Affinage

PCSK1

Neuroendocrine convertase 1 · UniProt P29120

Length
753 aa
Mass
84.2 kDa
Annotated
2026-04-29
100 papers in source corpus 27 papers cited in narrative 26 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PCSK1 encodes prohormone convertase 1/3 (PC1/3), a calcium-dependent subtilisin-like serine endoprotease that is the principal processing enzyme for neuroendocrine prohormones in the regulated secretory pathway. PC1/3 undergoes sequential autocatalytic activation—N-terminal propeptide removal in the ER followed by C-terminal truncation (87→74→66 kDa) in secretory granules—yielding progressively more active forms with shifted pH optima and altered substrate specificity, and cleaves proinsulin, POMC, proglucagon, prosomatostatin, provasopressin, proghrelin, and pro-GHRH at paired basic residues (PMID:8449925, PMID:8034588, PMID:8070378, PMID:9528943, PMID:27941249). Targeting to dense-core secretory granules depends on a C-terminal α-helical sorting domain (residues 738–750) whose hydrophobic patch (centered on L745) promotes calcium-dependent membrane aggregation, while enzyme activity is further regulated by homodimerization, substrate-induced delatentization, and the endogenous inhibitor proSAAS (PMID:19376969, PMID:21303942, PMID:11517193). Loss-of-function and dominant-negative PCSK1 mutations—including ER-retained missense variants that activate the unfolded protein response and recruit wild-type PC1/3 into proteasomal degradation—cause monogenic obesity with impaired prohormone processing, and reduced PCSK1 expression downstream of SNORD116 loss mechanistically links Prader–Willi syndrome to its characteristic endocrinopathy (PMID:18604207, PMID:24828610, PMID:26207343, PMID:24890885, PMID:27941249).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1993 High

    Establishing PC1/3 as a calcium-dependent, acidic-pH-optimum endoprotease with paired-basic-residue specificity resolved how prohormones are cleaved within the regulated secretory pathway.

    Evidence Purification of recombinant mouse PC1 from CHO cells with fluorogenic substrate kinetics, proenkephalin cleavage, and inhibitor profiling; parallel cell-based prosomatostatin processing assays

    PMID:8095501 PMID:8449925

    Open questions at the time
    • Crystal structure of the catalytic domain not yet determined
    • Full kinetic parameters for diverse prohormone substrates not systematically measured
  2. 1994 High

    Demonstrating that PC1/3 undergoes autocatalytic C-terminal truncation generating 74/66-kDa forms with higher activity and narrower pH optima revealed a built-in activation cascade that tunes enzyme function along the secretory pathway.

    Evidence In vitro spontaneous conversion assays, kinetics of multiple PC1 forms, and in vitro POMC processing with product mapping

    PMID:8034588 PMID:8070378

    Open questions at the time
    • Cellular compartment where each truncation step occurs was inferred but not directly visualized
    • Structural basis for activity change upon truncation unknown
  3. 1995 High

    Mapping the C-terminal truncation site to Arg590–Arg591 and showing that a truncated construct still sorts to secretory granules separated the enzyme-activation role of the C-terminus from its granule-targeting function.

    Evidence Site-directed mutagenesis in PC12 cells with proneurotensin processing and subcellular localization readouts

    PMID:7559585

    Open questions at the time
    • Sorting determinant downstream of residue 591 not yet mapped
    • Protease responsible for C-terminal cleavage in vivo not identified
  4. 1997 High

    Identifying the P-domain RRGDL motif as essential for ER zymogen processing, granule-compartment truncation, and correct trafficking established a single structural element governing multiple maturation checkpoints.

    Evidence Mutagenesis of RRGDL in BSC40/PC12/GH4C1 cells with pulse-chase, immunocytochemistry, and POMC processing assays

    PMID:9307023

    Open questions at the time
    • Structural role of RRGDL in folding versus direct sorting interaction not resolved
    • Whether P-domain mutations affect calcium binding was not tested
  5. 1998 High

    Showing that the 86-kDa and 64-kDa PC1/3 forms have different cleavage-site preferences on provasopressin demonstrated that C-terminal truncation is not merely activating but also specificity-altering, explaining tissue-specific prohormone processing patterns.

    Evidence In vitro processing of radiolabeled provasopressin with defined recombinant SPC3 forms

    PMID:9523585

    Open questions at the time
    • Mechanism by which C-terminal domain allosterically restricts cleavage-site selection unknown
  6. 1998 High

    Demonstrating that PC1 overexpression drives intestinal-type proglucagon processing (glicentin, oxyntomodulin, GLP-2) while PC2 generates glucagon resolved the long-standing question of how tissue-specific proglucagon products arise from differential convertase expression.

    Evidence Stable PC1 transfection and antisense PC2 depletion in InR1-G9 cells with HPLC/RIA product analysis

    PMID:9528943

    Open questions at the time
    • GLP-1(7-36NH2) was not increased by PC1 alone, implying additional processing steps or enzymes
  7. 2001 Medium

    Identification of proSAAS as a potent endogenous PC1/3 inhibitor co-expressed in neuroendocrine tissues established a physiological feedback mechanism for controlling convertase activity in vivo.

    Evidence In situ hybridization double-labeling of proSAAS and SPC3 throughout rat CNS and endocrine tissues

    PMID:11517193

    Open questions at the time
    • Direct in vivo demonstration that proSAAS regulates PC1/3 activity (e.g., proSAAS KO phenotype) was not shown in this study
    • Stoichiometry and kinetics of inhibition in granule lumen not measured
  8. 2001 High

    Demonstrating that thyroid hormone receptor α1 directly represses the PCSK1 promoter via novel TRE-like elements revealed a hormonal transcriptional control layer for PC1/3 expression.

    Evidence Promoter-deletion and EMSA with purified TRα1/RXRβ in GH3 cells

    PMID:11120670

    Open questions at the time
    • In vivo thyroid hormone regulation of PC1/3 protein levels and prohormone processing not demonstrated
  9. 2003 High

    Discovery that a 64-kDa PC1/3 form contains a transmembrane domain (residues 619–638) anchoring it to lipid rafts in secretory granule membranes, sufficient for granule targeting of a heterologous protein, revealed an unexpected membrane-tethered convertase population.

    Evidence Detergent resistance, sucrose gradient flotation, protease protection, IL2R-Tac chimera targeting assay

    PMID:12950171

    Open questions at the time
    • Whether the transmembrane form represents a physiologically significant fraction of total PC1/3 in vivo is unclear
    • Relationship between transmembrane and soluble C-terminally truncated forms not fully resolved
  10. 2009 High

    NMR structure of the C-terminal sorting domain (residues 711–753) pinpointed a second α-helix (738–750) with a hydrophobic patch centered on L745 as the necessary and sufficient granule-sorting signal, with calcium-dependent aggregation as the targeting mechanism.

    Evidence NMR in micelles, deletion/point mutagenesis targeting assays, calcium-binding aggregation assay

    PMID:19376969

    Open questions at the time
    • Membrane receptor or lipid species mediating initial helix–granule interaction not identified
    • Sorting mechanism shared with PC2/PC5 helix not structurally compared
  11. 2008 High

    Linking the common obesity-associated N221D variant to impaired catalytic activity in vitro and demonstrating that N222D knock-in mice phenocopy human PC1/3 deficiency (obesity, abnormal proinsulin processing, reduced α-MSH) provided the first direct genetic evidence that partial PC1/3 loss causes metabolic disease.

    Evidence In vitro catalytic assays of N221D; N222D knock-in mouse metabolic phenotyping and proinsulin processing

    PMID:16644867 PMID:18604207

    Open questions at the time
    • Whether the variant affects folding, ER exit, or catalysis per se was not fully dissected at this stage
  12. 2011 High

    Demonstrating that 87-kDa PC1/3 forms latent oligomers whose activity is relieved by dilution or substrate peptides uncovered a self-regulatory mechanism whereby enzyme concentration and substrate availability gate convertase output.

    Evidence Ion exchange chromatography, gel filtration, cross-linking, and fluorogenic activity assays with substrate peptides

    PMID:21303942

    Open questions at the time
    • Oligomer interface not structurally mapped
    • In vivo relevance of concentration-dependent latency not tested
  13. 2014 High

    Showing that the N222D mutant undergoes ER retention and proteasomal degradation and exerts a dominant-negative effect on wild-type PC1/3 maturation via co-immunoprecipitable interaction explained how heterozygous missense variants cause haploinsufficiency-exceeding disease severity.

    Evidence Pulse-chase, metabolic labeling, proteasome-inhibitor rescue, co-IP in transfected cells

    PMID:24828610

    Open questions at the time
    • Whether ER-associated degradation is ERAD-L or ERAD-C pathway not specified
    • Chaperone partners mediating retention not identified
  14. 2014 Medium

    A heterozygous nonsense mutation (p.Arg80*) producing a truncated propeptide that inhibits PC1/3 in trans established propeptide-mediated dominant-negative inhibition as a distinct pathogenic mechanism for monogenic obesity.

    Evidence In vitro inhibition assays of truncated propeptide; co-segregation in a three-generation family

    PMID:24890885

    Open questions at the time
    • Physical interaction between truncated propeptide and mature enzyme was not detected, leaving mechanism of inhibition unclear
    • Only one family studied
  15. 2015 High

    Demonstrating that additional ER-retained PC1/3 mutants (G209R, G593R) induce the unfolded protein response and block wild-type prodomain cleavage generalized the dominant-negative/ER-stress mechanism beyond N221D to a class of pathogenic variants.

    Evidence Co-expression of mutant and WT PC1/3 with ER stress marker assays and Western blot

    PMID:26207343

    Open questions at the time
    • Whether UPR activation contributes to disease phenotype beyond PC1/3 loss was not tested
  16. 2016 High

    Establishing that SNORD116 loss reduces NHLH2 and PC1/3 expression in iPSC-derived neurons and that Snord116-KO mice have defective prohormone processing identified PC1/3 deficiency as the mechanistic bridge between SNORD116 deletion and Prader–Willi syndrome endocrinopathy.

    Evidence PWS patient iPSC-derived neurons, Snord116p−/m+ mice, in vivo prohormone processing of proinsulin/pro-GHRH/proghrelin

    PMID:27941249

    Open questions at the time
    • Direct mechanism by which SNORD116 snoRNA regulates NHLH2/PCSK1 mRNA (splicing, stability, translation) not elucidated
  17. 2016 Medium

    Revealing that PC1/3 controls TLR9 endosomal trafficking and inflammatory polarization in macrophages expanded the enzyme's role beyond neuroendocrine prohormone processing to innate immune regulation.

    Evidence PC1/3 knockdown in NR8383 macrophages and KO mouse macrophages with TLR9/Rab7 co-localization, STAT3/NF-κB pathway readouts, secretome proteomics

    PMID:26330543 PMID:26778167

    Open questions at the time
    • PC1/3 substrate in macrophages that mediates TLR9 trafficking not identified
    • Whether catalytic activity or a non-enzymatic function is required was not determined
  18. 2017 High

    CRISPR and shRNA ablation of PCSK1 in human ESC-derived hypothalamic neurons recapitulated impaired POMC processing with reduced ACTH/α-MSH secretion, validating the enzyme's non-redundant role in a human neuronal context.

    Evidence PCSK1 KO/KD in hESC-derived hypothalamic neurons with POMC peptide quantification

    PMID:28132887

    Open questions at the time
    • Compensation by other convertases (PC2, furin) in human neurons not systematically assessed
  19. 2020 High

    Identification of Creb3l1 as a direct transcriptional activator binding the Pcsk1 promoter G-box added a second transcription factor (beyond TRα1) to the regulatory circuit controlling PC1/3 expression in hypothalamic neurons.

    Evidence RNA-seq, promoter-binding assay, viral Creb3l1 overexpression/knockdown in vivo (supraoptic nucleus) and in AtT20 cells

    PMID:32319174

    Open questions at the time
    • Physiological stimuli that activate Creb3l1 upstream of Pcsk1 not defined
    • Whether Creb3l1 regulation extends beyond hypothalamic neurons not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major unresolved questions include the structural basis for substrate selectivity and C-terminal allosteric regulation, the identity of PC1/3 substrates in macrophages and other non-neuroendocrine cells, the mechanism by which SNORD116 controls PCSK1 expression, and whether dominant-negative ER-stress effects of pathogenic variants contribute to disease beyond simple loss of enzyme activity.
  • No high-resolution full-length structure of PC1/3
  • Macrophage substrate identity unknown
  • SNORD116–PCSK1 regulatory mechanism undefined
  • In vivo contribution of UPR activation to disease pathogenesis untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 12 GO:0016787 hydrolase activity 3
Localization
GO:0031410 cytoplasmic vesicle 4 GO:0005783 endoplasmic reticulum 3 GO:0005768 endosome 1
Pathway
R-HSA-392499 Metabolism of proteins 9 R-HSA-9609507 Protein localization 3 R-HSA-162582 Signal Transduction 2 R-HSA-168256 Immune System 2
Partners
CREB3L1PAX6PCSK1NPOMCTHRATLR9

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 PC1/3 is a calcium-dependent serine proteinase with optimal activity at pH 5.5–6.5 that undergoes autocatalytic cleavage of its N-terminal prosegment (at RSKR motif, residues 80–83) early in biosynthesis, and cleaves proenkephalin to yield peptide B-sized fragment; specificity studies show preference for arginine 4 amino acids N-terminal to the cleavage site. Purification of recombinant mouse PC1 from CHO conditioned medium, fluorogenic substrate assays, in vitro proenkephalin cleavage, inhibitor profiling The Journal of biological chemistry High 8449925
1994 PC1/3 undergoes autocatalytic C-terminal truncation from 87 kDa to 74/66 kDa forms in vitro; the truncated forms have narrower pH optimum (5.0–5.5), are more enzymatically active but less stable, and show altered sensitivity to protease inhibitors compared with the 87-kDa form. In vitro spontaneous conversion assay, limited proteolysis, purification, fluorogenic substrate kinetics, inhibitor profiling The Journal of biological chemistry High 8034588
1994 Recombinant PC1 cleaves POMC in vitro at all paired-basic residue sites (except Lys-Arg and Lys-Lys in beta-lipotropin/beta-endorphin), generating ACTH intermediates, ACTH, joining peptide, 16-kDa N-POMC, N-POMC-(1-74), and beta-lipotropin, with a pH optimum of 6.0. In vitro processing of mouse POMC with partially purified recombinant rat PC1 from stably transfected L-cells, peptide product identification Endocrinology High 8070378
1995 The C-terminal truncation site of PC1 is at Arg590-Arg591; mutation of this site prevents processing from 87 kDa form, while a truncated mutant ending at this site is correctly routed to secretory granules and processes proneurotensin efficiently, indicating the C-terminal extension is not required for granule sorting but regulates enzyme activity. Site-directed mutagenesis of PC1 expressed in PC12 cells, proneurotensin processing assay, secretory pathway analysis The Journal of biological chemistry High 7559585
1997 The RRGDL motif in the P-domain of PC1 is critical for zymogen processing in the ER, C-terminal autocatalytic processing to the 66-kDa form in secretory granules, and proper trafficking to granules; RRGDL mutations cause ER retention/degradation, mis-sorting to the constitutive pathway, and impaired POMC processing. Site-directed mutagenesis (ARGDL, RAGDL, RRGEL variants), vaccinia-virus expression in BSC40/PC12/GH4C1 cells, pulse-chase analysis, immunocytochemistry, alpha1-PDX inhibitor co-expression The Biochemical journal High 9307023
1998 PC1/SPC3 cleaves provasopressin at both vasopressin-neurophysin and neurophysin-glycopeptide junctions; cleavage specificity differs between the 86-kDa (unprocessed C-terminus) and 64-kDa (C-terminally truncated) forms: 86-kDa form cleaves only at the neurophysin-glycopeptide site, while 64-kDa forms cleave at both sites, demonstrating that the C-terminus alters cleavage specificity. In vitro processing of radiolabeled provasopressin and prooxytocin with different recombinant SPC3 forms, including 64-kDa SPC3-T truncation construct Journal of neurochemistry High 9523585
2003 PC3/PC1 (86 and 64 kDa forms) associates with lipid rafts in secretory granule membranes; a 64-kDa form (PC3-TM) contains a transmembrane domain (residues 619–638) anchoring it to lipid rafts with an ~115-residue cytoplasmic tail; the transmembrane domain alone is sufficient to target a heterologous protein (IL2 receptor Tac ectodomain) to secretory granules. TX-100 detergent resistance, sucrose gradient flotation, cholesterol depletion, protease protection, immunolabeling, biotinylation of intact granules, 2D gel electrophoresis, IL2R-Tac chimera targeting assay Biochemistry High 12950171
2009 The extreme C-terminal sorting domain of PC1/3 (residues 711–753) adopts two alpha-helices (722–728 and 738–750) by NMR; the second helix is necessary and sufficient to target a constitutively secreted protein to dense core secretory granules, and L745 anchors a hydrophobic patch critical for sorting; calcium binding by this helix promotes aggregation via the hydrophobic patch. NMR structure determination of PC1/3(711-753) in micelles, deletion/mutagenesis functional targeting assays, calcium-binding aggregation assay Proceedings of the National Academy of Sciences of the United States of America High 19376969
2007 PC1/3, PC2, and PC5/6A are targeted to dense core secretory granules by a common mechanism requiring a C-terminal alpha-helix with clustered hydrophobic residues; predicted alpha-helix in PC5/6A C-terminus redirects a constitutively secreted protein to granules in AtT-20 cells. C-terminal fusion protein targeting assays in AtT-20 cells, alpha-helix prediction, comparison of PC1/3, PC2, PC5/6A sorting domains The FEBS journal High 17645548
1993 PC1 (but not furin or PC2) efficiently cleaves prosomatostatin at the dibasic Arg-Lys site to produce somatostatin-14 in heterologous cell expression; furin mediates monobasic cleavage in the constitutive pathway, while PC1 is required for dibasic cleavage in the regulated pathway. Transient transfection of PC1, PC2 in COS-7 and AtT-20 cells; PSS processing product analysis; correlation with endogenous convertase expression The Journal of biological chemistry High 8095501
1998 Overexpression of PC1 in islet-derived InR1-G9 cells drives proglucagon processing toward glicentin, oxyntomodulin, and GLP-2 (intestinal-type products), but does not increase GLP-1(7-36NH2); antisense depletion of PC2 eliminates glicentin but does not alter glucagon, establishing distinct roles for PC1 and PC2 in proglucagon processing. Stable transfection of PC1 or antisense PC2 in InR1-G9 cells, HPLC and RIA of proglucagon-derived peptides Endocrinology High 9528943
2008 The N221D variant of PC1/3 (encoded by rs6232) has significantly impaired catalytic activity in vitro; in N222D knock-in mice, the mutation causes obesity, abnormal proinsulin processing, reduced hypothalamic alpha-MSH, and impaired autocatalytic activation of mature PC1, phenocopying human PC1 deficiency. Functional analysis of N221D mutant in vitro; N222D mouse knock-in model with metabolic phenotyping, proinsulin processing assay Nature genetics / Human molecular genetics High 16644867 18604207
2014 The PC1/3 N222D mutation causes ER retention and accelerated proteasomal degradation of the mutant protein; coimmunoprecipitation shows N222D protein interacts with wild-type PC1/3 and exerts a modest dominant-negative effect on intracellular retention of WT enzyme. Pulse-chase immunoprecipitation, metabolic labeling, immunohistochemistry, ubiquitin-proteasome inhibitor experiments, co-IP in transfected cells Endocrinology High 24828610
2015 ER-retained PC1/3 mutants (G209R and G593R) induce ER stress markers and exert dominant-negative blockade of wild-type PC1/3 prodomain cleavage and expression, facilitating entry of WT protein into a proteasomal degradation pathway. Expression of mutants alongside WT PC1/3 in transfected cells, ER stress marker assays, Western blot analysis of WT PC1/3 processing Endocrinology High 26207343
2011 PC1/3 exists as multiple ionic forms including inactive aggregates and stable oligomers; the most active form is a probable homodimer of 87-kDa PC1/3; enzyme activity of 87-kDa oligomers exhibits partial latency that is relieved by dilution or by preincubation with fluorogenic substrate or peptides containing paired basic residues, suggesting regulation by self-interaction and substrate binding. Ion exchange chromatography, 2D gel electrophoresis, gel filtration, cross-linking, fluorogenic activity assays with and without substrate peptides Endocrinology High 21303942
2001 proSAAS (encoded by Pcsk1n) is a potent and specific inhibitor of PC1/3 (SPC3) and is co-expressed with SPC3 in nearly all neuroendocrine cells and neurons throughout the brain and peripheral endocrine tissues, supporting an in vivo inhibitory role. In situ hybridization histochemistry double-labeling in rat CNS and peripheral tissues; correlation with prior in vitro inhibition data Endocrinology Medium 11517193
2012 Pax6 transcription factor directly binds the Pcsk1n (proSAAS) promoter and down-regulates its expression; Pax6 deficiency elevates proSAAS levels, which inhibits PC1/3 C-terminal cleavage and reduces PC1/3 activity, thereby impairing proinsulin processing. Luciferase reporter assay, chromatin immunoprecipitation, EMSA, Pcsk1n RNAi in MIN6 cells, PC1/3 activity assay, proinsulin processing assay PloS one High 23056534
2001 Thyroid hormone receptor alpha1 (TRalpha1) negatively regulates PC1 promoter activity by binding to novel TRE-like sequences located at −10 to +19 bp relative to the transcription start site, both as monomer/homodimer and as TRalpha1/RXRbeta heterodimer/multimer. 5' deletion constructs of hPC1 promoter transfected into GH3 cells, EMSA with purified TRalpha1 and RXRbeta, point mutations of putative TREs American journal of physiology. Endocrinology and metabolism High 11120670
2020 Transcription factor Creb3l1 directly binds a G-box motif in the Pcsk1 promoter and transcriptionally activates PC1/3 expression; viral Creb3l1 over-expression in hypothalamic supraoptic nuclei increases Pcsk1, while knockdown reduces it; in AtT20 cells, Creb3l1 knockdown reduces Pcsk1 expression. RNA-seq of Creb3l1 KD AtT20 cells, promoter-binding assay, viral vector over-expression/knockdown in vivo and in vitro Journal of neuroendocrinology High 32319174
1995 Recombinant PC1 cleaves anthrax toxin protective antigen (PA83) at the tetrabasic RKKR167 site to generate PA63 and PA20, with pH optimum 6.0 and calcium dependence; PC1 prefers substrates with basic residues at −1 and −4 positions; bovine intermediate lobe secretory vesicle membrane PC1 (immunodepleted) also cleaves PA, confirming in vivo relevance. In vitro cleavage of PA with recombinant PC1 from L-cells, N-terminal sequencing of products, site-directed mutagenesis of PA cleavage site, immunodepletion with PC1/PC2 antisera, cellular toxicity assay Archives of biochemistry and biophysics High 7840657
2016 In macrophages, PC1/3 inhibition (knockdown or genetic KO) promotes an M1 pro-inflammatory phenotype characterized by filopodial extensions, TLR4 MyD88-dependent signaling, increased calcium entry, and secretion of pro-inflammatory factors recruiting cytotoxic T cells. PC1/3 siRNA knockdown in NR8383 macrophages, validation in PC1/3-deficient mouse macrophages, proteomic analysis of secretomes and intracellular proteins Molecular & cellular proteomics : MCP Medium 26330543
2016 PC1/3 co-localizes with and controls TLR9 trafficking in macrophages; PC1/3 knockdown causes TLR9 clustering in multivesicular bodies (Rab7+), dampens anti-inflammatory STAT3 signaling, and promotes pro-inflammatory NF-kB signaling and cytokine secretion. PC1/3 knockdown in NR8383 macrophages and PC1/3 KO mice macrophages, co-localization imaging with TLR9/Rab7 markers, STAT3/NF-kB pathway readouts, cytokine ELISA Scientific reports Medium 26778167
2014 A heterozygous nonsense PCSK1 mutation (p.Arg80*) produces a truncated propeptide fragment that inhibits PCSK1 enzyme activity in vitro; this inhibition does not involve strong physical interaction with the mature enzyme, yet is sufficient to cause dominantly inherited obesity in a three-generation family. In vitro functional analysis of truncated propeptide, co-segregation analysis in family, activity assays International journal of obesity Medium 24890885
2016 In Prader-Willi syndrome, loss of SNORD116 leads to reduced NHLH2 and PC1/3 (PCSK1) expression in iPSC-derived neurons and mouse hypothalamus; Snord116 paternal KO mice show in vivo defects in prohormone processing of proinsulin, pro-GHRH, and proghrelin, establishing PC1/3 as the mechanistic link between SNORD116 deficiency and PWS endocrinopathy. iPSC-derived neurons from PWS patients, Snord116p-/m+ mice, in vivo prohormone processing assays (proinsulin, pro-GHRH, proghrelin), PC1/3 protein quantification in islet/hypothalamus/stomach The Journal of clinical investigation High 27941249
2021 GLP-1 receptor agonist liraglutide increases PC1/3 (PCSK1) mRNA expression in a subset of pancreatic alpha cells in a beta-cell GLP-1R-dependent manner in mice, promoting a beta-cell-like gene expression signature and increased bihormonal insulin+glucagon+ cells. Mouse GLP-1R beta-cell-specific KO models, human islet scRNA-seq (DART-Seq), IHC for bihormonal cells JCI insight Medium 33554958
2017 CRISPR-Cas9 and shRNA-mediated PCSK1 deficiency in hESC-derived hypothalamic neurons results in increased unprocessed POMC, decreased ratios of processed POMC peptides (ACTH, alpha-MSH), increased melanocortin receptor expression, increased PRCP expression, and reduced ACTH secretion, phenocopying PC1/3-null mice and human patients. CRISPR-Cas9 KO and shRNA KD of PCSK1 in hESC-derived hypothalamic neurons, POMC peptide processing analysis Stem cell reports High 28132887

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 PC3 is a cell line characteristic of prostatic small cell carcinoma. The Prostate 375 21432867
1992 Distribution and regulation of the prohormone convertases PC1 and PC2 in the rat pituitary. Molecular endocrinology (Baltimore, Md.) 261 1316544
2008 Common nonsynonymous variants in PCSK1 confer risk of obesity. Nature genetics 225 18604207
2001 In search of a function for the TIS21/PC3/BTG1/TOB family. FEBS letters 216 11377414
2017 Nec-1 alleviates cognitive impairment with reduction of Aβ and tau abnormalities in APP/PS1 mice. EMBO molecular medicine 130 27861127
1994 The developmental expression in rat of proteases furin, PC1, PC2, and carboxypeptidase E: implications for early maturation of proteolytic processing capacity. The Journal of neuroscience : the official journal of the Society for Neuroscience 125 8046441
1992 Mammalian subtilisin-related proteinases in cleavage activation of the paramyxovirus fusion glycoprotein: superiority of furin/PACE to PC2 or PC1/PC3. Journal of virology 120 1404596
1993 Purification and characterization of the prohormone convertase PC1(PC3). The Journal of biological chemistry 116 8449925
2016 PCSK1 Mutations and Human Endocrinopathies: From Obesity to Gastrointestinal Disorders. Endocrine reviews 114 27187081
2016 Deficiency in prohormone convertase PC1 impairs prohormone processing in Prader-Willi syndrome. The Journal of clinical investigation 113 27941249
2006 Obesity, hyperphagia and increased metabolic efficiency in Pc1 mutant mice. Human molecular genetics 111 16644867
1999 The cell biology of the prohormone convertases PC1 and PC2. Progress in nucleic acid research and molecular biology 110 10506829
1999 The subtilisin/kexin family of precursor convertases. Emphasis on PC1, PC2/7B2, POMC and the novel enzyme SKI-1. Annals of the New York Academy of Sciences 108 10816641
2013 The anticancer effect of fucoidan in PC-3 prostate cancer cells. Marine drugs 91 23966032
1994 Enzymatic properties of carboxyl-terminally truncated prohormone convertase 1 (PC1/SPC3) and evidence for autocatalytic conversion. The Journal of biological chemistry 89 8034588
2016 PCSK1 Variants and Human Obesity. Progress in molecular biology and translational science 85 27288825
1994 Developmental expression of the prohormone convertases PC1 and PC2 in mouse pancreatic islets. Endocrinology 81 7925129
1993 Heterologous processing of prosomatostatin in constitutive and regulated secretory pathways. Putative role of the endoproteases furin, PC1, and PC2. The Journal of biological chemistry 79 8095501
2009 Luteolin inhibits invasion of prostate cancer PC3 cells through E-cadherin. Molecular cancer therapeutics 77 19509250
2004 Dual control of neurogenesis by PC3 through cell cycle inhibition and induction of Math1. The Journal of neuroscience : the official journal of the Society for Neuroscience 75 15056715
2000 NEC1, a novel gene, highly expressed in nectary tissue of Petunia hybrida. The Plant journal : for cell and molecular biology 72 11135107
2002 BTG2(TIS21/PC3) induces neuronal differentiation and prevents apoptosis of terminally differentiated PC12 cells. Oncogene 64 12360398
1996 Effects of alendronate and taxol on PC-3 ML cell bone metastases in SCID mice. Invasion & metastasis 64 9186547
2007 Atorvastatin and celecoxib inhibit prostate PC-3 tumors in immunodeficient mice. Clinical cancer research : an official journal of the American Association for Cancer Research 63 17875778
1998 nec1, a gene conferring a necrogenic phenotype, is conserved in plant-pathogenic Streptomyces spp. and linked to a transposase pseudogene. Molecular plant-microbe interactions : MPMI 60 9768513
2007 Inhibition of medulloblastoma tumorigenesis by the antiproliferative and pro-differentiative gene PC3. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 59 17371797
2001 Effect of scopoletin on PC3 cell proliferation and apoptosis. Acta pharmacologica Sinica 55 11749777
2009 Association of variants in the PCSK1 gene with obesity in the EPIC-Norfolk study. Human molecular genetics 54 19528091
2002 Horizontal transfer of the plant virulence gene, nec1, and flanking sequences among genetically distinct Streptomyces strains in the Diastatochromogenes cluster. Applied and environmental microbiology 54 11823214
2014 A nonsense loss-of-function mutation in PCSK1 contributes to dominantly inherited human obesity. International journal of obesity (2005) 53 24890885
1996 SPC3, a V3 loop-derived synthetic peptide inhibitor of HIV-1 infection, binds to cell surface glycosphingolipids. Biochemistry 53 8961929
1992 The cDNA sequence of the human pro-hormone and pro-protein convertase PC1. DNA and cell biology 49 1605851
1991 Chromosomal assignments of the genes for neuroendocrine convertase PC1 (NEC1) to human 5q15-21, neuroendocrine convertase PC2 (NEC2) to human 20p11.1-11.2, and furin (mouse 7[D1-E2] region). Genomics 49 1765368
2021 GLP-1 receptor signaling increases PCSK1 and β cell features in human α cells. JCI insight 47 33554958
2005 Barley necrotic locus nec1 encodes the cyclic nucleotide-gated ion channel 4 homologous to the Arabidopsis HLM1. Molecular genetics and genomics : MGG 47 16341885
2022 Natural History of Obesity Due to POMC, PCSK1, and LEPR Deficiency and the Impact of Setmelanotide. Journal of the Endocrine Society 46 35528826
2011 Association of type 2 diabetes susceptibility genes (TCF7L2, SLC30A8, PCSK1 and PCSK2) and proinsulin conversion in a Chinese population. Molecular biology reports 46 21437630
2010 Association of obesity risk SNPs in PCSK1 with insulin sensitivity and proinsulin conversion. BMC medical genetics 46 20534142
2016 60 YEARS OF POMC: From the prohormone theory to pro-opiomelanocortin and to proprotein convertases (PCSK1 to PCSK9). Journal of molecular endocrinology 43 26762158
2019 PPIP5K2 and PCSK1 are Candidate Genetic Contributors to Familial Keratoconus. Scientific reports 42 31852976
2014 The association of common variants in PCSK1 with obesity: a HuGE review and meta-analysis. American journal of epidemiology 42 25355447
2012 Selection signature analysis implicates the PC1/PCSK1 region for chicken abdominal fat content. PloS one 42 22792402
2007 Streptomyces turgidiscabies secretes a novel virulence protein, Nec1, which facilitates infection. Molecular plant-microbe interactions : MPMI 41 17555268
2003 The prohormone processing enzyme PC3 is a lipid raft-associated transmembrane protein. Biochemistry 41 12950171
1997 The integrity of the RRGDL sequence of the proprotein convertase PC1 is critical for its zymogen and C-terminal processing and for its cellular trafficking. The Biochemical journal 41 9307023
1997 In addition to SEC11, a newly identified gene, SPC3, is essential for signal peptidase activity in the yeast endoplasmic reticulum. The Journal of biological chemistry 40 9148930
1999 Melatonin receptors in PC3 human prostate tumor cells. Journal of pineal research 39 10340723
1994 In vitro processing of proopiomelanocortin by recombinant PC1 (SPC3). Endocrinology 39 8070378
2012 Cell killing and radiosensitizing effects of atorvastatin in PC3 prostate cancer cells. Journal of radiation research 38 22510595
2000 PC3 overexpression affects the pattern of cell division of rat cortical precursors. Mechanisms of development 37 10585559
1998 Membrane glycoprotein PC-1 and insulin resistance. Molecular and cellular biochemistry 37 9609127
2016 MtDNA depleted PC3 cells exhibit Warburg effect and cancer stem cell features. Oncotarget 36 27248169
1995 Mutational analysis of PC1 (SPC3) in PC12 cells. 66-kDa PC1 is fully functional. The Journal of biological chemistry 36 7559585
1998 Proglucagon processing in an islet cell line: effects of PC1 overexpression and PC2 depletion. Endocrinology 31 9528943
2018 MicroRNA-652 induces NED in LNCaP and EMT in PC3 prostate cancer cells. Oncotarget 29 29721191
2001 Coexpression of proprotein convertase SPC3 and the neuroendocrine precursor proSAAS. Endocrinology 29 11517193
2001 Partial silencing of the NEC1 gene results in early opening of anthers in Petunia hybrida. Molecular genetics and genomics : MGG 28 11405624
2015 Molecular Consequences of Proprotein Convertase 1/3 (PC1/3) Inhibition in Macrophages for Application to Cancer Immunotherapy: A Proteomic Study. Molecular & cellular proteomics : MCP 26 26330543
2023 Analytical performance of the FDA-cleared Parsortix® PC1 system. Journal of circulating biomarkers 25 37601320
2017 PC1/3 Deficiency Impacts Pro-opiomelanocortin Processing in Human Embryonic Stem Cell-Derived Hypothalamic Neurons. Stem cell reports 25 28132887
2013 Exome sequencing finds a novel PCSK1 mutation in a child with generalized malabsorptive diarrhea and diabetes insipidus. Journal of pediatric gastroenterology and nutrition 25 24280991
2009 Functional and structural characterization of a dense core secretory granule sorting domain from the PC1/3 protease. Proceedings of the National Academy of Sciences of the United States of America 25 19376969
1998 Differential cleavage of provasopressin by the major molecular forms of SPC3. Journal of neurochemistry 25 9523585
1995 Expression of activin and activin receptors in pc3 human prostatic-cancer cells. International journal of oncology 25 21556577
2019 c-Myc is a regulator of the PKD1 gene and PC1-induced pathogenesis. Human molecular genetics 24 30388220
2016 Effect of AQP9 Expression in Androgen-Independent Prostate Cancer Cell PC3. International journal of molecular sciences 24 27187384
2013 Functional consequences of a novel variant of PCSK1. PloS one 24 23383060
2001 Regulation of prohormone convertase 1 (PC1) by thyroid hormone. American journal of physiology. Endocrinology and metabolism 24 11120670
2020 Transcription factor Creb3l1 regulates the synthesis of prohormone convertase enzyme PC1/3 in endocrine cells. Journal of neuroendocrinology 23 32319174
2015 Intracellular EP2 prostanoid receptor promotes cancer-related phenotypes in PC3 cells. Cellular and molecular life sciences : CMLS 22 25828575
2011 Modulation of PC1/3 activity by self-interaction and substrate binding. Endocrinology 22 21303942
2015 Revisiting PC1/3 Mutants: Dominant-Negative Effect of Endoplasmic Reticulum-Retained Mutants. Endocrinology 21 26207343
2008 Expression of nucleostemin in prostate cancer and its effect on the proliferation of PC-3 cells. Chinese medical journal 21 18304460
2012 Pax6 directly down-regulates Pcsk1n expression thereby regulating PC1/3 dependent proinsulin processing. PloS one 20 23056534
2020 A rice bran phytochemical, cyanidin 3-glucoside, inhibits the progression of PC3 prostate cancer cell. Anatomy & cell biology 19 32839357
2019 Salinomycin triggers endoplasmic reticulum stress through ATP2A3 upregulation in PC-3 cells. BMC cancer 19 31023247
2017 In Vitro Incorporation of Radioiodinated Eugenol on Adenocarcinoma Cell Lines (Caco2, MCF7, and PC3). Cancer biotherapy & radiopharmaceuticals 19 28358602
2016 Enhanced Cytotoxicity of Biomolecules Loaded Metallic Silver Nanoparticles Against Human Liver (HepG2) and Prostate (PC3) Cancer Cell Lines. Journal of nanoscience and nanotechnology 19 27483851
2014 Defective transport of the obesity mutant PC1/3 N222D contributes to loss of function. Endocrinology 19 24828610
2013 Association of the rs6235 variant in the proprotein convertase subtilisin/kexin type 1 (PCSK1) gene with obesity and related traits in a Taiwanese population. Gene 19 24140494
2011 Inhibition of prohormone convertases PC1/3 and PC2 by 2,5-dideoxystreptamine derivatives. Molecular pharmacology 19 22169851
2009 Skp2 enhances polyubiquitination and degradation of TIS21/BTG2/PC3, tumor suppressor protein, at the downstream of FoxM1. Experimental cell research 18 19615363
2006 Inhibition of caveolin-1 expression by incadronate in PC-3 prostate cells. Anticancer research 18 16886623
1999 Distribution and regulation of proconvertases PC1 and PC2 in human pituitary adenomas. Pituitary 18 11081197
2021 Investigation of molecular mechanisms underlying the antiproliferative effects of colchicine against PC3 prostate cancer cells. Toxicology in vitro : an international journal published in association with BIBRA 17 33684465
2020 A novel mutation in the mouse Pcsk1 gene showing obesity and diabetes. Mammalian genome : official journal of the International Mammalian Genome Society 17 31974728
2018 Inhibition of neddylation facilitates cell migration through enhanced phosphorylation of caveolin-1 in PC3 and U373MG cells. BMC cancer 17 29301501
2015 Inhibition of Transient Receptor Potential Melastain 7 Enhances Apoptosis Induced by TRAIL in PC-3 cells. Asian Pacific journal of cancer prevention : APJCP 17 26028116
2008 Transplantation of PC1/3-Expressing alpha-cells improves glucose handling and cold tolerance in leptin-resistant mice. Molecular therapy : the journal of the American Society of Gene Therapy 17 18941442
2002 Thioester function is conserved in SpC3, the sea urchin homologue of the complement component C3. Developmental and comparative immunology 17 12074925
2020 Induction of proliferative and mutagenic activity by benzo(a)pyrene in PC-3 cells via JAK2/STAT3 pathway. Mutation research 15 32841893
2011 Differential disease resistance response in the barley necrotic mutant nec1. BMC plant biology 15 21496226
2007 PC1/3, PC2 and PC5/6A are targeted to dense core secretory granules by a common mechanism. The FEBS journal 15 17645548
1995 In vitro processing of anthrax toxin protective antigen by recombinant PC1 (SPC3) and bovine intermediate lobe secretory vesicle membranes. Archives of biochemistry and biophysics 15 7840657
2022 Saffron extract feed improves the antioxidant status of laying hens and the inhibitory effect on cancer cells (PC3 and MCF7) Growth. Veterinary medicine and science 14 36063535
2020 Simplicilones A and B Isolated from the Endophytic Fungus Simplicillium subtropicum SPC3. Antibiotics (Basel, Switzerland) 14 33138149
2018 Blue Diaper Syndrome and PCSK1 Mutations. Pediatrics 14 29610180
2016 The proprotein convertase PC1/3 regulates TLR9 trafficking and the associated signaling pathways. Scientific reports 14 26778167
2005 Incadronate inhibits aminopeptidase N expression in prostatic PC-3 cells. Cancer letters 14 16019130
1997 Expression of the putative inhibitor of the insulin receptor tyrosine kinase PC-1 in dermal fibroblasts from patients with syndromes of severe insulin resistance. Clinical endocrinology 14 9302374