Affinage

PCSK2

Neuroendocrine convertase 2 · UniProt P16519

Length
638 aa
Mass
70.6 kDa
Annotated
2026-04-29
100 papers in source corpus 35 papers cited in narrative 34 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PCSK2 (PC2) is a neuroendocrine-specific, calcium-dependent subtilisin-like serine endoprotease that cleaves prohormone and proneuropeptide precursors at dibasic residues within the acidic environment of dense-core secretory granules, generating bioactive peptides including glucagon, α-MSH, β-endorphin, insulin, somatostatin, dynorphins, CART, neuromedin N, and IAPP in a tissue-specific manner distinct from the related convertase PC1/PC3 (PMID:2023902, PMID:9192619, PMID:7592866, PMID:10987860). PC2 is synthesized as an inactive 75-kDa zymogen (proPC2) that requires the neuroendocrine-specific chaperone 7B2 for ER exit and proper folding; 7B2 binds proPC2 via a calcium-dependent interaction in the ER, accompanies it through the secretory pathway, and its C-terminal peptide potently inhibits mature PC2 until PC2 itself cleaves this inhibitory peptide in secretory granules, providing an elegant self-disinhibition mechanism (PMID:7913882, PMID:8016065, PMID:8643504). Autocatalytic propeptide removal occurs intramolecularly at acidic pH (optimum ~5.0) within maturing secretory granules, and the C-terminal domain of PC2 is sufficient for sorting into the regulated secretory pathway (PMID:9989936, PMID:8810291). PC2-null mice exhibit fasting hypoglycemia, near-complete loss of glucagon and α-MSH, severely impaired processing of proinsulin, prosomatostatin, prodynorphin, pro-IAPP, and pro-CART, and accumulation of unprocessed proIAPP that promotes amyloid formation and β-cell apoptosis (PMID:9192619, PMID:12859669, PMID:16873681).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1991 High

    Establishing that PC2 is a functional prohormone convertase that cleaves POMC at multiple dibasic sites with broader specificity than PC1 answered the fundamental question of which enzymes carry out neuropeptide precursor processing in the regulated secretory pathway.

    Evidence Recombinant vaccinia virus coexpression of PC2 with POMC in BSC-40, PC12, AtT-20, and chromaffin cells with cleavage product analysis

    PMID:1647029 PMID:2023902

    Open questions at the time
    • Crystal structure of PC2-substrate complex not determined
    • Relative contributions of PC1 vs PC2 to each POMC cleavage site in vivo not resolved
  2. 1991 High

    Enzymatic characterization revealed PC2 is a calcium-dependent serine endoprotease with an acidic pH optimum (~5.5) and selectivity for dibasic substrates, establishing the biochemical framework for understanding where in the secretory pathway PC2 functions.

    Evidence Fluorogenic substrate assays with inhibitor profiling in Xenopus oocyte expression system

    PMID:2060650

    Open questions at the time
    • Kinetic parameters for individual prohormone substrates not yet determined
    • Structural basis for dibasic selectivity unknown
  3. 1992 High

    Identifying PC2 as the specific type 2 proinsulin endopeptidase that cleaves at the C-peptide/A-chain junction resolved the long-standing question of which enzyme mediates this specific processing step in insulin biosynthesis.

    Evidence Co-elution chromatography, immunoprecipitation of enzymatic activity, and N-terminal sequencing of purified PC2 from insulin granules

    PMID:1528899 PMID:1634553

    Open questions at the time
    • In vivo confirmation in knockout model not yet available at this time
  4. 1993 High

    Demonstrating that proPC2 maturation is autocatalytic — requiring the tetrabasic propeptide cleavage site and an intact active-site Asp — and can proceed intermolecularly established the zymogen activation mechanism of PC2.

    Evidence Site-directed mutagenesis of cleavage site and active-site residues; cell-free Xenopus egg extract reconstitution; pulse-chase analysis

    PMID:7836407 PMID:8276855 PMID:8397508

    Open questions at the time
    • Whether intramolecular or intermolecular cleavage dominates in vivo unresolved at this stage
  5. 1994 High

    Discovery that 7B2 serves as both an obligate ER chaperone for proPC2 folding/transport and a potent endogenous inhibitor of mature PC2 (via its C-terminal peptide) revealed a dual-function regulatory mechanism unique among prohormone convertases.

    Evidence Reciprocal coimmunoprecipitation with metabolic labeling and pulse-chase; in vitro enzyme inhibition assays with recombinant 7B2 and domain fragments

    PMID:7913882 PMID:8016065

    Open questions at the time
    • Stoichiometry of the proPC2–7B2 complex not defined
    • Structural basis of 7B2 chaperone versus inhibitor functions not resolved
  6. 1994 High

    Showing that PC2 is the enzyme responsible for proglucagon processing to glucagon in pancreatic α-cells — generating the α-cell cleavage pattern distinct from PC1/PC3's intestinal L-cell pattern — established PC2 as the molecular basis for tissue-specific differential proglucagon processing.

    Evidence Antisense PC2 knockdown in αTC1-6 cells; vaccinia expression in AtT-20/PC2 cells with product analysis

    PMID:7592866 PMID:8159732

    Open questions at the time
    • In vivo confirmation in whole animal not yet demonstrated
  7. 1995 High

    Mapping the 7B2 inhibitory determinant to Lys171-Lys172, identifying 7B2's proPC2-binding hexapeptide (RRKRRS), and characterizing pH/calcium-dependent proPC2 aggregation defined the molecular rules governing the 7B2–PC2 interaction and proPC2 sorting into secretory granules.

    Evidence Structure-function mutagenesis of 7B2; coimmunoprecipitation with calcium chelation; in vitro sedimentation assays at varying pH/calcium

    PMID:7722516 PMID:7782286 PMID:8034613

    Open questions at the time
    • Three-dimensional structure of 7B2–proPC2 complex not determined
    • Relative contribution of aggregation versus receptor-mediated sorting to granule targeting unknown
  8. 1996 High

    Discovering that PC2 cleaves the 7B2 CT inhibitory peptide at its internal Lys-Lys site within granules — with carboxypeptidase E trimming the product — established a self-disinhibition mechanism whereby PC2 destroys its own inhibitor to become fully active.

    Evidence In vitro incubation of radiolabeled CT peptide with purified recombinant PC2; metabolic labeling and immunoprecipitation in cells

    PMID:8643504

    Open questions at the time
    • Temporal kinetics of CT peptide destruction relative to substrate processing onset not quantified
  9. 1996 High

    Demonstrating that the C-terminal domain of PC2 is sufficient for regulated secretory pathway sorting resolved which structural element directs PC2 to dense-core granules rather than the constitutive pathway.

    Evidence Furin–PC2 C-terminal chimeras stably expressed in AtT-20 cells; immunofluorescence and immuno-electron microscopy

    PMID:8810291

    Open questions at the time
    • Identity of the sorting receptor or lipid-binding mechanism not identified
  10. 1997 High

    PC2 knockout mice revealed that PC2 is essential in vivo for processing proglucagon (to glucagon), prosomatostatin, and proinsulin (at the C-peptide/A-chain junction), causing chronic fasting hypoglycemia and validating decades of in vitro substrate assignments.

    Evidence Gene disruption by neomycin insertion in exon 3; glucose tolerance tests; pancreatic hormone measurements; islet morphology; pulse-chase in isolated islets

    PMID:9192619 PMID:9452465

    Open questions at the time
    • CNS neuropeptide processing phenotypes not yet characterized
    • Compensatory changes in other convertases not fully assessed
  11. 1999 High

    Purified proPC2 reconstitution demonstrated that zymogen activation is intramolecular, pH-driven (optimum 4.0–4.9), calcium-independent, and not inhibited by the 7B2 CT peptide, settling the debate over the mechanism and compartment of proPC2 maturation.

    Evidence Purified recombinant proPC2 from CHO cells; pH titration; EDTA chelation; concentration-independence kinetics

    PMID:9989936

    Open questions at the time
    • Earlier in vitro data suggested calcium dependence (PMID:7836407); discrepancy with purified system not fully reconciled
  12. 2000 High

    PC2 knockout mice extended the substrate repertoire to prodynorphin in the brain, showing PC2 mediates monobasic cleavage events required for Dyn A-8 and efficient Dyn A-17/Dyn B-13 production, demonstrating PC2 function beyond classical dibasic processing.

    Evidence PC2 knockout mice; HPLC and immunological quantification of dynorphin peptides in brain extracts

    PMID:10987860

    Open questions at the time
    • Which monobasic sites PC2 cleaves directly versus indirectly not established
  13. 2001 High

    Establishing that PC2 is specifically required for N-terminal proIAPP processing — and that loss of this processing leads to amyloid-prone intermediate accumulation — linked PC2 activity to islet amyloid pathogenesis.

    Evidence Western blot and immunofluorescence with site-specific antisera in PC2-null mouse islets

    PMID:11246872

    Open questions at the time
    • Whether reduced PC2 activity contributes to human type 2 diabetes amyloidosis not tested
  14. 2002 High

    Identification of VGF and pro-neurotensin/neuromedin N as additional PC2 substrates broadened the known neuropeptide substrate repertoire and demonstrated region-specific processing deficits in the brain.

    Evidence Ectopic PC2 expression with MS product identification (VGF); PC2-KO mouse brain RIA for neurotensin/neuromedin N

    PMID:12065665 PMID:12358783

    Open questions at the time
    • Full CNS peptidomic profiling of PC2-KO not performed
    • Physiological consequences of VGF processing deficits unknown
  15. 2003 High

    Demonstrating near-complete loss of α-MSH and exclusive PC2 responsibility for CART II production in knockout mice established PC2 as the essential convertase for melanocortin and CART neuropeptide maturation, with implications for energy homeostasis.

    Evidence PC2-KO mice; RIA, RP-HPLC, and Western blot for α-MSH, ACTH, β-endorphin; cell-based and KO mouse analysis for CART peptides with MS identification

    PMID:12584191 PMID:12859669

    Open questions at the time
    • Whether PC2 deficiency-related obesity is solely α-MSH-dependent not resolved
  16. 2004 High

    Mutagenesis of the proglucagon interdomain site Lys70-Arg71 showed that PC2 initiates processing at this site as a prerequisite for efficient glucagon liberation, defining the ordered cleavage pathway for glucagon biogenesis.

    Evidence Cotransfection of wild-type and mutant proglucagon with PC2 in GH4C1 cells; HPLC product analysis

    PMID:15528303

    Open questions at the time
    • Whether this ordered pathway operates identically in primary α-cells not confirmed
  17. 2006 High

    Rescue of PC2 expression in PC2-null islets expressing human proIAPP restored N-terminal processing, decreased amyloid deposition, and reduced β-cell apoptosis, establishing a causal link between PC2 processing activity and protection against islet amyloid toxicity.

    Evidence Adenoviral PC2 overexpression in PC2-null islets expressing human proIAPP; TUNEL assay; immunoblotting

    PMID:16873681

    Open questions at the time
    • Relevance to physiological PC2 levels in human β-cells not demonstrated
  18. 2013 High

    Identifying FGF-23 and proBMP1 as PC2/7B2-dependent substrates in osteoblasts expanded PC2 function beyond classical neuroendocrine processing to bone mineral metabolism, and pharmacological restoration of 7B2·PC2 activity rescued the HYP phenotype.

    Evidence PC2/7B2 transfection and 7B2 siRNA in osteoblasts; analysis of FGF-23, proBMP1, and DMP1 in hyp-mouse bone; Hexa-D-arginine rescue in vivo

    PMID:22886699

    Open questions at the time
    • Whether PC2 processes FGF-23 directly or indirectly via BMP1 activation not fully delineated
    • Expression level and regulation of PC2 in osteoblasts under physiological conditions unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of PC2-7B2 interaction, the complete in vivo peptidomic substrate repertoire, the mechanism by which PC2 achieves monobasic cleavage selectivity, and whether reduced PC2 activity contributes to human metabolic or neurodegenerative disease.
  • No crystal structure of PC2 alone or in complex with 7B2
  • Comprehensive peptidomics of PC2-KO tissues not completed
  • Human genetic studies linking PCSK2 variants to disease phenotypes are sparse

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 17 GO:0016787 hydrolase activity 3
Localization
GO:0005783 endoplasmic reticulum 3 GO:0031410 cytoplasmic vesicle 2 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-392499 Metabolism of proteins 19 R-HSA-162582 Signal Transduction 3 R-HSA-9609507 Protein localization 1
Partners
CPEFGF23GCGINSPDYNPOMCSCG5VGF
Complex memberships
proPC2–7B2 complex

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1991 PC2 is a prohormone convertase that cleaves POMC at distinct pairs of basic residues: PC2 cleaves POMC at all five pairs of basic residues analyzed (generating beta-endorphin, N-terminally extended ACTH, and alpha-MSH/desacetyl-alpha-MSH), whereas PC1 preferentially cleaves only two sites, indicating PC2 has broader substrate specificity than PC1. Recombinant vaccinia virus coexpression of PC1/PC2 with POMC in BSC-40, PC12, and AtT-20 cells; monitoring of cleavage products Proceedings of the National Academy of Sciences of the United States of America High 2023902
1991 PC2 and PC3 are Kex2-like endoproteases that accurately cleave POMC at paired basic residues in the regulated secretory pathway of mammalian cells; PC2 coexpression with PC3 results in efficient conversion of beta-lipotropin to gamma-lipotropin and beta-endorphin. Recombinant vaccinia virus expression in processing-deficient BSC-40 cells and bovine adrenomedullary chromaffin cells; analysis of POMC processing products Proceedings of the National Academy of Sciences of the United States of America High 1647029
1992 PC2 selectively cleaves proinsulin at the C-peptide-A-chain junction (type II proinsulin processing activity), establishing its role as the endogenous type 2 proinsulin endopeptidase; PC2 immunoreactivity co-elutes with type 2 proinsulin endopeptidase activity and anti-PC2 antisera specifically immunoprecipitates type 2 activity from insulin granule extracts. Recombinant vaccinia virus coinfection in COS-7 cells; co-elution on chromatography; immunoprecipitation of enzymatic activity; N-terminal sequencing of purified PC2 The Journal of biological chemistry High 1528899 1634553
1991 PC2 expressed in Xenopus oocytes displays calcium-dependent endopeptidase activity with a pH optimum of 5.5, cleaving dibasic (but not monobasic) substrates; activity is inhibited by EDTA and serine protease inhibitors consistent with a calcium-dependent serine protease. In vitro mRNA synthesis and microinjection into Xenopus oocytes; fluorogenic substrate assay with inhibitor profiling FEBS letters High 2060650
1991 PC2 biosynthesis involves an 88-kDa prepropolypeptide processed to a 75-kDa glycosylated precursor (proPC2) and then to the 68-kDa mature enzyme; prosegment cleavage of glycosylated proPC2 occurs in the Golgi apparatus, while unglycosylated proPC2 can be cleaved in a pre-Golgi/ER compartment. Furin cannot cleave either proPC1 or proPC2. Pulse-chase analysis in GH4C1 cells infected with vaccinia recombinants; brefeldin A, low-temperature, and CCCP treatments; coexpression with furin; endoglycosidase H digestion The Biochemical journal High 8397508
1993 ProPC2 undergoes slow autocatalytic maturation; cleavage of the 75-kDa proPC2 to the 68-kDa mature enzyme occurs after the sequence Arg-Lys-Lys-Arg84; deletion of this tetrabasic sequence or mutation of the active site Asp142→Asn blocks cleavage; intermolecular cleavage by wild-type PC2 of catalytically inactive PC2M4 also demonstrated. Site-directed mutagenesis; cell-free Xenopus egg extract translation/translocation system; pulse-chase analysis The Journal of biological chemistry High 8276855
1994 7B2 is a neuroendocrine chaperone that transiently and specifically interacts with proPC2 in the ER early in the secretory pathway; this interaction is required for PC2 activation, as 7B2 prevents premature activation of proPC2. Dissociation coincides with cleavage of 7B2 and proPC2 in later secretory compartments. In vitro association assay with recombinant 7B2 and pituitary proteins; coimmunoprecipitation with metabolic labeling; pulse-chase analysis Cell High 7913882
1994 7B2 is a potent endogenous inhibitor of PC2 (but not PC1/PC3); intact 7B2 prevents proPC2 cleavage in vitro; a C-terminal peptide of 7B2 (CT peptide) is specifically inhibitory; the 21-kDa cleavage product of 7B2 is virtually inactive as an inhibitor. In vitro enzyme inhibition assay with recombinant 7B2; comparison of 7B2 domains Proceedings of the National Academy of Sciences of the United States of America High 8016065
1994 PC2 processes POMC in a strict temporal order: PC2 expression in AtT-20 cells (which normally express only PC1) confers all intermediate-pituitary cleavages of POMC but does not affect the earliest processing steps; PC2-dependent cleavages appear only in middle and late biosynthetic steps. Stable transfection of AtT-20 corticotropes with full-length PC2 cDNA; biosynthetic pulse-chase analysis The Journal of biological chemistry High 8380577
1994 PC2 is the key endoprotease responsible for proglucagon processing to glucagon in alpha cells; antisense RNA knockdown of PC2 in alpha TC1-6 cells inhibits both PC2 production and proglucagon processing concomitantly. Antisense RNA expression in alpha TC1-6 cells; continuous and pulse-chase labeling; PC2 immunoblot Proceedings of the National Academy of Sciences of the United States of America High 8159732
1995 The C-terminal region of 7B2 responsible for PC2 inhibition was mapped to a short segment containing Lys171-Lys172; single mutations at this dibasic site strongly diminish and double mutations abolish inhibitory potency of 7B2 toward PC2. In vitro mutagenesis; prokaryotic expression of mutant 7B2 proteins; in vitro PC1/PC3 and PC2 enzyme inhibition assays The Journal of biological chemistry High 7782286
1995 ProPC2 undergoes calcium- and acid pH-dependent aggregation; the pro-form aggregates at pH 7.0 and 6.5 in a calcium-dependent manner and associates with membranes at pH 5.5. The mature PC2 remains soluble under the same conditions. The N-terminal propeptide (amino acids 57-85) can compete pro-PC2 away from membranes. In vitro Xenopus oocyte translation/translocation; sedimentation assays at varying pH/calcium; peptide competition assay The Journal of biological chemistry High 8034613
1995 ProPC2 maturation has a pH optimum of 5.5-6.0 and requires high calcium (K0.5 = 2-4 mM), whereas proPC3 matures rapidly at pH 7.0-8.0 without additional calcium; site-directed mutagenesis of active site Asp→Asn suggests proPC2 cleavage is catalyzed by the mature 68-kDa PC2 (intermolecular). In vitro Xenopus egg extract translation/translocation; pH and calcium titration; active-site mutagenesis The Journal of biological chemistry High 7836407
1995 7B2 specifically binds proPC2 (but not furin, PC1, PACE4, or PC5) in the ER; binding is calcium-dependent; the intact hexapeptide RRKRRS of pro-7B2 is critical, and mutations of RR152 abolish while R151 or S156 mutations greatly diminish binding. Coimmunoprecipitation; site-directed mutagenesis of 7B2; calcium chelation experiments Journal of neurochemistry High 7722516
1995 PC2 differentially processes proglucagon compared to PC3: PC2 generates glucagon and leaves the C-terminal half (MPGF) unprocessed (alpha-cell phenotype), whereas PC3 generates GLP-1 and GLP-2 (intestinal L-cell phenotype). In AtT-20/PC2 cells, glicentin is efficiently processed to glucagon by PC2. Vaccinia virus vector expression; stable transfection of AtT-20/PC2 cells; analysis of proglucagon processing products in multiple cell lines The Journal of biological chemistry High 7592866
1996 PC2 cleaves the 7B2 CT peptide at an internal Lys-Lys site in secretory granules, inactivating it; carboxypeptidase E further removes terminal lysines from the cleavage product, providing an efficient mechanism for intracellular inactivation of the CT peptide inhibitor. Metabolic labeling; immunoprecipitation; in vitro incubation of radiolabeled CT peptide with purified recombinant PC2; RIA; gel filtration Proceedings of the National Academy of Sciences of the United States of America High 8643504
1996 The C-terminal domain of PC2 is sufficient to sort it into the regulated secretory pathway (dense-core granules); chimeras of furin with the C-terminal domain of PC2 (F-S-P) were retained intracellularly and released in a regulated manner, whereas truncated furin lacking this domain was not stored. Chimeric protein construction; stable transfection in AtT-20 cells; immunofluorescence and immuno-electron microscopy The Journal of biological chemistry High 8810291
1997 PC2 (SPC2) is essential in vivo for the processing of proglucagon in alpha cells, prosomatostatin in delta cells, and partially for proinsulin in beta cells; PC2 knockout mice have chronic fasting hypoglycemia, glucagon deficiency, and severely impaired processing of proglucagon, prosomatostatin, and proinsulin in pancreatic islets. PC2 gene knockout mice (neomycin insertion in exon 3); glucose tolerance tests; pancreatic hormone measurements; islet morphology Proceedings of the National Academy of Sciences of the United States of America High 9192619
1997 PC2 alone, together with carboxypeptidase E, is sufficient for the pancreatic alpha-cell processing pathway of proglucagon to glucagon; purified recombinant PC2 converts oxyntomodulin (a processing intermediate) quantitatively to glucagon in vitro. Adenovirus-mediated coexpression of proglucagon and PC2 in GH4C1 cells; in vitro incubation of oxyntomodulin with purified recombinant PC2 plus carboxypeptidase E FEBS letters High 9287128
1998 PC2 knockout mice show incomplete proinsulin processing: absence of PC2 results in ~60% circulating proinsulin and accumulation of des-31,32 proinsulin (4-5-fold elevation), consistent with PC2's specific role in cleaving proinsulin at the C-peptide/A-chain junction (Lys64-Arg65). PC3 preferentially initiates processing at the B-chain/C-peptide junction. PC2 knockout mice; pulse-chase experiments in isolated islets; HPLC and RIA analysis of proinsulin processing intermediates The Journal of biological chemistry High 9452465
1998 The PC2 proregion is required but not sufficient for 7B2 binding; the P domain is essential for PC2 structural stability; the C-terminal domain is not involved in 7B2 binding; a single substitution Tyr194→Asp in the catalytic domain prevents 7B2 binding and blocks PC2 activation. Sequential deletions, site-directed mutagenesis, and domain-swapping between PC2 and PC1; expression in AtT-20 cells; coimmunoprecipitation and enzymatic activity assays The Journal of biological chemistry High 9422782
1999 ProPC2 maturation is an autocatalytic, intramolecular, pH-driven process: conversion is most extensive between pH 4.0 and 4.9; it is not calcium-dependent; it is not inhibited by the 7B2 CT peptide; and the rate is similar across a 10-fold range of zymogen concentration, indicating intramolecular cleavage. Purified recombinant proPC2 from CHO cells; pH titration; calcium chelation (EDTA); enzyme concentration-response; N-terminal sequencing of mature enzyme Archives of biochemistry and biophysics High 9989936
1999 ProPC1 propeptide cleavage occurs in the ER (rapidly), while proPC2 exits the ER without propeptide cleavage, in complex with 7B2; PC2 propeptide removal occurs in maturing secretory granules, likely through autocatalysis, and requires prior association with 7B2 for generation of active enzyme. Review synthesizing pulse-chase, temperature-block, and coimmunoprecipitation data from multiple studies Progress in nucleic acid research and molecular biology Medium 10506829
2000 PC2 is essential for prodynorphin processing in vivo: PC2 knockout mice lack Dyn A-8 completely and show substantial reductions in Dyn A-17 and Dyn B-13, indicating PC2 mediates monobasic cleavage events generating these opioid peptides from prodynorphin. PC2 gene disruption in mice; enzymological and immunological assays of dynorphin peptides in brain extracts; HPLC; Western blots for other convertases Journal of neurochemistry High 10987860
2001 PC2 is essential for NH2-terminal processing of proIAPP in vivo; PC2 null mice show accumulation of a ~6-kDa NH2-terminally extended proIAPP intermediate (only COOH-terminally processed), with no detectable mature 4-kDa IAPP, demonstrating that PC3 processes proIAPP only at the COOH-terminal site while PC2 processes the NH2-terminal site. Western blot and immunofluorescence of islets from PC2 null mice; antisera to NH2- and COOH-terminal flanking regions Diabetes High 11246872
2002 PC2 is involved in processing of the VGF precursor: ectopic expression of PC2 in GH3 cells generates VGF20; the KRKRKK488 motif in VGF sequence is the PC2 (and PC1/3) target generating VGF20. Ectopic expression of PC2 and PC1/3 in GH3 cells; site-directed mutagenesis of VGF sequence; mass spectrometry and Edman degradation of products Journal of neurochemistry High 12065665
2002 PC2 plays a critical role in processing of pro-neurotensin/neuromedin N in mouse brain; PC2 knockout mice show 15% decrease in neurotensin and 50% decrease in neuromedin N brain levels, with regionally variable loss most pronounced in medial preoptic area and hypothalamic nuclei. PC2 knockout mice; radioimmunoassay of neurotensin and neuromedin N; immunohistochemistry Journal of neurochemistry High 12358783
2003 PC2 is critical for alpha-MSH production in vivo: PC2-deficient mice show essentially complete loss of alpha-MSH in pituitary and brain, with accumulation of ACTH, ACTH-containing intermediates, POMC precursor, and increased beta-endorphin1-31, confirming ACTH as a PC2 substrate for alpha-MSH production. PC2 knockout mice; RIA for alpha-MSH (non-cross-reacting with POMC, ACTH, beta-endorphin); RP-HPLC; Western blotting with anti-ACTH and anti-beta-endorphin Journal of neurochemistry High 12859669
2003 PC2 is exclusively responsible for generating bioactive CART II (residues 62-102) from pro-CART; PC2 is more efficient than PC1/3 in generating CART I (55-102); in vivo studies in PC2 knockout mice confirm PC2 is required for CART II production. PC1/3 predominantly generates intermediate CART fragments. Transient transfection in cell lines with/without endogenous PC2 or PC1/3; knockout mouse hypothalamic extract analysis; microsequencing; HPLC/MS product identification The Journal of biological chemistry High 12584191
2004 PC2 initiates proglucagon processing at the interdomain site Lys70-Arg71, which is a prerequisite for efficient glucagon production; mutation of this site (K70Q-R71Q or R71A) reduces glucagon production 5-fold by PC2 and increases unprocessed precursor; PC2 can generate glucagon from glicentin but not efficiently from the major proglucagon fragment. Cotransfection studies in GH4C1 cells with wild-type and mutant proglucagon; HPLC analysis of processing products Endocrinology High 15528303
2006 Impaired NH2-terminal processing of proIAPP by PC2 leads to amyloid formation and cell death; rescue of PC2 expression (via adenoviral PC2) in PC2-null mouse islets expressing human proIAPP restores NH2-terminal processing, decreases amyloid formation, and reduces beta-cell apoptosis. Adenoviral PC2 overexpression in PC2-null islets expressing human proIAPP; TUNEL assay; immunoblotting for proIAPP processing intermediates Diabetes High 16873681
1999 The Drosophila PC2 homolog amontillado (amon) is required for hatching behavior; expression is restricted to specific neurons late in embryogenesis, and larvae lacking amontillado chromosomal region fail to hatch normally; ubiquitous amon expression rescues behavior, but a catalytic histidine mutant cannot, establishing that proteolytic activity is required. Drosophila genetics (deficiency mapping); in situ hybridization; behavioral analysis; ubiquitous rescue with wild-type vs. catalytic mutant amontillado The Journal of neuroscience : the official journal of the Society for Neuroscience High 10436051
2003 Drosophila amontillado (PC2 homolog) is required during embryogenesis and larval development; amon mutants display partial embryonic lethality and arrest at first-to-second instar larval molt; heat-shock rescue confirms developmental requirement for amon protease activity. EMS mutagenesis; genetic complementation; heat-shock rescue; developmental analysis Genetics High 12586710
2013 PC2 (together with its chaperone 7B2) cleaves FGF-23 in osteoblasts; decreased 7B2·PC2 activity in hyp-mice results in reduced FGF-23 cleavage, increased Fgf-23 mRNA (via impaired BMP1 activation from proBMP1 and consequent reduced DMP1 cleavage). Hexa-D-arginine treatment of hyp-mice restores 7B2·PC2 activity, normalizing FGF-23 and rescuing the HYP phenotype. Transfection of murine osteoblasts with PC2 and 7B2; siRNA knockdown of 7B2; analysis of FGF-23, proBMP1/BMP1, DMP1 in hyp-mouse bone; pharmacological rescue with Hexa-D-arginine Journal of bone and mineral research High 22886699

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1991 PC1 and PC2 are proprotein convertases capable of cleaving proopiomelanocortin at distinct pairs of basic residues. Proceedings of the National Academy of Sciences of the United States of America 596 2023902
2011 ncRNA- and Pc2 methylation-dependent gene relocation between nuclear structures mediates gene activation programs. Cell 508 22078878
1991 Identification of a cDNA encoding a second putative prohormone convertase related to PC2 in AtT20 cells and islets of Langerhans. Proceedings of the National Academy of Sciences of the United States of America 482 1988934
1991 Cloning and primary sequence of a mouse candidate prohormone convertase PC1 homologous to PC2, Furin, and Kex2: distinct chromosomal localization and messenger RNA distribution in brain and pituitary compared to PC2. Molecular endocrinology (Baltimore, Md.) 482 2017186
2003 The polycomb protein Pc2 is a SUMO E3. Cell 469 12679040
1997 Defective prohormone processing and altered pancreatic islet morphology in mice lacking active SPC2. Proceedings of the National Academy of Sciences of the United States of America 340 9192619
1991 Kex2-like endoproteases PC2 and PC3 accurately cleave a model prohormone in mammalian cells: evidence for a common core of neuroendocrine processing enzymes. Proceedings of the National Academy of Sciences of the United States of America 334 1647029
1992 Proinsulin processing by the subtilisin-related proprotein convertases furin, PC2, and PC3. Proceedings of the National Academy of Sciences of the United States of America 290 1528899
1992 Distribution and regulation of the prohormone convertases PC1 and PC2 in the rat pituitary. Molecular endocrinology (Baltimore, Md.) 261 1316544
1993 The prohormone convertases PC1 and PC2 mediate distinct endoproteolytic cleavages in a strict temporal order during proopiomelanocortin biosynthetic processing. The Journal of biological chemistry 226 8380577
1994 7B2 is a neuroendocrine chaperone that transiently interacts with prohormone convertase PC2 in the secretory pathway. Cell 191 7913882
1993 Comparative biosynthesis, covalent post-translational modifications and efficiency of prosegment cleavage of the prohormone convertases PC1 and PC2: glycosylation, sulphation and identification of the intracellular site of prosegment cleavage of PC1 and PC2. The Biochemical journal 187 8397508
1994 Proglucagon is processed to glucagon by prohormone convertase PC2 in alpha TC1-6 cells. Proceedings of the National Academy of Sciences of the United States of America 184 8159732
1995 Differential processing of proglucagon by the subtilisin-like prohormone convertases PC2 and PC3 to generate either glucagon or glucagon-like peptide. The Journal of biological chemistry 173 7592866
1998 Incomplete processing of proinsulin to insulin accompanied by elevation of Des-31,32 proinsulin intermediates in islets of mice lacking active PC2. The Journal of biological chemistry 157 9452465
2007 TAZ promotes PC2 degradation through a SCFbeta-Trcp E3 ligase complex. Molecular and cellular biology 155 17636028
2016 Structure of the polycystic kidney disease TRP channel Polycystin-2 (PC2). Nature structural & molecular biology 148 27991905
1994 The neuroendocrine polypeptide 7B2 is an endogenous inhibitor of prohormone convertase PC2. Proceedings of the National Academy of Sciences of the United States of America 146 8016065
2000 Regulation of pancreatic PC1 and PC2 associated with increased glucagon-like peptide 1 in diabetic rats. The Journal of clinical investigation 138 10749575
1992 Identification of the type 2 proinsulin processing endopeptidase as PC2, a member of the eukaryote subtilisin family. The Journal of biological chemistry 135 1634553
2005 Pc2-mediated sumoylation of Smad-interacting protein 1 attenuates transcriptional repression of E-cadherin. The Journal of biological chemistry 131 16061479
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
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