Affinage

PCSK5

Proprotein convertase subtilisin/kexin type 5 · UniProt Q92824

Length
1860 aa
Mass
206.9 kDa
Annotated
2026-04-29
100 papers in source corpus 32 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PCSK5 (PC5/6) is a subtilisin/kexin-family serine endoprotease that cleaves precursor proteins at basic amino acid motifs to activate a broad range of substrates in developmental, endocrine, vascular, and immune contexts. It exists as two isoforms—soluble PC5/6A, which is targeted to regulated secretory granules via a C-terminal alpha-helix sorting signal, and membrane-bound PC5/6B, which localizes to the Golgi—and processes substrates including GDF11 (with selectivity conferred by a P1' Asn), BMP-4, VEGF-C, PCSK9, pro-TGF-beta, alphav integrin, prorenin, hepcidin, osteopontin, alpha-dystroglycan N-terminus, inhibin subunits, CCK, and viral hemagglutinins (PMID:8341687, PMID:8947550, PMID:18519639, PMID:9707432, PMID:12782675, PMID:16912035, PMID:29126984, PMID:26077903). Conditional genetic studies in mouse demonstrate that PCSK5 is essential for embryonic anteroposterior patterning and nephrogenesis largely through GDF11 activation and Hox gene regulation, for cardiogenesis via action in cranio-cardiac mesoderm, for uterine receptivity and embryo implantation, for bone mineralization through osteopontin processing, and for intestinal tumor suppression in the ApcMin/+ model (PMID:18378898, PMID:27, PMID:19737405, PMID:15601911, PMID:29126984). In the vasculature, PCSK5 activates alphav integrin in smooth muscle cells to promote adhesion, migration, and FAK/Akt signaling, and cleaves pro-TGF-beta in adventitial fibroblasts to drive TGF-beta/SMAD2/3-dependent extracellular matrix production (PMID:14970114, PMID:38972101).

Mechanistic history

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

    Identification of PCSK5 as a new member of the proprotein convertase family established that subtilisin/kexin-like processing enzymes extend beyond furin and PC1/2, with expression in both endocrine and non-endocrine tissues.

    Evidence cDNA cloning, Northern blotting, and in situ hybridization from mouse tissues

    PMID:8341687

    Open questions at the time
    • Endogenous substrates unknown
    • Enzymatic specificity versus furin/PACE4 not defined
    • No loss-of-function data
  2. 1994 High

    Demonstration that PC5/6 can proteolytically activate avian influenza hemagglutinin in furin-deficient cells established it as a functionally active basic-amino-acid-directed endoprotease with overlapping but distinct substrate capacity relative to furin.

    Evidence Vaccinia virus expression system in furin-deficient LoVo cells with rescue of viral replication

    PMID:8057485

    Open questions at the time
    • Substrate selectivity rules not established
    • No known physiological substrates in mammals yet
    • Prosomatostatin shown not to be a substrate, highlighting unexplained specificity (PMID:7720860)
  3. 1996 High

    Discovery that PCSK5 generates two isoforms (soluble PC5-A and membrane-bound PC5-B) sorted to distinct compartments—secretory granules versus Golgi—resolved how one gene could serve both regulated and constitutive secretory pathways, with a C-terminal 38-residue segment directing granule entry.

    Evidence Stable transfection of AtT-20 cells, electron microscopy immunohistochemistry, C-terminal deletion mutagenesis

    PMID:8947550

    Open questions at the time
    • Structural basis of the sorting signal not resolved at atomic level
    • Relative contributions of PC5-A vs PC5-B to specific substrate processing unknown
  4. 1996 High

    Identification of the first endogenous mammalian substrates—RPTPmu and prorenin—showed that PC5/6 operates on diverse precursor classes beyond neuropeptides, with active-site mutagenesis confirming catalytic dependence.

    Evidence COS cell co-transfection with active-site Ser→Ala mutant (RPTPmu), co-transfection in GH4C1 cells with prorenin cleavage-site mutants

    PMID:8620001 PMID:8901832

    Open questions at the time
    • In vivo relevance of RPTPmu and prorenin cleavage by PC5 not tested genetically
    • Redundancy with furin for these substrates not resolved
  5. 1998 High

    PC5-A was shown to process pro-neurotensin/neuromedin N in early compartments of the regulated secretory pathway and BMP-4 in Xenopus oocytes, establishing roles in both neuroendocrine and developmental morphogen processing.

    Evidence Stable transfection in PC12 cells with metabolic labeling; Xenopus oocyte cleavage assays with alpha1-PDX inhibition and epistasis

    PMID:9707432 PMID:9738000

    Open questions at the time
    • BMP-4 cleavage redundancy with furin not resolved genetically
    • P1' determinants of selectivity not yet identified
  6. 2001 Medium

    Evidence that PC5 processes pro-CCK in neuronal cell lines lacking PC1/PC2 extended the substrate repertoire to gut-brain peptide hormones, later confirmed by siRNA knockdown reducing CCK22 secretion.

    Evidence RT-PCR/Western blot for convertase expression in GT1-7 cells; siRNA knockdown of PC5 in STC-1 cells with CCK radioimmunoassay

    PMID:11457520 PMID:16266771

    Open questions at the time
    • No direct in vitro reconstitution of PC5 cleaving pro-CCK
    • Compensatory PC2 upregulation upon PC5 knockdown complicates interpretation
    • In vivo genetic validation not performed
  7. 2003 High

    Identification of VEGF-C and alphav integrin as PC5 substrates connected the enzyme to angiogenesis/lymphangiogenesis and vascular smooth muscle cell biology, with VEGF-C cleavage validated in vivo via tumor xenografts and alphav processing linked to FAK/Akt signaling.

    Evidence LoVo cell reconstitution and CHO xenograft model for VEGF-C; antisense oligonucleotides and dec-CMK inhibitor in VSMCs, adhesion/migration assays, human endarterectomy tissue

    PMID:12649739 PMID:12782675 PMID:14970114

    Open questions at the time
    • Relative contributions of furin, PC5, and PC7 to VEGF-C processing in specific tissues unresolved
    • Direct in vitro cleavage of alphav by purified PC5 not shown
  8. 2004 High

    In vivo knockdown of PC6 in the mouse uterus completely blocked embryo implantation, establishing the first essential non-redundant physiological role for PCSK5 in reproduction.

    Evidence Morpholino antisense knockdown in mouse uterus, immunohistochemistry in mouse/rhesus/human endometrium

    PMID:15601911

    Open questions at the time
    • Identity of the critical substrate(s) mediating implantation not established
    • Genetic knockout confirmation not yet performed
  9. 2006 High

    Discovery that PC5/6A cleaves PCSK9 at RFHR↓218—with gain-of-function hypercholesterolemia mutations abolishing this cleavage—established a link between PCSK5 activity and cholesterol metabolism regulation.

    Evidence Cell transfection with PCSK9 mutants, immunoblotting, human plasma analysis

    PMID:16912035

    Open questions at the time
    • In vivo significance of PC5/6A-mediated PCSK9 inactivation versus furin not genetically resolved
    • Relative contribution to circulating PCSK9 levels unknown
  10. 2008 High

    ENU mutagenesis and conditional knockout in mice revealed that PCSK5 is essential for embryonic anteroposterior patterning, kidney development, and skeletal organization primarily through activation of GDF11 at a P1' Asn-containing cleavage motif, resolving the key in vivo substrate and the molecular basis of selectivity over other convertases.

    Evidence ENU-induced C470R mutation, epiblast-specific conditional deletion, in vitro cleavage assays with P1' mutagenesis, comparison with Gdf11-knockout phenotype

    PMID:18378898 PMID:18519639

    Open questions at the time
    • Whether all patterning phenotypes are GDF11-dependent or involve additional substrates
    • Crystal structure of PC5/6 explaining P1' Asn preference not available
  11. 2008 High

    Demonstration that PC5 cleaves preprohepcidin at the polybasic site for hepcidin maturation connected PCSK5 to systemic iron homeostasis, though with redundancy among multiple convertases.

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

    PMID:18664504

    Open questions at the time
    • Relative in vivo importance of PC5 versus furin/PACE4/PC7 for hepcidin maturation unresolved
    • No genetic iron phenotype reported for Pcsk5 knockouts
  12. 2009 High

    Enterocyte-specific Pcsk5 knockout in ApcMin/+ mice demonstrated a tumor-suppressive function, with increased duodenal tumors and premature mortality, paralleled by systematic PCSK5 downregulation in human intestinal tumors.

    Evidence Conditional Pcsk5 knockout crossed to ApcMin/+ model, tumor enumeration, human tumor expression analysis

    PMID:19737405

    Open questions at the time
    • Identity of the substrate(s) mediating tumor suppression unknown
    • Mechanism of PCSK5 downregulation in human tumors not defined
  13. 2015 High

    Identification of alpha-dystroglycan N-terminus as a PC6 substrate required for embryo attachment to endometrial epithelium provided a molecular mechanism for the implantation role discovered a decade earlier.

    Evidence In vitro cleavage of PC6-site peptide, PC6 siRNA knockdown, cleavage-site mutagenesis, blastocyst adhesion assay, in vivo endometrial tissue analysis

    PMID:26077903

    Open questions at the time
    • Whether alpha-DG-N is the sole critical substrate for implantation or acts alongside others
    • Genetic rescue of implantation defect by alpha-DG-N removal not shown
  14. 2017 High

    Systematic conditional deletion across multiple Cre lines established that PCSK5 is required specifically in cranio-cardiac mesoderm for cardiogenesis, refining the tissue-of-action beyond what epiblast-wide deletion could show.

    Evidence Multiple tissue-specific Cre-mediated Pcsk5 deletions with MRI phenotyping of embryonic hearts

    PMID:28446132

    Open questions at the time
    • The specific substrate(s) processed by PC5/6 in cranio-cardiac mesoderm for heart development remain unknown
    • Whether the cardiogenesis role is GDF11-dependent or involves distinct substrates not resolved
  15. 2017 High

    Identification of osteopontin as a direct PC5/6A substrate in bone, with KO mice showing altered OPN processing and reduced mineralization, established a role for PCSK5 in skeletal mineralization.

    Evidence Cell-free enzyme-substrate assay, mass spectrometry of cleavage products, micro-CT of KO embryos, in situ hybridization

    PMID:29126984

    Open questions at the time
    • Whether OPN processing is the primary mechanism for mineralization defects or secondary to broader developmental abnormalities
    • Cleavage at noncanonical sites not fully characterized kinetically
  16. 2024 Medium

    Co-immunoprecipitation of PCSK5 with pro-TGF-beta and demonstration of enhanced SMAD2/3 signaling upon PCSK5 overexpression in adventitial fibroblasts linked the enzyme to vascular fibrosis in Takayasu arteritis, extending substrate repertoire to TGF-beta superfamily ligands beyond GDF11/BMP-4.

    Evidence Co-IP of PCSK5 and pro-TGF-beta, overexpression in fibroblasts, SMAD2/3 phosphorylation, leflunomide inhibition

    PMID:38972101

    Open questions at the time
    • Direct in vitro cleavage assay of pro-TGF-beta by purified PC5/6 not shown
    • Specificity versus furin for pro-TGF-beta not tested
    • Leflunomide mechanism of inhibition not biochemically defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • No crystal or cryo-EM structure of PC5/6 exists, and the structural basis for its P1' Asn selectivity, isoform-specific substrate channeling, and the identities of critical substrates in cardiogenesis and intestinal tumor suppression remain undefined.
  • No atomic-resolution structure of PC5/6
  • Substrate identity for cardiogenesis unknown
  • Mechanism of tumor suppression in intestine uncharacterized at substrate level
  • Relative in vivo redundancy with furin and PACE4 for most substrates not genetically dissected

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 12
Localization
GO:0005794 Golgi apparatus 3 GO:0031410 cytoplasmic vesicle 3 GO:0005576 extracellular region 1
Pathway
R-HSA-392499 Metabolism of proteins 12 R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 2
Partners
BMP4DAG1GDF11ITGAVOPNPCSK9TGFB1VEGFC

Evidence

Reading pass · 32 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 encoded by multiple mRNAs, with a C-terminal Cys-rich domain, expressed in endocrine and non-endocrine tissues; its closest homologue is PACE4, and cAMP upregulates its expression in adrenocortical cells. RT-PCR, cDNA cloning, Northern blotting, in situ hybridization Proceedings of the National Academy of Sciences of the United States of America High 8341687
1994 PC6 (PCSK5) can proteolytically activate the hemagglutinin of virulent avian influenza viruses at authentic cleavage sites, functioning similarly to furin, as demonstrated in furin-deficient LoVo cells complemented with PC6. Vaccinia virus expression in LoVo cells (furin-deficient), rescue of viral replication, cleavage site mutant analysis Journal of virology High 8057485
1995 PC5 (PCSK5) cannot process rat prosomatostatin into somatostatin-14 or somatostatin-28 in either constitutive (LoVo) or regulated (AtT-20) secretory cell lines, unlike PC1, PC2, furin, and PACE4. Recombinant vaccinia virus co-expression, gel-permeation HPLC analysis of processed products FEBS letters High 7720860
1995 The PCSK5 gene was mapped to mouse chromosome 19 and human chromosome 9. RFLP analysis of backcross DNA panel, Southern blot of somatic cell hybrid DNA panel Genomics Medium 7782070
1996 PC5 (PCSK5) generates two isoforms, PC5-A (soluble, 915 aa) and PC5-B (membrane-bound, 1877 aa), that are sorted to distinct subcellular compartments: PC5-A to regulated secretory granules (including glucagon-containing granules in pancreatic cells) and PC5-B to the Golgi. A C-terminal 38-amino-acid segment in PC5-A is required for entry into the regulated secretory pathway. Stable transfection of AtT-20 cells, biosynthetic analyses, immunofluorescence, electron microscopy immunohistochemistry of pancreatic cells, C-terminal deletion mutagenesis The Journal of cell biology High 8947550
1996 PC5 (PCSK5) cleaves receptor protein tyrosine phosphatase mu (RPTPmu) at its RXK/RR motif; active-site serine-to-alanine mutant PC5 lacks this activity; PACE4 does not cleave RPTPmu; PC5 mRNA is upregulated >30-fold at confluence in human umbilical vein endothelial cells. COS cell co-transfection with RPTPmu and PC5 or PACE4 expression plasmids, immunoblotting, active-site mutagenesis (Ser→Ala), RNA blot analysis Biochemistry High 8620001
1996 PC5 (PCSK5) can process human prorenin into active renin dependent on the dibasic amino acids at positions 42/43 of the prorenin prosegment; this processing occurs only in cells with dense-core secretory granules (GH4C1 cells) and PC5 co-localizes with renin in the zona glomerulosa of human adrenal cortex. Co-transfection of prorenin and PC5 in GH4C1 cells, prorenin site-directed mutants, immunohistochemistry Hypertension High 8901832
1996 Human PC6A and PC6B isoforms of PCSK5 are expressed in human CD4+ T lymphocytes and are candidate proteases for HIV-1 gp160 processing in these cells, which are competent for infectious 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 Medium 8755538
1996 The human PCSK5 gene was mapped to chromosome 9q21.3 near markers D9S175 and D9S276. Somatic cell hybrid analysis, YAC clone analysis, fluorescence in situ hybridization (FISH) Cytogenetics and cell genetics Medium 9067430
1998 PC5-A (PCSK5) functions as a prohormone convertase in the regulated secretory pathway; in PC12 cells it processes pro-neurotensin/neuromedin N in early compartments of the regulated secretory pathway according to a pattern resembling adrenal medulla processing and distinct from PC1 and PC2. Stable transfection of PC12 cells with PC5-A, metabolic labeling, immunochemical studies, subcellular fractionation, co-localization with immunoreactive neurotensin The Journal of biological chemistry High 9738000
1998 BMP-4 is proteolytically activated by furin and/or PC6 (PCSK5) during vertebrate embryogenesis; in Xenopus oocytes, both furin and PC6B cleave BMP-4 at its RSKR site and are sensitive to the inhibitor alpha1-PDX. Xenopus oocyte translation assay, in vitro digestion assay with PC family members, ectopic expression of alpha1-antitrypsin Portland (alpha1-PDX) in embryos, epistasis with downstream BMP pathway components The EMBO journal High 9707432
1999 PC5-A (PCSK5) immunoreactivity in rat brain neurons is concentrated in the Golgi apparatus and small vesicular elements in perikarya and dendrites, but not in axons or astrocytes, consistent with activity in early compartments of the neuronal regulated secretory pathway. Immunohistochemistry with N-terminal specific antibody, co-localization with Golgi marker MG-160, absence of co-localization with synaptic marker Dynamin-1, absence in S-100alpha-positive glia Neuroscience Medium 10408612
2003 Furin, PC5 (PCSK5), and PC7 activate VEGF-C by cleaving its precursor (proVEGF-C) at the dibasic motif HSIIRR↓SL; this processing is essential for VEGF-C-induced angiogenesis, lymphangiogenesis and tumor growth in vivo. Co-transfection in LoVo (furin-deficient) cells, in vitro digestion of synthetic fluorogenic peptide, inhibition with prosegment inhibitors, CHO cell xenograft model in nude mice with cleavage-site mutants The Journal of clinical investigation High 12782675
2003 PC5A (PCSK5) co-localizes with alphav integrin in vascular smooth muscle cells (VSMCs) during vascular remodeling in vivo; endoproteolytic cleavage of alphav integrin by PC5 occurs in the trans-Golgi network, as shown by brefeldin A inhibition; furin mRNA is not upregulated during neointima formation, whereas PC5A mRNA is, indicating PC5 is the major convertase for alphav integrin activation in this context. Comparative immunocytochemistry, Northern blot, in situ hybridization, Golgi disruption with brefeldin A, balloon injury model in rodents Histochemistry and cell biology Medium 12649739
2004 PC5 (PCSK5) is required for alphav integrin endoproteolytic activation in vascular smooth muscle cells; PC5-specific antisense oligonucleotides and the pharmacological PC inhibitor dec-CMK block alphav cleavage, inhibit VSMC adhesion to vitronectin, inhibit migration on vitronectin, and reduce focal adhesion kinase (Y397) autophosphorylation and Akt activation without affecting ERK1/2 phosphorylation. Antisense oligonucleotides against PC5, pharmacological inhibitor (dec-CMK), immunoblotting, VSMC adhesion and migration assays, FAK/Akt/ERK phosphorylation analysis, immunohistochemistry of human endarterectomy lesions Circulation High 14970114
2004 PC6 (PCSK5) is specifically induced in uterine stromal cells at the embryo attachment site during early pregnancy in mice; morpholino antisense oligonucleotide-mediated knockdown of PC6 in the mouse uterus completely blocks embryo implantation; PC6 is also dramatically upregulated during uterine decidualization in primates. In vivo morpholino antisense knockdown in mice, immunohistochemistry during early pregnancy (mouse, rhesus monkey, human), timed pregnancy studies Biology of reproduction High 15601911
2006 PCSK9 is inactivated by furin and/or PC5/6A through cleavage at the motif RFHR↓218; gain-of-function PCSK9 mutations (R218S, F216L, D374Y) associated with hypercholesterolemia result in loss of furin/PC5/6A processing; this cleavage may reduce PCSK9 lifetime and its ability to degrade LDL receptor. Cell transfection experiments, site-directed mutagenesis of PCSK9, immunoblotting for cleavage products, analysis of circulating human plasma The Journal of biological chemistry High 16912035
2006 Poly-arginine peptides (up to nona-L-Arg) are potent nanomolar inhibitors of PC5/6A (Ki ~150 nM for nona-L-Arg), with nona-D-Arg being even more potent (Ki ~19 nM); positional scanning libraries reveal strong preference for basic residues in all positions of the PC5/6A active site. Positional scanning-synthetic peptide combinatorial library (PS-SPCL) screening, enzymatic inhibition assays (Ki determination) Molecular pharmacology High 17012622
2007 A predicted alpha-helix in the C-terminus of PC5/6A (PCSK5) is critical for targeting to dense-core secretory granules in AtT-20 cells, functioning by the same mechanism as the granule-targeting helices of PC1/3 and PC2; hydrophobic amino acid clustering in the helix correlates with granule-sorting efficiency. C-terminal domain fusion proteins targeting heterologous constitutively secreted protein, subcellular distribution analysis in AtT-20 cells, mutagenesis of predicted alpha-helix The FEBS journal High 17645548
2008 GDF11 is cleaved and activated by PCSK5A but not by PCSK5A-C470R; selectivity resides in a P1' Asn in the RSRR↓N cleavage motif; PCSK5 is essential for embryonic anteroposterior patterning, nephrogenesis, skeletal, and anorectal development, at least partly through GDF11 activation and consequent regulation of Hox gene paralogs (Hoxa, Hoxc, Hoxd) and Mnx1. ENU-induced mouse mutation (C470R), compound Pcsk5 mutants, epiblast-specific conditional deletion, in vitro and ex vivo cleavage assays, in situ hybridization, P1' mutagenesis, Gdf11-deficient embryo comparison Genes & development High 18519639
2008 PC5/6 (PCSK5) is required for embryo implantation and is essential for anteroposterior patterning (extra vertebrae, tail agenesis, kidney agenesis) in a GDF11-dependent manner; Gdf11 P1' Asn confers selectivity for PC5/6 over other convertases; epiblast-specific deletion confirms the embryonic requirement. Conditional epiblast-specific Pcsk5 knockout (CD1/129/Sv/C57BL/6 background), in vitro and ex vivo cleavage assays, in situ hybridization for Pcsk5 and Gdf11, P1' Asn mutagenesis of cleavage motif Proceedings of the National Academy of Sciences of the United States of America High 18378898
2008 Furin, PACE4, PC5, and PC7 all cleave preprohepcidin at the RRRRR↓59DT motif to generate active hepcidin; site-directed mutagenesis of the cleavage site abrogates processing; hepcidin with RRRRR→SSSSS mutation is inactive as an inducer of ferroportin degradation. Cell transfection in Huh-7 and LoVo cells, inhibitor studies with alpha1-PDX and ppFurin, site-directed mutagenesis, in vitro peptide digestion, developmental expression analysis Gut High 18664504
2009 PC5/6 (PCSK5) is protective against intestinal tumorigenesis; enterocyte-specific Pcsk5 knockout in the ApcMin/+ mouse model results in significantly higher tumor numbers in the duodenum and premature mortality; human intestinal tumors systematically downregulate PC5/6 expression. Enterocyte-specific conditional Pcsk5 knockout, ApcMin/+ double mutant mouse model, tumor enumeration, human tumor expression analysis Molecular cancer High 19737405
2010 Zebrafish PCSK5.1 and PCSK5.2 are co-orthologs of mammalian PCSK5; PC5.1-deficient embryos display abnormal neuromast deposition in the lateral line system and loss of normal touch response, demonstrating a role in sensory organ development. cDNA cloning of zebrafish PCSK5.1 and PCSK5.2, morpholino-mediated knockdown of PC5.1, synteny analysis, in situ hybridization Developmental dynamics Medium 20882679
2011 PCSK5 (PC5/6) expression is selectively elevated during the transition from two-layer secondary to pre-antral follicle in the mouse ovary; activin A selectively enhances PCSK5 expression; inhibition of proconvertase activity blocks inhibin alpha- and beta-subunit maturation; overexpression of PC5/6 in furin-deficient cells increases inhibin alpha- and beta(B)-subunit maturation, identifying inhibin subunits as substrates of PCSK5. Real-time quantitative RT-PCR, inhibitor dec-RVKR-CMK in granulosa cells, overexpression of PC5/6 in furin-deficient cells, immunoblotting for inhibin subunit maturation PloS one High 21408162
2015 PC6 (PCSK5) cleaves the N-terminus of alpha-dystroglycan (alpha-DG-N) at a PC6-cleavage site near alpha-DG-N; this removal is required for embryo attachment to endometrial epithelial cells; PC6 knockdown reduces alpha-DG-N removal from the cell surface and blastocyst adhesion; mutating the PC6-cleavage site prevents alpha-DG-N removal and causes retention of full-length alpha-DG with loss of cell adhesiveness; alpha-DG-N is removed from endometrial tissue in vivo coinciding with receptivity. In vitro cleavage assay of PC6-cleavage site peptide, PC6 siRNA knockdown, site-directed mutagenesis of cleavage site, blastocyst adhesion assay, in vivo endometrial tissue analysis, flow cytometry for cell surface alpha-DG FASEB journal High 26077903
2017 Osteopontin (OPN) is a novel substrate for PC5/6 (PCSK5) in bone; PC5/6A directly cleaves OPN at noncanonical and canonical consensus sequences, reducing full-length OPN (~70 kDa) to N-terminal (~50 kDa) and C-terminal (~18/16 kDa) fragments; PC5/6-knockout mice show altered OPN processing in bone and reduced mineralization; Pcsk5 and Opn are co-expressed in bone cells. In silico cleavage site analysis, ex vivo co-transfection of OPN and PC5/6, cell-free enzyme-substrate assay, mass spectrometry of cleavage products, micro-CT of KO embryos, in situ hybridization, immunoblotting of bone extracts from KO vs. WT mice Bone High 29126984
2017 Pcsk5 is required specifically in the cranio-cardiac mesoderm for cardiogenesis; conditional deletion in all epiblastic lineages recapitulates all developmental malformations except tracheo-esophageal defects; deletion specifically in cardiogenic or pharyngeal mesodermal progenitors (forming later from cranio-cardiac mesoderm) or in neural crest does not affect heart development. MRI of mouse embryo heart development, multiple tissue-specific conditional Cre-mediated Pcsk5 deletions (epiblast, cranio-cardiac mesoderm, cardiogenic progenitors, pharyngeal mesoderm, neural crest) BMC developmental biology High 28446132
2024 PCSK5 activates precursor TGF-beta (pro-TGF-beta) by binding and cleaving at the pro-TGF-beta cleavage site, thereby activating the TGF-beta/SMAD2/3 pathway and promoting extracellular matrix expression in adventitial fibroblasts; this contributes to vascular fibrosis in Takayasu arteritis. Leflunomide inhibits PCSK5 and pro-TGF-beta binding, reducing TGF-beta activation. Co-immunoprecipitation of PCSK5 and pro-TGF-beta, overexpression of PCSK5 in adventitial fibroblasts, immunoblotting for mature TGF-beta and SMAD2/3 phosphorylation, ECM protein expression, leflunomide treatment in cells and patients Journal of autoimmunity Medium 38972101
2022 The most efficiently cleaved PC5/6A fluorogenic substrate is acetyl-Arg-Arg-Tle-Lys-Arg-AMC (highest kcat/KM), establishing the active-site substrate preference of PC5/6A among a panel of novel synthetic substrates. In vitro enzymatic assay of novel fluorogenic peptide substrates with purified PC5/6A, kinetic characterization (kcat, KM, kcat/KM) Analytical biochemistry High 35964735
2001 PC5 (PCSK5) processes pro-CCK into glycine-extended CCK 12 and CCK 22 in neuronal cell lines (GT1-7, SK-N-MC, SK-N-SH) that express PC5 but not PC1 or PC2, demonstrating a role for PC5 in CCK processing distinct from PC1/PC2. RT-PCR and Western blot for convertase expression, stable CCK overexpression, radioimmunoassay for pro-CCK cleavage products, gel filtration chromatography, carboxypeptidase B treatment Peptides Medium 11457520
2005 siRNA-mediated knockdown of PC5 (PCSK5) in STC-1 intestinal cells reduces CCK secretion (particularly CCK 22 in media) and causes a compensatory ~3-fold increase in PC2 mRNA and protein, providing direct evidence that PC5 is involved in CCK processing. Stable transfection with siRNA hairpin constructs targeting PC5, quantitative PCR, Western blot, CCK radioimmunoassay Peptides Medium 16266771

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 235 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 105 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 53 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
2004 Inhibiting uterine PC6 blocks embryo implantation: an obligatory role for a proprotein convertase in fertility. Biology of reproduction 41 15601911
2010 Resveratrol reduces oxidative stress and cell death and increases mitochondrial antioxidants and XIAP in PC6.3-cells. Neuroscience letters 40 21094207
2009 The effects of acupuncture stimulation at PC6 (Neiguan) on chronic mild stress-induced biochemical and behavioral responses. Neuroscience letters 39 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
2007 Effects and mechanisms of electroacupuncture at PC6 on frequency of transient lower esophageal sphincter relaxation in cats. World journal of gastroenterology 30 17828819
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) 29 21273245
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
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
2023 Electroacupuncture at Neiguan (PC6) attenuates cardiac dysfunction caused by cecal ligation and puncture via the vagus nerve. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 19 36996679
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 16 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
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
2019 Acupuncture at PC6 prevents cardiac hypertrophy in isoproterenol-treated mice. Acupuncture in medicine : journal of the British Medical Acupuncture Society 13 30843422
2019 LRRTM4 and PCSK5 Genetic Polymorphisms as Markers for Cognitive Impairment in A Hypotensive Aging Population: A Genome-Wide Association Study in Taiwan. Journal of clinical medicine 13 31362389
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 Antihypertensive and Antifibrosis Effects of Acupuncture at PC6 Acupoints in Spontaneously Hypertensive Rats and the Underlying Mechanisms. Frontiers in physiology 10 32982761
2017 Pcsk5 is required in the early cranio-cardiac mesoderm for heart development. BMC developmental biology 10 28446132
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
2020 [Effect of electroacupuncture preconditioning of "Neiguan"(PC6) on myocardial LKB1/AMPK/PFK2 pathway in myocardial ischemia rats]. Zhen ci yan jiu = Acupuncture research 9 32144918
2018 The Beneficial Effects of Electroacupuncture at PC6 Acupoints (Neiguan) on Myocardial Ischemia in ASIC3 -/- mice. Journal of acupuncture and meridian studies 9 29608997
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 8 28900460
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
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
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 4 35377129
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 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 3 38972101
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
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
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 2 38764114
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 [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 1 40369922
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 Genetic Association of PCSK5 and MUC2 Gene Polymorphisms with Recurrent Pregnancy Loss (RPL). International journal of molecular sciences 0 40724834
2020 [Effect of manual acupuncture of "Shuigou" (GV26)"Neiguan" (PC6) on neurological function and expression of apoptosis-related factors in brain tissues surrounding hematoma in intracerebral hemorrhage rats]. Zhen ci yan jiu = Acupuncture research 0 33788447