{"gene":"PCSK5","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":1993,"finding":"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.","method":"Reverse transcriptase/PCR cloning, cDNA sequencing, Northern blotting, in situ hybridization","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cDNA cloning and structural characterization with multiple orthogonal methods (RT-PCR, Northern blot, in situ hybridization), single lab","pmids":["8341687"],"is_preprint":false},{"year":1996,"finding":"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.","method":"Stable transfection of AtT-20 cells, biosynthetic analysis, immunofluorescence, deletion mutagenesis, electron microscopy/immunogold labeling","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (mutagenesis, immunofluorescence, EM), functional sorting signal identified, replicated across cell types","pmids":["8947550"],"is_preprint":false},{"year":1994,"finding":"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.","method":"Vaccinia virus expression in LoVo (furin-deficient) cells, viral replication assay, site-directed mutant HA panel","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — functional rescue in furin-deficient cells with authentic viral substrate, sequence specificity confirmed with mutant panel","pmids":["8057485"],"is_preprint":false},{"year":1998,"finding":"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.","method":"In vitro digestion assay, Xenopus oocyte translation assay, alpha1-PDX inhibitor misexpression in embryos, epistasis with downstream BMP signaling components","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro cleavage assay combined with in vivo Xenopus genetic epistasis and inhibitor rescue experiments","pmids":["9707432"],"is_preprint":false},{"year":1996,"finding":"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.","method":"COS cell cotransfection, active-site serine-to-alanine mutagenesis, immunoblotting, RNA blot analysis","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — active-site mutagenesis abolishes cleavage, single lab but mechanistically rigorous with direct catalytic evidence","pmids":["8620001"],"is_preprint":false},{"year":1996,"finding":"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.","method":"RT-PCR, Northern blot analysis, comparison with furin-deficient LoVo cells","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Low","confidence_rationale":"Tier 3 / Weak — expression-based inference in T cells, no direct cleavage assay for gp160 by PC6 was performed in this study","pmids":["8755538"],"is_preprint":false},{"year":1996,"finding":"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.","method":"Co-transfection of PC5 and prorenin in GH4C1 cells, site-directed mutagenesis of prorenin cleavage site, immunohistochemistry","journal":"Hypertension","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional cleavage assay with mutagenesis of substrate site, co-localization confirmed by IHC, single lab","pmids":["8901832"],"is_preprint":false},{"year":1998,"finding":"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.","method":"Stable transfection of PC12 cells, metabolic labeling, immunochemistry, subcellular fractionation, HPLC analysis of cleavage products","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct demonstration of prohormone processing in regulated secretory pathway with subcellular co-localization and product characterization","pmids":["9738000"],"is_preprint":false},{"year":2003,"finding":"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.","method":"Cotransfection in LoVo (furin-deficient) cells, in vitro fluorogenic peptide cleavage assay, site-directed mutagenesis of cleavage site, nude mouse xenograft assay","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods including in vitro assay, cell-based assay in furin-deficient cells, mutagenesis of substrate, and in vivo functional validation","pmids":["12782675"],"is_preprint":false},{"year":2004,"finding":"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.","method":"Antisense oligonucleotide knockdown, pharmacological inhibition (dec-CMK), immunoblotting, adhesion and migration assays, FAK/Akt signaling assays, immunohistochemistry of human tissue","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal loss-of-function approaches (antisense + pharmacological), defined downstream signaling phenotypes, human tissue co-localization","pmids":["14970114"],"is_preprint":false},{"year":2003,"finding":"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.","method":"Balloon injury in vivo model, Northern blot, immunocytochemistry, brefeldin A treatment, in situ hybridization","journal":"Histochemistry and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — coordinated regulation shown in vivo and in vitro with functional Golgi blockade experiment, single lab","pmids":["12649739"],"is_preprint":false},{"year":2004,"finding":"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.","method":"Morpholino antisense oligonucleotide knockdown in vivo (mouse uterus), immunohistochemistry, in situ localization during early pregnancy in mouse and primates","journal":"Biology of reproduction","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo loss-of-function with complete phenotypic block of implantation, replicated across species (mouse, monkey, human)","pmids":["15601911"],"is_preprint":false},{"year":2006,"finding":"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.","method":"Cell-based processing assays, site-directed mutagenesis of PCSK9 cleavage site, immunoblotting, analysis of circulating PCSK9 forms in human plasma","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional processing assay with multiple natural mutations tested, validated in human plasma, mechanistic link to LDL receptor regulation established","pmids":["16912035"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Fusion protein analysis, deletion mutagenesis of C-terminal domain, subcellular distribution assay in AtT-20 cells, structural prediction","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis with functional targeting assay, single lab, defines sorting signal","pmids":["17645548"],"is_preprint":false},{"year":2008,"finding":"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.","method":"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","journal":"Proceedings of the National Academy of Sciences of the United States of America / Genes & development","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro cleavage with substrate mutagenesis, in vivo conditional knockout with phenotypic analysis, mechanistic validation of mutation, independently reported in two concurrent papers","pmids":["18378898","18519639"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Xenopus oocyte antisense knockdown, alpha1-PDX inhibitor (furin/PC6-selective), engineered alpha1-PDX variant targeting PC7, in vivo cleavage assays in embryos","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — orthogonal genetic and pharmacological approaches in both oocytes and embryos, site-specific cleavage mapping","pmids":["19651771"],"is_preprint":false},{"year":2008,"finding":"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).","method":"Cell transfection in LoVo cells, in vitro fluorogenic peptide cleavage assay, site-directed mutagenesis, furin inhibitor (alpha1-PDX, ppFurin)","journal":"Gut","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro assay plus cell-based rescue in furin-deficient cells with mutagenesis, single lab","pmids":["18664504"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Conditional enterocyte-specific Pcsk5 knockout in ApcMin/+ mouse model, tumor counting, survival analysis, human tumor expression analysis","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic loss-of-function with clear phenotypic readout, single lab","pmids":["19737405"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Overexpression in furin-deficient LoVo cells, pharmacological inhibition (dec-CMK) in granulosa cells, quantitative RT-PCR, Western blotting","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional rescue in furin-deficient cells plus loss-of-function with inhibitor, single lab","pmids":["21408162"],"is_preprint":false},{"year":2015,"finding":"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.","method":"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","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro cleavage assay, mutagenesis of substrate cleavage site, knockdown with functional adhesion readout, in vivo validation","pmids":["26077903"],"is_preprint":false},{"year":2001,"finding":"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.","method":"Stable transfection, radioimmunoassay, carboxypeptidase B treatment, gel filtration chromatography, RT-PCR, Western blot","journal":"Peptides","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-based assay with product characterization in cells lacking PC1/PC2, single lab","pmids":["11457520"],"is_preprint":false},{"year":2005,"finding":"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.","method":"Stable siRNA transfection, quantitative RT-PCR, Western blot, CCK radioimmunoassay","journal":"Peptides","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct knockdown with specific phenotypic readout (reduced CCK 22), single lab","pmids":["16266771"],"is_preprint":false},{"year":2017,"finding":"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.","method":"In silico site prediction, co-transfection (ex vivo), cell-free enzyme-substrate assay, mass spectrometry, micro-CT of knockout embryos, in situ hybridization, immunoblotting","journal":"Bone","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with mass spectrometry cleavage site identification, validated in PC5/6-knockout tissue, multiple orthogonal methods","pmids":["29126984"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Conditional tissue-specific Pcsk5 knockout (multiple Cre drivers), magnetic resonance imaging of embryonic hearts","journal":"BMC developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic conditional deletion with multiple Cre drivers, MRI phenotyping, single lab","pmids":["28446132"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Co-immunoprecipitation, overexpression in adventitial fibroblasts, Western blotting for SMAD2/3 activation, pharmacological inhibition (leflunomide), immunohistochemistry in TAK patient tissue","journal":"Journal of autoimmunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct protein interaction by Co-IP, functional overexpression and pharmacological disruption, single lab","pmids":["38972101"],"is_preprint":false},{"year":2025,"finding":"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.","method":"In-cell GDF11 maturation assay, reconstitution of PCSK5-null cells with different alleles, 3D matrigel culture, intraductal xenograft assay, anterograde transport assay","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — optimized in-cell assay with allelic reconstitution in null background, multiple readouts; preprint, not yet peer-reviewed","pmids":["40093128"],"is_preprint":true},{"year":1995,"finding":"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.","method":"Recombinant vaccinia virus co-expression, gel-permeation HPLC analysis of processing products","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct negative result in functional cell-based assay; establishes substrate exclusion for PC5","pmids":["7720860"],"is_preprint":false},{"year":1999,"finding":"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.","method":"Immunohistochemistry with N-terminal-directed antibody, co-localization with Golgi marker MG-160 and synaptic marker dynamin-1, glial marker S-100alpha","journal":"Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic subcellular localization by immunohistochemistry with multiple markers, consistent with sorting data from cell lines","pmids":["10408612"],"is_preprint":false},{"year":2006,"finding":"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.","method":"Positional scanning synthetic peptide combinatorial library (PS-SPCL) screening, enzyme kinetic assays (Ki determination)","journal":"Molecular pharmacology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — systematic enzymatic characterization of active site preference, single lab","pmids":["17012622"],"is_preprint":false}],"current_model":"PCSK5 (PC5/6) is a subtilisin-like serine endoprotease that cleaves precursor proteins at paired/multibasic amino acid motifs (K/R-Xn-K/R↓) in the trans-Golgi network and regulated secretory granules; it exists as two alternatively sorted isoforms—soluble PC5/6A (targeted to dense core granules via a C-terminal alpha-helical sorting signal) and membrane-bound PC5/6B (Golgi-resident)—and its established substrates include GDF11 (essential for anteroposterior patterning and kidney development), BMP-4, pro-VEGF-C, prorenin, alpha-dystroglycan N-terminus (required for endometrial receptivity), alphav integrin (required for VSMC adhesion and signaling), PCSK9, pro-TGF-beta, osteopontin, pro-neurotensin, pro-CCK, prohepcidin, and the hemagglutinin of virulent influenza viruses."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":1993,"claim":"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","pmids":["8341687"],"confidence":"Medium","gaps":["No substrate identified at cloning stage","ACTH/cAMP regulation shown only in Y1 cells"]},{"year":1996,"claim":"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","pmids":["8947550"],"confidence":"High","gaps":["Functional substrates of each isoform not yet mapped","Molecular sorting receptor for PC5/6A not identified"]},{"year":1996,"claim":"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","pmids":["8620001"],"confidence":"High","gaps":["Physiological consequence of RPTPmu cleavage not defined"]},{"year":1994,"claim":"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","pmids":["8057485"],"confidence":"High","gaps":["Relative contribution of PC5 vs furin in natural infection unresolved"]},{"year":1996,"claim":"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","pmids":["8901832","8755538"],"confidence":"Medium","gaps":["gp160 cleavage by PC6 inferred from expression only, no direct cleavage assay","Prorenin activation shown in cell lines, not in vivo kidney"]},{"year":1998,"claim":"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","pmids":["9707432"],"confidence":"High","gaps":["alpha1-PDX does not distinguish furin from PC6","Endogenous convertase identity at each site unresolved"]},{"year":1995,"claim":"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","pmids":["7720860"],"confidence":"Medium","gaps":["Structural basis of substrate exclusion not defined"]},{"year":1998,"claim":"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","pmids":["9738000"],"confidence":"High","gaps":["In vivo requirement for neurotensin processing not tested"]},{"year":1999,"claim":"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","pmids":["10408612"],"confidence":"Medium","gaps":["Single-marker dynamin-1 negative used to infer terminal exclusion"]},{"year":2001,"claim":"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","pmids":["11457520"],"confidence":"Medium","gaps":["Endogenous contribution to CCK biosynthesis not isolated"]},{"year":2004,"claim":"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","pmids":["14970114","12649739"],"confidence":"High","gaps":["dec-CMK not PC5-selective","Direct cleavage of alphav not reconstituted in vitro"]},{"year":2003,"claim":"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","pmids":["12782675"],"confidence":"High","gaps":["Redundancy with furin/PC7 leaves in vivo PC5 contribution unclear"]},{"year":2006,"claim":"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","pmids":["16912035"],"confidence":"High","gaps":["Quantitative role of PC5 vs furin in vivo plasma PCSK9 processing not separated"]},{"year":2008,"claim":"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","pmids":["18378898","18519639"],"confidence":"High","gaps":["GDF11-independent knockout phenotypes have undefined substrates"]},{"year":2008,"claim":"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","pmids":["18664504"],"confidence":"Medium","gaps":["Redundancy obscures in vivo PC5 contribution","No knockout validation of hepcidin defect"]},{"year":2009,"claim":"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","pmids":["19651771"],"confidence":"High","gaps":["Identity of the embryonic S1-site convertase unresolved"]},{"year":2009,"claim":"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","pmids":["19737405"],"confidence":"Medium","gaps":["Substrate mediating tumor protection not identified"]},{"year":2011,"claim":"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","pmids":["21408162"],"confidence":"Medium","gaps":["No in vivo ovarian knockout validation","Inhibitor not PC5-selective"]},{"year":2004,"claim":"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","pmids":["15601911","26077903"],"confidence":"High","gaps":["Full set of implantation substrates beyond alpha-DG not enumerated"]},{"year":2017,"claim":"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","pmids":["29126984","28446132"],"confidence":"High","gaps":["Cardiac substrate(s) in cranio-cardiac mesoderm not identified","OPN-processing consequence for mineralization mechanism not fully defined"]},{"year":2006,"claim":"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","pmids":["17012622"],"confidence":"Medium","gaps":["Inhibitors not selective over PC7"]},{"year":2024,"claim":"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","pmids":["38972101"],"confidence":"Medium","gaps":["Single Co-IP without reciprocal validation","In vivo requirement not tested"]},{"year":2025,"claim":"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)","pmids":["40093128"],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","Clinical/genetic disease association not established"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[4,14,8,12,22,19]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[4,28,14]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,12,24]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[1,27,10]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[1,7,27]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[7,12,16,8]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[14,3,22,23]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[9,24,12]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[11,19,18]}],"complexes":[],"partners":["GDF11","BMP4","VEGFC","PCSK9","TGFB1","ITGAV","REN","DAG1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q92824","full_name":"Proprotein convertase subtilisin/kexin type 5","aliases":["Proprotein convertase 5","PC5","Proprotein convertase 6","PC6","hPC6","Subtilisin/kexin-like protease PC5"],"length_aa":1860,"mass_kda":206.9,"function":"Serine endoprotease that processes various proproteins by cleavage at paired basic amino acids, recognizing the RXXX[KR]R consensus motif. Likely functions in the constitutive and regulated secretory pathways. Plays an essential role in pregnancy establishment by proteolytic activation of a number of important factors such as BMP2, CALD1 and alpha-integrins","subcellular_location":"Endomembrane system","url":"https://www.uniprot.org/uniprotkb/Q92824/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PCSK5","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PCSK5","total_profiled":1310},"omim":[{"mim_id":"607786","title":"PROPROTEIN CONVERTASE, SUBTILISIN/KEXIN-TYPE, 9; PCSK9","url":"https://www.omim.org/entry/607786"},{"mim_id":"603936","title":"GROWTH/DIFFERENTIATION FACTOR 11; GDF11","url":"https://www.omim.org/entry/603936"},{"mim_id":"600488","title":"PROPROTEIN CONVERTASE, SUBTILISIN/KEXIN-TYPE, 5; PCSK5","url":"https://www.omim.org/entry/600488"},{"mim_id":"600487","title":"PROPROTEIN CONVERTASE, SUBTILISIN/KEXIN-TYPE, 4; PCSK4","url":"https://www.omim.org/entry/600487"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Golgi apparatus","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"intestine","ntpm":24.4}],"url":"https://www.proteinatlas.org/search/PCSK5"},"hgnc":{"alias_symbol":["PC5","PC6","SPC6"],"prev_symbol":[]},"alphafold":{"accession":"Q92824","domains":[{"cath_id":"3.30.70.850","chopping":"36-108","consensus_level":"high","plddt":83.9464,"start":36,"end":108},{"cath_id":"3.40.50.200","chopping":"127-462","consensus_level":"high","plddt":91.3618,"start":127,"end":462},{"cath_id":"2.60.120.260","chopping":"464-603","consensus_level":"medium","plddt":90.7877,"start":464,"end":603},{"cath_id":"2.10.220.10","chopping":"1310-1356","consensus_level":"medium","plddt":82.4472,"start":1310,"end":1356},{"cath_id":"2.10.220.10","chopping":"1652-1730","consensus_level":"high","plddt":76.4458,"start":1652,"end":1730}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92824","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q92824-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q92824-F1-predicted_aligned_error_v6.png","plddt_mean":76.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PCSK5","jax_strain_url":"https://www.jax.org/strain/search?query=PCSK5"},"sequence":{"accession":"Q92824","fasta_url":"https://rest.uniprot.org/uniprotkb/Q92824.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q92824/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92824"}},"corpus_meta":[{"pmid":"10026183","id":"PMC_10026183","title":"Mitochondrial depolarization accompanies cytochrome c release during apoptosis in PC6 cells.","date":"1999","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10026183","citation_count":299,"is_preprint":false},{"pmid":"8341687","id":"PMC_8341687","title":"cDNA structure of the mouse and rat subtilisin/kexin-like PC5: a candidate proprotein convertase expressed in endocrine and nonendocrine cells.","date":"1993","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/8341687","citation_count":247,"is_preprint":false},{"pmid":"16912035","id":"PMC_16912035","title":"The proprotein convertase (PC) PCSK9 is inactivated by furin and/or PC5/6A: functional consequences of natural mutations and post-translational modifications.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16912035","citation_count":236,"is_preprint":false},{"pmid":"9707432","id":"PMC_9707432","title":"BMP-4 is proteolytically activated by furin and/or PC6 during vertebrate embryonic development.","date":"1998","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/9707432","citation_count":191,"is_preprint":false},{"pmid":"8057485","id":"PMC_8057485","title":"Proprotein-processing endoproteases PC6 and furin both activate hemagglutinin of virulent avian influenza viruses.","date":"1994","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/8057485","citation_count":183,"is_preprint":false},{"pmid":"12782675","id":"PMC_12782675","title":"The secretory proprotein convertases furin, PC5, and PC7 activate VEGF-C to induce tumorigenesis.","date":"2003","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/12782675","citation_count":175,"is_preprint":false},{"pmid":"8947550","id":"PMC_8947550","title":"The isoforms of proprotein convertase PC5 are sorted to different subcellular compartments.","date":"1996","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/8947550","citation_count":137,"is_preprint":false},{"pmid":"18519639","id":"PMC_18519639","title":"VACTERL/caudal regression/Currarino syndrome-like malformations in mice with mutation in the proprotein convertase Pcsk5.","date":"2008","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/18519639","citation_count":106,"is_preprint":false},{"pmid":"8698813","id":"PMC_8698813","title":"SPC4, SPC6, and the novel protease SPC7 are coexpressed with bone morphogenetic proteins at distinct sites during embryogenesis.","date":"1996","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/8698813","citation_count":85,"is_preprint":false},{"pmid":"18378898","id":"PMC_18378898","title":"In vivo functions of the proprotein convertase PC5/6 during mouse development: Gdf11 is a likely substrate.","date":"2008","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/18378898","citation_count":85,"is_preprint":false},{"pmid":"7891135","id":"PMC_7891135","title":"Distinct mRNA expression of the highly homologous convertases PC5 and PACE4 in the rat brain and pituitary.","date":"1995","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/7891135","citation_count":78,"is_preprint":false},{"pmid":"7720860","id":"PMC_7720860","title":"Comparative proteolytic processing of rat prosomatostatin by the convertases PC1, PC2, furin, PACE4 and PC5 in constitutive and regulated secretory pathways.","date":"1995","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/7720860","citation_count":65,"is_preprint":false},{"pmid":"19651771","id":"PMC_19651771","title":"Site-specific cleavage of BMP4 by furin, PC6, and PC7.","date":"2009","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19651771","citation_count":60,"is_preprint":false},{"pmid":"8620001","id":"PMC_8620001","title":"Increased proteolytic processing of protein tyrosine phosphatase mu in confluent vascular endothelial cells: the role of PC5, a member of the subtilisin family.","date":"1996","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8620001","citation_count":57,"is_preprint":false},{"pmid":"10912951","id":"PMC_10912951","title":"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.","date":"2000","source":"Anti-cancer drugs","url":"https://pubmed.ncbi.nlm.nih.gov/10912951","citation_count":54,"is_preprint":false},{"pmid":"8755538","id":"PMC_8755538","title":"Isolation of the human PC6 gene encoding the putative host protease for HIV-1 gp160 processing in CD4+ T lymphocytes.","date":"1996","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/8755538","citation_count":50,"is_preprint":false},{"pmid":"17012622","id":"PMC_17012622","title":"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.","date":"2006","source":"Molecular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/17012622","citation_count":47,"is_preprint":false},{"pmid":"9738000","id":"PMC_9738000","title":"PC5-A-mediated processing of pro-neurotensin in early compartments of the regulated secretory pathway of PC5-transfected PC12 cells.","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9738000","citation_count":46,"is_preprint":false},{"pmid":"16244876","id":"PMC_16244876","title":"Proprotein convertases furin and PC5: targeting atherosclerosis and restenosis at multiple levels.","date":"2005","source":"Journal of molecular medicine (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/16244876","citation_count":42,"is_preprint":false},{"pmid":"21094207","id":"PMC_21094207","title":"Resveratrol reduces oxidative stress and cell death and increases mitochondrial antioxidants and XIAP in PC6.3-cells.","date":"2010","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/21094207","citation_count":41,"is_preprint":false},{"pmid":"15601911","id":"PMC_15601911","title":"Inhibiting uterine PC6 blocks embryo implantation: an obligatory role for a proprotein convertase in fertility.","date":"2004","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/15601911","citation_count":41,"is_preprint":false},{"pmid":"19427367","id":"PMC_19427367","title":"The effects of acupuncture stimulation at PC6 (Neiguan) on chronic mild stress-induced biochemical and behavioral responses.","date":"2009","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/19427367","citation_count":40,"is_preprint":false},{"pmid":"9013936","id":"PMC_9013936","title":"The developmental expression in the rat CNS and peripheral tissues of proteases PC5 and PACE4 mRNAs: comparison with other proprotein processing enzymes.","date":"1997","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/9013936","citation_count":38,"is_preprint":false},{"pmid":"22378585","id":"PMC_22378585","title":"The influence of PC6 on cardiovascular disorders: a review of central neural mechanisms.","date":"2012","source":"Acupuncture in medicine : journal of the British Medical Acupuncture Society","url":"https://pubmed.ncbi.nlm.nih.gov/22378585","citation_count":37,"is_preprint":false},{"pmid":"23948501","id":"PMC_23948501","title":"Enzymatic conversion of D-galactose to D-tagatose: cloning, overexpression and characterization of L-arabinose isomerase from Pediococcus pentosaceus PC-5.","date":"2013","source":"Microbiological research","url":"https://pubmed.ncbi.nlm.nih.gov/23948501","citation_count":35,"is_preprint":false},{"pmid":"14970114","id":"PMC_14970114","title":"Endoproteolytic activation of alpha(v) integrin by proprotein convertase PC5 is required for vascular smooth muscle cell adhesion to vitronectin and integrin-dependent signaling.","date":"2004","source":"Circulation","url":"https://pubmed.ncbi.nlm.nih.gov/14970114","citation_count":33,"is_preprint":false},{"pmid":"17828819","id":"PMC_17828819","title":"Effects and mechanisms of electroacupuncture at PC6 on frequency of transient lower esophageal sphincter relaxation in cats.","date":"2007","source":"World journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/17828819","citation_count":30,"is_preprint":false},{"pmid":"21273245","id":"PMC_21273245","title":"PC6 levels in uterine lavage are closely associated with uterine receptivity and significantly lower in a subgroup of women with unexplained infertility.","date":"2011","source":"Human reproduction (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/21273245","citation_count":30,"is_preprint":false},{"pmid":"8901832","id":"PMC_8901832","title":"Prohormone convertase PC5 is a candidate processing enzyme for prorenin in the human adrenal cortex.","date":"1996","source":"Hypertension (Dallas, Tex. : 1979)","url":"https://pubmed.ncbi.nlm.nih.gov/8901832","citation_count":29,"is_preprint":false},{"pmid":"9291583","id":"PMC_9291583","title":"Murine subtilisin-like proteinase SPC6 is expressed during embryonic implantation, somitogenesis, and skeletal formation.","date":"1997","source":"Developmental genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9291583","citation_count":28,"is_preprint":false},{"pmid":"18664504","id":"PMC_18664504","title":"Regulation of prohepcidin processing and activity by the subtilisin-like proprotein convertases Furin, PC5, PACE4 and PC7.","date":"2008","source":"Gut","url":"https://pubmed.ncbi.nlm.nih.gov/18664504","citation_count":27,"is_preprint":false},{"pmid":"11181735","id":"PMC_11181735","title":"Selective expression of the proprotein convertases furin, pc5, and pc7 in proliferating vascular smooth muscle cells of the rat aorta in vitro.","date":"2001","source":"The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society","url":"https://pubmed.ncbi.nlm.nih.gov/11181735","citation_count":27,"is_preprint":false},{"pmid":"7782070","id":"PMC_7782070","title":"Chromosomal assignment of the genes for proprotein convertases PC4, PC5, and PACE 4 in mouse and human.","date":"1995","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/7782070","citation_count":27,"is_preprint":false},{"pmid":"11882580","id":"PMC_11882580","title":"Proprotein convertase PC5 regulation by PDGF-BB involves PI3-kinase/p70(s6)-kinase activation in vascular smooth muscle cells.","date":"2002","source":"Hypertension (Dallas, Tex. : 1979)","url":"https://pubmed.ncbi.nlm.nih.gov/11882580","citation_count":26,"is_preprint":false},{"pmid":"9729404","id":"PMC_9729404","title":"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.","date":"1998","source":"Brain research. Molecular brain research","url":"https://pubmed.ncbi.nlm.nih.gov/9729404","citation_count":26,"is_preprint":false},{"pmid":"17636173","id":"PMC_17636173","title":"Pro-protein convertases (PCs) other than PC6 are not tightly regulated for implantation in the human endometrium.","date":"2007","source":"Reproduction (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/17636173","citation_count":24,"is_preprint":false},{"pmid":"11298388","id":"PMC_11298388","title":"Growth and differentiation of PC6 cells: the effects of pulsed electromagnetic fields (PEMF).","date":"2001","source":"Bioelectromagnetics","url":"https://pubmed.ncbi.nlm.nih.gov/11298388","citation_count":23,"is_preprint":false},{"pmid":"36996679","id":"PMC_36996679","title":"Electroacupuncture at Neiguan (PC6) attenuates cardiac dysfunction caused by cecal ligation and puncture via the vagus nerve.","date":"2023","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/36996679","citation_count":23,"is_preprint":false},{"pmid":"21408162","id":"PMC_21408162","title":"Role of PCSK5 expression in mouse ovarian follicle development: identification of the inhibin α- and β-subunits as candidate substrates.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21408162","citation_count":22,"is_preprint":false},{"pmid":"10408612","id":"PMC_10408612","title":"Immunohistochemical distribution of the prohormone convertase PC5-A in rat brain.","date":"1999","source":"Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/10408612","citation_count":22,"is_preprint":false},{"pmid":"19737405","id":"PMC_19737405","title":"The proprotein convertase PC5/6 is protective against intestinal tumorigenesis: in vivo mouse model.","date":"2009","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/19737405","citation_count":22,"is_preprint":false},{"pmid":"11457520","id":"PMC_11457520","title":"Neuronal cell lines expressing PC5, but not PC1 or PC2, process Pro-CCK into glycine-extended CCK 12 and 22.","date":"2001","source":"Peptides","url":"https://pubmed.ncbi.nlm.nih.gov/11457520","citation_count":21,"is_preprint":false},{"pmid":"21480163","id":"PMC_21480163","title":"PCSK5 and GDF11 expression in the hindgut region of mouse embryos with anorectal malformations.","date":"2011","source":"European journal of pediatric surgery : official journal of Austrian Association of Pediatric Surgery ... [et al] = Zeitschrift fur Kinderchirurgie","url":"https://pubmed.ncbi.nlm.nih.gov/21480163","citation_count":20,"is_preprint":false},{"pmid":"21327784","id":"PMC_21327784","title":"The nonstructural protein pC6 of rice grassy stunt virus trans-complements the cell-to-cell spread of a movement-defective tomato mosaic virus.","date":"2011","source":"Archives of virology","url":"https://pubmed.ncbi.nlm.nih.gov/21327784","citation_count":20,"is_preprint":false},{"pmid":"26077903","id":"PMC_26077903","title":"Posttranslational removal of α-dystroglycan N terminus by PC5/6 cleavage is important for uterine preparation for embryo implantation in women.","date":"2015","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/26077903","citation_count":19,"is_preprint":false},{"pmid":"21876715","id":"PMC_21876715","title":"Electroacupuncture at PC6 (Neiguan) Improves Extracellular Signal-Regulated Kinase Signaling Pathways Through the Regulation of Neuroendocrine Cytokines in Myocardial Hypertrophic Rats.","date":"2011","source":"Evidence-based complementary and alternative medicine : eCAM","url":"https://pubmed.ncbi.nlm.nih.gov/21876715","citation_count":19,"is_preprint":false},{"pmid":"34114404","id":"PMC_34114404","title":"Electroacupuncture Pretreatment at Neiguan (PC6) attenuates autophagy in rats with myocardial ischemia reperfusion through the phosphatidylinositol 3-kinase-Akt-mammalian target of rapamycin pathway.","date":"2021","source":"Journal of traditional Chinese medicine = Chung i tsa chih ying wen pan","url":"https://pubmed.ncbi.nlm.nih.gov/34114404","citation_count":18,"is_preprint":false},{"pmid":"7931173","id":"PMC_7931173","title":"Correlation of proteolytic cleavage of F protein precursors in paramyxoviruses with expression of the fur, PACE4 and PC6 genes in mammalian cells.","date":"1994","source":"The Journal of general virology","url":"https://pubmed.ncbi.nlm.nih.gov/7931173","citation_count":16,"is_preprint":false},{"pmid":"20882679","id":"PMC_20882679","title":"Molecular cloning and embryonic expression of zebrafish PCSK5 co-orthologues: functional assessment during lateral line development.","date":"2010","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/20882679","citation_count":15,"is_preprint":false},{"pmid":"17645548","id":"PMC_17645548","title":"PC1/3, PC2 and PC5/6A are targeted to dense core secretory granules by a common mechanism.","date":"2007","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/17645548","citation_count":15,"is_preprint":false},{"pmid":"12649739","id":"PMC_12649739","title":"Coordinated regulation and colocalization of alphav integrin and its activating enzyme proprotein convertase PC5 in vivo.","date":"2003","source":"Histochemistry and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/12649739","citation_count":15,"is_preprint":false},{"pmid":"28293268","id":"PMC_28293268","title":"Antihypertensive and Antihypertrophic Effects of Acupuncture at PC6 Acupoints in Spontaneously Hypertensive Rats and the Underlying Mechanisms.","date":"2017","source":"Evidence-based complementary and alternative medicine : eCAM","url":"https://pubmed.ncbi.nlm.nih.gov/28293268","citation_count":15,"is_preprint":false},{"pmid":"30843422","id":"PMC_30843422","title":"Acupuncture at PC6 prevents cardiac hypertrophy in isoproterenol-treated mice.","date":"2019","source":"Acupuncture in medicine : journal of the British Medical Acupuncture Society","url":"https://pubmed.ncbi.nlm.nih.gov/30843422","citation_count":14,"is_preprint":false},{"pmid":"310338","id":"PMC_310338","title":"Restorative effects of levamisole on cell-mediated immune responses following chemotherapy with aniline mustard in mice bearing ADJ-PC5 plasmacytoma.","date":"1978","source":"Cancer treatment reports","url":"https://pubmed.ncbi.nlm.nih.gov/310338","citation_count":14,"is_preprint":false},{"pmid":"10708868","id":"PMC_10708868","title":"Evolution of the prohormone convertases: identification of a homologue of PC6 in the protochordate amphioxus.","date":"2000","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/10708868","citation_count":14,"is_preprint":false},{"pmid":"17487164","id":"PMC_17487164","title":"pC6-2/caspase-6 system to purify glutathione-S-transferase-free recombinant fusion proteins expressed in Escherichia coli.","date":"2006","source":"Nature protocols","url":"https://pubmed.ncbi.nlm.nih.gov/17487164","citation_count":13,"is_preprint":false},{"pmid":"29126984","id":"PMC_29126984","title":"Osteopontin as a novel substrate for the proprotein convertase 5/6 (PCSK5) in bone.","date":"2017","source":"Bone","url":"https://pubmed.ncbi.nlm.nih.gov/29126984","citation_count":12,"is_preprint":false},{"pmid":"33313955","id":"PMC_33313955","title":"MicroRNA‑338‑3p regulates age‑associated osteoporosis via targeting PCSK5.","date":"2020","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/33313955","citation_count":11,"is_preprint":false},{"pmid":"28446132","id":"PMC_28446132","title":"Pcsk5 is required in the early cranio-cardiac mesoderm for heart development.","date":"2017","source":"BMC developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/28446132","citation_count":10,"is_preprint":false},{"pmid":"26055999","id":"PMC_26055999","title":"PCSK5 mutation in a patient with the VACTERL association.","date":"2015","source":"BMC research notes","url":"https://pubmed.ncbi.nlm.nih.gov/26055999","citation_count":10,"is_preprint":false},{"pmid":"25351954","id":"PMC_25351954","title":"Intake levels of dietary polyunsaturated fatty acids modify the association between the genetic variation in PCSK5 and HDL cholesterol.","date":"2014","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25351954","citation_count":10,"is_preprint":false},{"pmid":"32982761","id":"PMC_32982761","title":"Antihypertensive and Antifibrosis Effects of Acupuncture at PC6 Acupoints in Spontaneously Hypertensive Rats and the Underlying Mechanisms.","date":"2020","source":"Frontiers in physiology","url":"https://pubmed.ncbi.nlm.nih.gov/32982761","citation_count":10,"is_preprint":false},{"pmid":"32144918","id":"PMC_32144918","title":"[Effect of electroacupuncture preconditioning of \"Neiguan\"(PC6) on myocardial LKB1/AMPK/PFK2 pathway in myocardial ischemia rats].","date":"2020","source":"Zhen ci yan jiu = Acupuncture research","url":"https://pubmed.ncbi.nlm.nih.gov/32144918","citation_count":10,"is_preprint":false},{"pmid":"29608997","id":"PMC_29608997","title":"The Beneficial Effects of Electroacupuncture at PC6 Acupoints (Neiguan) on Myocardial Ischemia in ASIC3 -/- mice.","date":"2018","source":"Journal of acupuncture and meridian studies","url":"https://pubmed.ncbi.nlm.nih.gov/29608997","citation_count":10,"is_preprint":false},{"pmid":"17351018","id":"PMC_17351018","title":"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.","date":"2007","source":"Protein engineering, design & selection : PEDS","url":"https://pubmed.ncbi.nlm.nih.gov/17351018","citation_count":10,"is_preprint":false},{"pmid":"28900460","id":"PMC_28900460","title":"Manual Acupuncture at PC6 Ameliorates Acute Restraint Stress-Induced Anxiety in Rats by Normalizing Amygdaloid Noradrenergic Response.","date":"2017","source":"Evidence-based complementary and alternative medicine : eCAM","url":"https://pubmed.ncbi.nlm.nih.gov/28900460","citation_count":10,"is_preprint":false},{"pmid":"34016054","id":"PMC_34016054","title":"The dissection of R genes and locus Pc5.1 in Phytophthora capsici infection provides a novel view of disease resistance in peppers.","date":"2021","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/34016054","citation_count":9,"is_preprint":false},{"pmid":"7819286","id":"PMC_7819286","title":"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.","date":"1995","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/7819286","citation_count":8,"is_preprint":false},{"pmid":"2064832","id":"PMC_2064832","title":"Inhibition of human immunodeficiency virus forward and reverse transcription by PC6, a natural product from cones of pine trees.","date":"1991","source":"AIDS research and human retroviruses","url":"https://pubmed.ncbi.nlm.nih.gov/2064832","citation_count":8,"is_preprint":false},{"pmid":"797376","id":"PMC_797376","title":"Resistance of mice to Krebs ascites tumour, sarcoma S180 and PC6 plasmacytoma after immunisation with Salmonella enteritidis 11RX.","date":"1976","source":"The Australian journal of experimental biology and medical science","url":"https://pubmed.ncbi.nlm.nih.gov/797376","citation_count":8,"is_preprint":false},{"pmid":"15358338","id":"PMC_15358338","title":"Implications of proprotein Convertase 5 (PC5) in the arterial restenotic process in a porcine model.","date":"2004","source":"Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology","url":"https://pubmed.ncbi.nlm.nih.gov/15358338","citation_count":7,"is_preprint":false},{"pmid":"29392491","id":"PMC_29392491","title":"Targeting of rice grassy stunt virus pc6 protein to plasmodesmata requires the ER-to-Golgi secretory pathway and an actin-myosin VIII motility system.","date":"2018","source":"Archives of virology","url":"https://pubmed.ncbi.nlm.nih.gov/29392491","citation_count":7,"is_preprint":false},{"pmid":"11776387","id":"PMC_11776387","title":"Single-nucleotide polymorphisms of the proprotein convertase subtilisin/ kexin type 5 (PCSK5) gene.","date":"2001","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/11776387","citation_count":7,"is_preprint":false},{"pmid":"34238326","id":"PMC_34238326","title":"Full-length transcriptome analysis reveals the mechanism of acupuncture at PC6 improves cardiac function in myocardial ischemia model.","date":"2021","source":"Chinese medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34238326","citation_count":7,"is_preprint":false},{"pmid":"30945499","id":"PMC_30945499","title":"[Serum metabolic profile involving protective effect of \"Neiguan\"(PC6)-electroacupuncture preconditioning in rats with myocardial ischemia reperfusion injury].","date":"2019","source":"Zhen ci yan jiu = Acupuncture research","url":"https://pubmed.ncbi.nlm.nih.gov/30945499","citation_count":6,"is_preprint":false},{"pmid":"34939394","id":"PMC_34939394","title":"Efficacy on rabbits with arrhythmia: needling acupoint of Neiguan (PC6) at shallow or deep depth, and retaining needles for 10, 20, or 30 min.","date":"2021","source":"Journal of traditional Chinese medicine = Chung i tsa chih ying wen pan","url":"https://pubmed.ncbi.nlm.nih.gov/34939394","citation_count":5,"is_preprint":false},{"pmid":"24778705","id":"PMC_24778705","title":"The Effects of Needling Fenglong (ST40) and Neiguan (PC6) on IL-17 of ApoE-Gene-Knockout Mice's Liver.","date":"2014","source":"Evidence-based complementary and alternative medicine : eCAM","url":"https://pubmed.ncbi.nlm.nih.gov/24778705","citation_count":5,"is_preprint":false},{"pmid":"35377129","id":"PMC_35377129","title":"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.","date":"2022","source":"Journal of cardiovascular translational research","url":"https://pubmed.ncbi.nlm.nih.gov/35377129","citation_count":5,"is_preprint":false},{"pmid":"38972101","id":"PMC_38972101","title":"Pro-fibrotic effect of the susceptible gene PCSK5 in vascular fibrosis of Takayasu arteritis via TGF-β and SMAD3 signaling pathway activation.","date":"2024","source":"Journal of autoimmunity","url":"https://pubmed.ncbi.nlm.nih.gov/38972101","citation_count":4,"is_preprint":false},{"pmid":"16266771","id":"PMC_16266771","title":"Inhibition of PC5 expression decreases CCK secretion and increases PC2 expression.","date":"2005","source":"Peptides","url":"https://pubmed.ncbi.nlm.nih.gov/16266771","citation_count":4,"is_preprint":false},{"pmid":"35964735","id":"PMC_35964735","title":"Design, synthesis, and characterization of novel fluorogenic substrates of the proprotein convertases furin, PC1/3, PC2, PC5/6, and PC7.","date":"2022","source":"Analytical biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/35964735","citation_count":4,"is_preprint":false},{"pmid":"29138026","id":"PMC_29138026","title":"Hybrid DNA i-motif: Aminoethylprolyl-PNA (pC5) enhance the stability of DNA (dC5) i-motif structure.","date":"2017","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/29138026","citation_count":4,"is_preprint":false},{"pmid":"38553549","id":"PMC_38553549","title":"PCSK5 downregulation promotes the inhibitory effect of andrographolide on glioblastoma through regulating STAT3.","date":"2024","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/38553549","citation_count":3,"is_preprint":false},{"pmid":"38764114","id":"PMC_38764114","title":"Effect of electroacupuncture at \"Neiguan\" (PC6) on pain and brain orexin 1 receptor in mice with inflammatory pain.","date":"2024","source":"Zhen ci yan jiu = Acupuncture research","url":"https://pubmed.ncbi.nlm.nih.gov/38764114","citation_count":3,"is_preprint":false},{"pmid":"38110043","id":"PMC_38110043","title":"Genome-wide analysis in PC6 electroacupuncture to ameliorate carfilzomib-induced cardiotoxicity in mice.","date":"2023","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/38110043","citation_count":3,"is_preprint":false},{"pmid":"8664347","id":"PMC_8664347","title":"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.","date":"1996","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/8664347","citation_count":3,"is_preprint":false},{"pmid":"37570909","id":"PMC_37570909","title":"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.).","date":"2023","source":"Plants (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/37570909","citation_count":3,"is_preprint":false},{"pmid":"12508314","id":"PMC_12508314","title":"Molecular characterization of the cDNA and localization of the mRNA encoding the prohormone convertase PC5-A in the European green frog.","date":"2003","source":"The Journal of comparative neurology","url":"https://pubmed.ncbi.nlm.nih.gov/12508314","citation_count":3,"is_preprint":false},{"pmid":"38213246","id":"PMC_38213246","title":"Effect of electroacupuncture at Neiguan (PC6) at different time points on myocardial ischemia reperfusion arrhythmia in rats.","date":"2024","source":"Journal of traditional Chinese medicine = Chung i tsa chih ying wen pan","url":"https://pubmed.ncbi.nlm.nih.gov/38213246","citation_count":2,"is_preprint":false},{"pmid":"32333530","id":"PMC_32333530","title":"[Effect of acupuncture at different layers of local \"Neiguan\" (PC6) tissue on arrhythmia and expression of myocardial Cx43 in rabbits].","date":"2020","source":"Zhen ci yan jiu = Acupuncture research","url":"https://pubmed.ncbi.nlm.nih.gov/32333530","citation_count":2,"is_preprint":false},{"pmid":"40369922","id":"PMC_40369922","title":"[Regulatory effect of electroacupuncture at \"Neiguan\" (PC6) on mitochondrial autophagy during the ischemia and reperfusion phases in rats with myocardial ischemia-reperfusion injury].","date":"2025","source":"Zhongguo zhen jiu = Chinese acupuncture & moxibustion","url":"https://pubmed.ncbi.nlm.nih.gov/40369922","citation_count":2,"is_preprint":false},{"pmid":"40691032","id":"PMC_40691032","title":"[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].","date":"2025","source":"Zhen ci yan jiu = Acupuncture research","url":"https://pubmed.ncbi.nlm.nih.gov/40691032","citation_count":1,"is_preprint":false},{"pmid":"40938065","id":"PMC_40938065","title":"Stimulation of the wrist acupuncture point PC6 for preventing postoperative nausea and vomiting: a network meta-analysis.","date":"2025","source":"The Cochrane database of systematic reviews","url":"https://pubmed.ncbi.nlm.nih.gov/40938065","citation_count":1,"is_preprint":false},{"pmid":"9067430","id":"PMC_9067430","title":"Assignment of the human proprotein convertase gene PCSK5 to chromosome 9q21.3.","date":"1996","source":"Cytogenetics and cell genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9067430","citation_count":1,"is_preprint":false},{"pmid":"41566731","id":"PMC_41566731","title":"[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].","date":"2026","source":"Zhen ci yan jiu = Acupuncture research","url":"https://pubmed.ncbi.nlm.nih.gov/41566731","citation_count":1,"is_preprint":false},{"pmid":"25951641","id":"PMC_25951641","title":"[Effect of electro-acupuncture at Neiguan (PC6) and Lieque (LU7) on the expression of protein kinases in cardiomyocytes of myocardial ischemia rats].","date":"2015","source":"Zhongguo Zhong xi yi jie he za zhi Zhongguo Zhongxiyi jiehe zazhi = Chinese journal of integrated traditional and Western medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25951641","citation_count":1,"is_preprint":false},{"pmid":"9465315","id":"PMC_9465315","title":"[Neuronal differentiation of human small cell lung cancer cell line PC-6 by Solcoseryl].","date":"1997","source":"[Hokkaido igaku zasshi] The Hokkaido journal of medical science","url":"https://pubmed.ncbi.nlm.nih.gov/9465315","citation_count":1,"is_preprint":false},{"pmid":"40724834","id":"PMC_40724834","title":"Genetic Association of PCSK5 and MUC2 Gene Polymorphisms with Recurrent Pregnancy Loss (RPL).","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40724834","citation_count":0,"is_preprint":false},{"pmid":"40093128","id":"PMC_40093128","title":"PCSK5M452I is a recessive hypomorph exclusive to MCF10DCIS.com cells.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/40093128","citation_count":0,"is_preprint":false},{"pmid":"40003958","id":"PMC_40003958","title":"Direct Cloning and Heterologous Expression of the Dmxorosin Biosynthetic Gene Cluster from Streptomyces thermolilacinus SPC6, a Halotolerant Actinomycete Isolated from the Desert in China.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40003958","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":56551,"output_tokens":7783,"usd":0.143199,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":17132,"output_tokens":6290,"usd":0.121455,"stage2_stop_reason":"end_turn"},"total_usd":0.264654,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1993,\n      \"finding\": \"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.\",\n      \"method\": \"Reverse transcriptase/PCR cloning, cDNA sequencing, Northern blotting, in situ hybridization\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cDNA cloning and structural characterization with multiple orthogonal methods (RT-PCR, Northern blot, in situ hybridization), single lab\",\n      \"pmids\": [\"8341687\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"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.\",\n      \"method\": \"Stable transfection of AtT-20 cells, biosynthetic analysis, immunofluorescence, deletion mutagenesis, electron microscopy/immunogold labeling\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (mutagenesis, immunofluorescence, EM), functional sorting signal identified, replicated across cell types\",\n      \"pmids\": [\"8947550\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"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.\",\n      \"method\": \"Vaccinia virus expression in LoVo (furin-deficient) cells, viral replication assay, site-directed mutant HA panel\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — functional rescue in furin-deficient cells with authentic viral substrate, sequence specificity confirmed with mutant panel\",\n      \"pmids\": [\"8057485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro digestion assay, Xenopus oocyte translation assay, alpha1-PDX inhibitor misexpression in embryos, epistasis with downstream BMP signaling components\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro cleavage assay combined with in vivo Xenopus genetic epistasis and inhibitor rescue experiments\",\n      \"pmids\": [\"9707432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"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.\",\n      \"method\": \"COS cell cotransfection, active-site serine-to-alanine mutagenesis, immunoblotting, RNA blot analysis\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — active-site mutagenesis abolishes cleavage, single lab but mechanistically rigorous with direct catalytic evidence\",\n      \"pmids\": [\"8620001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"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.\",\n      \"method\": \"RT-PCR, Northern blot analysis, comparison with furin-deficient LoVo cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — expression-based inference in T cells, no direct cleavage assay for gp160 by PC6 was performed in this study\",\n      \"pmids\": [\"8755538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"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.\",\n      \"method\": \"Co-transfection of PC5 and prorenin in GH4C1 cells, site-directed mutagenesis of prorenin cleavage site, immunohistochemistry\",\n      \"journal\": \"Hypertension\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional cleavage assay with mutagenesis of substrate site, co-localization confirmed by IHC, single lab\",\n      \"pmids\": [\"8901832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"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.\",\n      \"method\": \"Stable transfection of PC12 cells, metabolic labeling, immunochemistry, subcellular fractionation, HPLC analysis of cleavage products\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct demonstration of prohormone processing in regulated secretory pathway with subcellular co-localization and product characterization\",\n      \"pmids\": [\"9738000\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"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.\",\n      \"method\": \"Cotransfection in LoVo (furin-deficient) cells, in vitro fluorogenic peptide cleavage assay, site-directed mutagenesis of cleavage site, nude mouse xenograft assay\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods including in vitro assay, cell-based assay in furin-deficient cells, mutagenesis of substrate, and in vivo functional validation\",\n      \"pmids\": [\"12782675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"Antisense oligonucleotide knockdown, pharmacological inhibition (dec-CMK), immunoblotting, adhesion and migration assays, FAK/Akt signaling assays, immunohistochemistry of human tissue\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal loss-of-function approaches (antisense + pharmacological), defined downstream signaling phenotypes, human tissue co-localization\",\n      \"pmids\": [\"14970114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"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.\",\n      \"method\": \"Balloon injury in vivo model, Northern blot, immunocytochemistry, brefeldin A treatment, in situ hybridization\",\n      \"journal\": \"Histochemistry and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — coordinated regulation shown in vivo and in vitro with functional Golgi blockade experiment, single lab\",\n      \"pmids\": [\"12649739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"Morpholino antisense oligonucleotide knockdown in vivo (mouse uterus), immunohistochemistry, in situ localization during early pregnancy in mouse and primates\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo loss-of-function with complete phenotypic block of implantation, replicated across species (mouse, monkey, human)\",\n      \"pmids\": [\"15601911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"Cell-based processing assays, site-directed mutagenesis of PCSK9 cleavage site, immunoblotting, analysis of circulating PCSK9 forms in human plasma\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional processing assay with multiple natural mutations tested, validated in human plasma, mechanistic link to LDL receptor regulation established\",\n      \"pmids\": [\"16912035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Fusion protein analysis, deletion mutagenesis of C-terminal domain, subcellular distribution assay in AtT-20 cells, structural prediction\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis with functional targeting assay, single lab, defines sorting signal\",\n      \"pmids\": [\"17645548\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America / Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro cleavage with substrate mutagenesis, in vivo conditional knockout with phenotypic analysis, mechanistic validation of mutation, independently reported in two concurrent papers\",\n      \"pmids\": [\"18378898\", \"18519639\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Xenopus oocyte antisense knockdown, alpha1-PDX inhibitor (furin/PC6-selective), engineered alpha1-PDX variant targeting PC7, in vivo cleavage assays in embryos\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — orthogonal genetic and pharmacological approaches in both oocytes and embryos, site-specific cleavage mapping\",\n      \"pmids\": [\"19651771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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).\",\n      \"method\": \"Cell transfection in LoVo cells, in vitro fluorogenic peptide cleavage assay, site-directed mutagenesis, furin inhibitor (alpha1-PDX, ppFurin)\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro assay plus cell-based rescue in furin-deficient cells with mutagenesis, single lab\",\n      \"pmids\": [\"18664504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional enterocyte-specific Pcsk5 knockout in ApcMin/+ mouse model, tumor counting, survival analysis, human tumor expression analysis\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic loss-of-function with clear phenotypic readout, single lab\",\n      \"pmids\": [\"19737405\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Overexpression in furin-deficient LoVo cells, pharmacological inhibition (dec-CMK) in granulosa cells, quantitative RT-PCR, Western blotting\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional rescue in furin-deficient cells plus loss-of-function with inhibitor, single lab\",\n      \"pmids\": [\"21408162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro cleavage assay, mutagenesis of substrate cleavage site, knockdown with functional adhesion readout, in vivo validation\",\n      \"pmids\": [\"26077903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"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.\",\n      \"method\": \"Stable transfection, radioimmunoassay, carboxypeptidase B treatment, gel filtration chromatography, RT-PCR, Western blot\",\n      \"journal\": \"Peptides\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-based assay with product characterization in cells lacking PC1/PC2, single lab\",\n      \"pmids\": [\"11457520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"Stable siRNA transfection, quantitative RT-PCR, Western blot, CCK radioimmunoassay\",\n      \"journal\": \"Peptides\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct knockdown with specific phenotypic readout (reduced CCK 22), single lab\",\n      \"pmids\": [\"16266771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"In silico site prediction, co-transfection (ex vivo), cell-free enzyme-substrate assay, mass spectrometry, micro-CT of knockout embryos, in situ hybridization, immunoblotting\",\n      \"journal\": \"Bone\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with mass spectrometry cleavage site identification, validated in PC5/6-knockout tissue, multiple orthogonal methods\",\n      \"pmids\": [\"29126984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional tissue-specific Pcsk5 knockout (multiple Cre drivers), magnetic resonance imaging of embryonic hearts\",\n      \"journal\": \"BMC developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic conditional deletion with multiple Cre drivers, MRI phenotyping, single lab\",\n      \"pmids\": [\"28446132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, overexpression in adventitial fibroblasts, Western blotting for SMAD2/3 activation, pharmacological inhibition (leflunomide), immunohistochemistry in TAK patient tissue\",\n      \"journal\": \"Journal of autoimmunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct protein interaction by Co-IP, functional overexpression and pharmacological disruption, single lab\",\n      \"pmids\": [\"38972101\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"In-cell GDF11 maturation assay, reconstitution of PCSK5-null cells with different alleles, 3D matrigel culture, intraductal xenograft assay, anterograde transport assay\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — optimized in-cell assay with allelic reconstitution in null background, multiple readouts; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"40093128\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"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.\",\n      \"method\": \"Recombinant vaccinia virus co-expression, gel-permeation HPLC analysis of processing products\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct negative result in functional cell-based assay; establishes substrate exclusion for PC5\",\n      \"pmids\": [\"7720860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"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.\",\n      \"method\": \"Immunohistochemistry with N-terminal-directed antibody, co-localization with Golgi marker MG-160 and synaptic marker dynamin-1, glial marker S-100alpha\",\n      \"journal\": \"Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic subcellular localization by immunohistochemistry with multiple markers, consistent with sorting data from cell lines\",\n      \"pmids\": [\"10408612\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"Positional scanning synthetic peptide combinatorial library (PS-SPCL) screening, enzyme kinetic assays (Ki determination)\",\n      \"journal\": \"Molecular pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic enzymatic characterization of active site preference, single lab\",\n      \"pmids\": [\"17012622\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PCSK5 (PC5/6) is a subtilisin-like serine endoprotease that cleaves precursor proteins at paired/multibasic amino acid motifs (K/R-Xn-K/R↓) in the trans-Golgi network and regulated secretory granules; it exists as two alternatively sorted isoforms—soluble PC5/6A (targeted to dense core granules via a C-terminal alpha-helical sorting signal) and membrane-bound PC5/6B (Golgi-resident)—and its established substrates include GDF11 (essential for anteroposterior patterning and kidney development), BMP-4, pro-VEGF-C, prorenin, alpha-dystroglycan N-terminus (required for endometrial receptivity), alphav integrin (required for VSMC adhesion and signaling), PCSK9, pro-TGF-beta, osteopontin, pro-neurotensin, pro-CCK, prohepcidin, and the hemagglutinin of virulent influenza viruses.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #28]. It is expressed as two alternatively sorted isoforms\\u2014soluble 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 [#1, #13]; PC5/6A acts in early compartments of the regulated secretory pathway and is not released with its substrates [#27]. 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 [#4, #14]. 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\\u2193N motif), as well as BMP-4; epiblast-specific deletion produces GDF11-related anteroposterior patterning, vertebral, and kidney-agenesis phenotypes [#14, #3]. 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 [#6, #8, #12, #24, #22, #7, #21, #16, #18]. In the vasculature it activates alphav integrin to drive smooth-muscle adhesion, migration, and FAK/Akt signaling [#9], and it cleaves alpha-dystroglycan and is required for embryo implantation [#19, #11]. PCSK5 additionally activates the hemagglutinin of virulent influenza viruses [#2] and is protective against intestinal tumorigenesis [#17].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"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.\",\n      \"evidence\": \"RT-PCR cloning, cDNA sequencing, Northern blot and in situ hybridization across tissues\",\n      \"pmids\": [\"8341687\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No substrate identified at cloning stage\", \"ACTH/cAMP regulation shown only in Y1 cells\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"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.\",\n      \"evidence\": \"Stable AtT-20 transfection, deletion mutagenesis, immunofluorescence, immunogold EM in pancreatic cells\",\n      \"pmids\": [\"8947550\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional substrates of each isoform not yet mapped\", \"Molecular sorting receptor for PC5/6A not identified\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"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.\",\n      \"evidence\": \"COS cotransfection, active-site Ser-to-Ala mutagenesis, immunoblot, RNA blot in HUVECs\",\n      \"pmids\": [\"8620001\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological consequence of RPTPmu cleavage not defined\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Showing PC6 restores influenza HA cleavage in furin-deficient cells established PCSK5 as a furin-like activator of viral fusion proteins relevant to pathogenicity.\",\n      \"evidence\": \"Vaccinia expression in LoVo cells, viral replication assay, mutant HA panel\",\n      \"pmids\": [\"8057485\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of PC5 vs furin in natural infection unresolved\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"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.\",\n      \"evidence\": \"Cotransfection in GH4C1 cells with prorenin site mutagenesis and IHC; expression inference in CD4+ T cells\",\n      \"pmids\": [\"8901832\", \"8755538\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"gp160 cleavage by PC6 inferred from expression only, no direct cleavage assay\", \"Prorenin activation shown in cell lines, not in vivo kidney\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vitro digestion, Xenopus oocyte translation, alpha1-PDX misexpression and BMP epistasis\",\n      \"pmids\": [\"9707432\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"alpha1-PDX does not distinguish furin from PC6\", \"Endogenous convertase identity at each site unresolved\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"The inability of PC5 to process prosomatostatin established that PCSK5 has a restricted substrate repertoire rather than indiscriminate multibasic cleavage.\",\n      \"evidence\": \"Vaccinia coexpression in LoVo and AtT-20 cells, HPLC product analysis\",\n      \"pmids\": [\"7720860\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of substrate exclusion not defined\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"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.\",\n      \"evidence\": \"Stable PC12 transfection, metabolic labeling, fractionation, HPLC of products\",\n      \"pmids\": [\"9738000\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo requirement for neurotensin processing not tested\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"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.\",\n      \"evidence\": \"Immunohistochemistry with Golgi, synaptic, and glial markers in rat brain\",\n      \"pmids\": [\"10408612\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-marker dynamin-1 negative used to infer terminal exclusion\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identifying PC5 as a pro-CCK convertase in cells lacking PC1/PC2 showed PCSK5 generates distinct CCK products, broadening its neuroendocrine processing role.\",\n      \"evidence\": \"Stable transfection of GT1-7/SK-N cells, RIA, carboxypeptidase B treatment, gel filtration\",\n      \"pmids\": [\"11457520\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous contribution to CCK biosynthesis not isolated\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"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.\",\n      \"evidence\": \"Antisense knockdown and dec-CMK inhibition, adhesion/migration assays, FAK/Akt blots, plaque IHC; in vivo balloon injury\",\n      \"pmids\": [\"14970114\", \"12649739\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"dec-CMK not PC5-selective\", \"Direct cleavage of alphav not reconstituted in vitro\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Demonstrating proVEGF-C cleavage by PC5 and others, with functional angio/lymphangiogenesis from mature ligand, connected PCSK5 to vascular growth-factor activation.\",\n      \"evidence\": \"LoVo cotransfection, fluorogenic peptide assay, cleavage-site mutagenesis, nude mouse assay\",\n      \"pmids\": [\"12782675\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Redundancy with furin/PC7 leaves in vivo PC5 contribution unclear\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Establishing that furin/PC5/6A cleave PCSK9 at RFHR218 and that hypercholesterolemia mutations block this cleavage linked PCSK5 activity to LDL-receptor regulation.\",\n      \"evidence\": \"Cell processing assays, PCSK9 site mutagenesis, human plasma analysis\",\n      \"pmids\": [\"16912035\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative role of PC5 vs furin in vivo plasma PCSK9 processing not separated\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vitro cleavage with substrate mutagenesis, conditional knockout, ENU mutagenesis, ER export assay\",\n      \"pmids\": [\"18378898\", \"18519639\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"GDF11-independent knockout phenotypes have undefined substrates\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showing prohepcidin processing by furin/PACE4/PC5/PC7 connected PCSK5 to iron homeostasis through generation of active hepcidin.\",\n      \"evidence\": \"LoVo rescue, fluorogenic peptide assay, cleavage-site mutagenesis\",\n      \"pmids\": [\"18664504\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Redundancy obscures in vivo PC5 contribution\", \"No knockout validation of hepcidin defect\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"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.\",\n      \"evidence\": \"Xenopus oocyte/embryo antisense knockdown, alpha1-PDX and engineered variants\",\n      \"pmids\": [\"19651771\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the embryonic S1-site convertase unresolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Enterocyte-specific Pcsk5 knockout increasing intestinal tumors on the ApcMin background, with downregulation in human tumors, established a tumor-protective role.\",\n      \"evidence\": \"Conditional knockout in ApcMin mice, tumor counts, survival, human expression analysis\",\n      \"pmids\": [\"19737405\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Substrate mediating tumor protection not identified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrating inhibin subunit maturation by PC5/6 and activin-driven PCSK5 induction linked the convertase to follicular development.\",\n      \"evidence\": \"LoVo overexpression, dec-CMK inhibition in granulosa cells, qRT-PCR, Western blot\",\n      \"pmids\": [\"21408162\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vivo ovarian knockout validation\", \"Inhibitor not PC5-selective\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"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.\",\n      \"evidence\": \"Uterine morpholino knockdown in vivo, IHC across mouse/primate; in vitro peptide cleavage, siRNA, substrate-site mutagenesis, blastocyst adhesion assay\",\n      \"pmids\": [\"15601911\", \"26077903\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full set of implantation substrates beyond alpha-DG not enumerated\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"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.\",\n      \"evidence\": \"In silico prediction, cotransfection, cell-free assay, mass spectrometry, micro-CT and Cre-conditional knockouts, MRI\",\n      \"pmids\": [\"29126984\", \"28446132\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cardiac substrate(s) in cranio-cardiac mesoderm not identified\", \"OPN-processing consequence for mineralization mechanism not fully defined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defining the polybasic active-site preference and potent nona-Arg inhibitors provided the biochemical basis for PCSK5 substrate selectivity and pharmacological targeting.\",\n      \"evidence\": \"Positional-scanning combinatorial peptide library screening, Ki kinetic assays\",\n      \"pmids\": [\"17012622\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Inhibitors not selective over PC7\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP, fibroblast overexpression, SMAD2/3 blots, leflunomide inhibition, patient tissue IHC\",\n      \"pmids\": [\"38972101\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single Co-IP without reciprocal validation\", \"In vivo requirement not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"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.\",\n      \"evidence\": \"In-cell GDF11 maturation assay, null-background allelic reconstitution, 3D matrigel and intraductal xenograft assays (preprint)\",\n      \"pmids\": [\"40093128\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not yet peer-reviewed\", \"Clinical/genetic disease association not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [4, 14, 8, 12, 22, 19]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [4, 28, 14]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 12, 24]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [1, 27, 10]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [1, 7, 27]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [7, 12, 16, 8]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [14, 3, 22, 23]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9, 24, 12]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [11, 19, 18]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"GDF11\", \"BMP4\", \"VEGFC\", \"PCSK9\", \"TGFB1\", \"ITGAV\", \"REN\", \"DAG1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}