuncture Society 14 30843422
2000 Evolution of the prohormone convertases: identification of a homologue of PC6 in the protochordate amphioxus. Biochimica et biophysica acta 14 10708868
1978 Restorative effects of levamisole on cell-mediated immune responses following chemotherapy with aniline mustard in mice bearing ADJ-PC5 plasmacytoma. Cancer treatment reports 14 310338
2006 pC6-2/caspase-6 system to purify glutathione-S-transferase-free recombinant fusion proteins expressed in Escherichia coli. Nature protocols 13 17487164
2017 Osteopontin as a novel substrate for the proprotein convertase 5/6 (PCSK5) in bone. Bone 12 29126984
2020 MicroRNA‑338‑3p regulates age‑associated osteoporosis via targeting PCSK5. Molecular medicine reports 11 33313955
2020 [Effect of electroacupuncture preconditioning of "Neiguan"(PC6) on myocardial LKB1/AMPK/PFK2 pathway in myocardial ischemia rats]. Zhen ci yan jiu = Acupuncture research 10 32144918
2020 Antihypertensive and Antifibrosis Effects of Acupuncture at PC6 Acupoints in Spontaneously Hypertensive Rats and the Underlying Mechanisms. Frontiers in physiology 10 32982761
2018 The Beneficial Effects of Electroacupuncture at PC6 Acupoints (Neiguan) on Myocardial Ischemia in ASIC3 -/- mice. Journal of acupuncture and meridian studies 10 29608997
2017 Pcsk5 is required in the early cranio-cardiac mesoderm for heart development. BMC developmental biology 10 28446132
2017 Manual Acupuncture at PC6 Ameliorates Acute Restraint Stress-Induced Anxiety in Rats by Normalizing Amygdaloid Noradrenergic Response. Evidence-based complementary and alternative medicine : eCAM 10 28900460
2015 PCSK5 mutation in a patient with the VACTERL association. BMC research notes 10 26055999
2014 Intake levels of dietary polyunsaturated fatty acids modify the association between the genetic variation in PCSK5 and HDL cholesterol. Journal of medical genetics 10 25351954
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
2021 The dissection of R genes and locus Pc5.1 in Phytophthora capsici infection provides a novel view of disease resistance in peppers. BMC genomics 9 34016054
1995 Amyloid precursor protein is not processed by furin, PACE 4, PC1/3, PC2, PC4 and PC5/6 of the furin family of proprotein processing enzymes. Biochimica et biophysica acta 8 7819286
1991 Inhibition of human immunodeficiency virus forward and reverse transcription by PC6, a natural product from cones of pine trees. AIDS research and human retroviruses 8 2064832
1976 Resistance of mice to Krebs ascites tumour, sarcoma S180 and PC6 plasmacytoma after immunisation with Salmonella enteritidis 11RX. The Australian journal of experimental biology and medical science 8 797376
2021 Full-length transcriptome analysis reveals the mechanism of acupuncture at PC6 improves cardiac function in myocardial ischemia model. Chinese medicine 7 34238326
2018 Targeting of rice grassy stunt virus pc6 protein to plasmodesmata requires the ER-to-Golgi secretory pathway and an actin-myosin VIII motility system. Archives of virology 7 29392491
2004 Implications of proprotein Convertase 5 (PC5) in the arterial restenotic process in a porcine model. Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology 7 15358338
2001 Single-nucleotide polymorphisms of the proprotein convertase subtilisin/ kexin type 5 (PCSK5) gene. Journal of human genetics 7 11776387
2019 [Serum metabolic profile involving protective effect of "Neiguan"(PC6)-electroacupuncture preconditioning in rats with myocardial ischemia reperfusion injury]. Zhen ci yan jiu = Acupuncture research 6 30945499
2022 Electroacupuncture at PC6 (Neiguan) Attenuates Angina Pectoris in Rats with Myocardial Ischemia-Reperfusion Injury Through Regulating the Alternative Splicing of the Major Inhibitory Neurotransmitter Receptor GABRG2. Journal of cardiovascular translational research 5 35377129
2021 Efficacy on rabbits with arrhythmia: needling acupoint of Neiguan (PC6) at shallow or deep depth, and retaining needles for 10, 20, or 30 min. Journal of traditional Chinese medicine = Chung i tsa chih ying wen pan 5 34939394
2014 The Effects of Needling Fenglong (ST40) and Neiguan (PC6) on IL-17 of ApoE-Gene-Knockout Mice's Liver. Evidence-based complementary and alternative medicine : eCAM 5 24778705
2024 Pro-fibrotic effect of the susceptible gene PCSK5 in vascular fibrosis of Takayasu arteritis via TGF-β and SMAD3 signaling pathway activation. Journal of autoimmunity 4 38972101
2022 Design, synthesis, and characterization of novel fluorogenic substrates of the proprotein convertases furin, PC1/3, PC2, PC5/6, and PC7. Analytical biochemistry 4 35964735
2017 Hybrid DNA i-motif: Aminoethylprolyl-PNA (pC5) enhance the stability of DNA (dC5) i-motif structure. Bioorganic & medicinal chemistry letters 4 29138026
2005 Inhibition of PC5 expression decreases CCK secretion and increases PC2 expression. Peptides 4 16266771
2024 PCSK5 downregulation promotes the inhibitory effect of andrographolide on glioblastoma through regulating STAT3. Molecular and cellular biochemistry 3 38553549
2024 Effect of electroacupuncture at "Neiguan" (PC6) on pain and brain orexin 1 receptor in mice with inflammatory pain. Zhen ci yan jiu = Acupuncture research 3 38764114
2023 Development and Application of a Cleaved Amplified Polymorphic Sequence Marker (Phyto) Linked to the Pc5.1 Locus Conferring Resistance to Phytophthora capsici in Pepper (Capsicum annuum L.). Plants (Basel, Switzerland) 3 37570909
2023 Genome-wide analysis in PC6 electroacupuncture to ameliorate carfilzomib-induced cardiotoxicity in mice. Gene 3 38110043
2003 Molecular characterization of the cDNA and localization of the mRNA encoding the prohormone convertase PC5-A in the European green frog. The Journal of comparative neurology 3 12508314
1996 Human lactase-phlorizin hydrolase is not processed by furin, PC1/PC3, PC2, PACE4 and PC5/PC6A of the family of subtilisin-like proprotein processing proteases. Biochimica et biophysica acta 3 8664347
2025 [Regulatory effect of electroacupuncture at "Neiguan" (PC6) on mitochondrial autophagy during the ischemia and reperfusion phases in rats with myocardial ischemia-reperfusion injury]. Zhongguo zhen jiu = Chinese acupuncture & moxibustion 2 40369922
2024 Effect of electroacupuncture at Neiguan (PC6) at different time points on myocardial ischemia reperfusion arrhythmia in rats. Journal of traditional Chinese medicine = Chung i tsa chih ying wen pan 2 38213246
2020 [Effect of acupuncture at different layers of local "Neiguan" (PC6) tissue on arrhythmia and expression of myocardial Cx43 in rabbits]. Zhen ci yan jiu = Acupuncture research 2 32333530
2026 [Effect of electroacupuncture of "Neiguan" (PC6) and "Shenmen" (HT7) on cardiac function and neovascularization in rats with chronic heart failure based on Notch signaling pathway]. Zhen ci yan jiu = Acupuncture research 1 41566731
2025 [Effects of transcutaneous electrical acupoint stimulation at Neiguan (PC6) and Jianshi (PC5) on autonomic nervous function and inflammatory factors in frail elderly patients after surgery]. Zhen ci yan jiu = Acupuncture research 1 40691032
2025 Stimulation of the wrist acupuncture point PC6 for preventing postoperative nausea and vomiting: a network meta-analysis. The Cochrane database of systematic reviews 1 40938065
2015 [Effect of electro-acupuncture at Neiguan (PC6) and Lieque (LU7) on the expression of protein kinases in cardiomyocytes of myocardial ischemia rats]. Zhongguo Zhong xi yi jie he za zhi Zhongguo Zhongxiyi jiehe zazhi = Chinese journal of integrated traditional and Western medicine 1 25951641
1997 [Neuronal differentiation of human small cell lung cancer cell line PC-6 by Solcoseryl]. [Hokkaido igaku zasshi] The Hokkaido journal of medical science 1 9465315
1996 Assignment of the human proprotein convertase gene PCSK5 to chromosome 9q21.3. Cytogenetics and cell genetics 1 9067430
2025 Direct Cloning and Heterologous Expression of the Dmxorosin Biosynthetic Gene Cluster from Streptomyces thermolilacinus SPC6, a Halotolerant Actinomycete Isolated from the Desert in China. International journal of molecular sciences 0 40003958
2025 PCSK5M452I is a recessive hypomorph exclusive to MCF10DCIS.com cells. bioRxiv : the preprint server for biology 0 40093128
2025 Genetic Association of PCSK5 and MUC2 Gene Polymorphisms with Recurrent Pregnancy Loss (RPL). International journal of molecular sciences 0 40724834

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