{"gene":"CPE","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":1997,"finding":"Membrane-associated carboxypeptidase E (CPE) functions as a sorting receptor at the trans-Golgi network for regulated secretory pathway proteins: CPE specifically bound prohormones (but not constitutively secreted proteins) in pituitary Golgi-enriched and secretory granule membranes, and in Cpe(fat) mice lacking CPE, pro-opiomelanocortin was missorted to the constitutive pathway and secreted in an unregulated manner.","method":"Biochemical binding assays with pituitary Golgi-enriched and secretory granule membrane fractions; in vivo missecretion analysis in Cpe(fat) mutant mice","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding assays combined with in vivo genetic loss-of-function demonstrating missorted secretion; replicated across multiple prohormone substrates","pmids":["9019408"],"is_preprint":false},{"year":1997,"finding":"CPE is required for normal proinsulin processing in pancreatic beta-cells: beta-cell lines from Cpe(fat)/Cpe(fat) mice accumulate pro-CPE (not mature CPE) in an ER-like compartment and show defective proinsulin processing, with enlarged electron-lucent granules observed by electron microscopy. Notably, insulin/proinsulin secretion remains regulated (stimulated by secretagogues), indicating CPE is not required for sorting proinsulin to the regulated pathway.","method":"Pulse-chase metabolic labeling, immunocytochemistry, electron microscopy, secretion assays in Cpe(fat)/Cpe(fat)-derived NIT-2/NIT-3 beta-cell lines","journal":"Endocrinology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (EM, ICC, biochemical assays) in isogenic cell lines","pmids":["9348219"],"is_preprint":false},{"year":1990,"finding":"CPE (carboxypeptidase E) is a carboxypeptidase B-like enzyme localized in neuronal cell bodies and terminals throughout the rat CNS and pituitary, with highest concentration in hypothalamic nuclei (median eminence, supraoptic, paraventricular, suprachiasmatic), posterior pituitary, intermediate pituitary melanotropes, and hippocampal pyramidal cells, consistent with a role in neuropeptide biosynthesis.","method":"Immunocytochemistry using specific polyclonal antisera to purified CPE enzyme in rat brain sections","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — detailed immunolocalization across multiple brain regions with specific antisera, single lab but comprehensive anatomical mapping","pmids":["2332799"],"is_preprint":false},{"year":2001,"finding":"CPE activity is required for normal biosynthesis of the majority of neuroendocrine peptides: peptidomic analysis of Cpe(fat/fat) mouse brain and pituitary identified over 100 peptides accumulating as C-terminally basic processing intermediates from 16 secretory pathway proteins including proenkephalin, POMC, protachykinins, and chromogranins, demonstrating CPE's broad substrate scope as the terminal exopeptidase.","method":"Affinity chromatography on anhydrotrypsin resin followed by mass spectrometry peptide identification; radioimmunoassay validation in wild-type mice","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — mass spectrometry-based peptidomics with RIA validation across multiple substrates in genetic loss-of-function model","pmids":["11481435"],"is_preprint":false},{"year":2001,"finding":"Loss of CPE activity in Cpe(fat) mice leads to reduced levels of PC1 and PC2 prohormone convertases in brain and pituitary, resulting in decreased alpha-MSH, altered beta-endorphin processing, and increased dynorphin A-17, indicating CPE activity indirectly supports endoproteolytic processing by maintaining normal convertase levels.","method":"Western blot and immunohistochemistry for PC1, PC2 in multiple brain regions; radioimmunoassay for opioid peptides in Cpe(fat) vs. wild-type mice","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Western blot, IHC, RIA) in genetic model, single lab","pmids":["11038363"],"is_preprint":false},{"year":2003,"finding":"Mutant CPE (pro-CPE202) from Cpe(fat)/Cpe(fat) mice has a half-life of ~3 h in beta-cells, with up to 45% escaping proteasomal degradation and trafficking to PC2-containing secretory granules (post-Golgi regulated secretory pathway), where it is secreted in a stimulated manner, supporting a potential sorting/retention receptor role even for the mutant form.","method":"Pulse-chase experiments, double-label immunofluorescence microscopy with calnexin and PC2 markers, stimulated secretion assay with glucagon-like peptide-1 in NIT3 cells","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (pulse-chase, co-localization, functional secretion assay), single lab","pmids":["12488357"],"is_preprint":false},{"year":2008,"finding":"Quantitative peptidomics of six brain regions of Cpe(fat/fat) mice demonstrated that CPE contributes to biosynthesis of the majority of neuropeptides; most secretory pathway peptides were greatly reduced while C-terminally basic processing intermediates were elevated, with partial compensation by carboxypeptidase D for a subset of peptides.","method":"Quantitative peptidomics with tandem mass spectrometry comparing six brain regions of Cpe(fat/fat) vs. wild-type mice","journal":"Journal of neurochemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — comprehensive quantitative MS across 6 brain regions in genetic model, replicates and extends earlier peptidomics findings","pmids":["19014391"],"is_preprint":false},{"year":2009,"finding":"FoxO1 ablation in POMC neurons increases CPE expression, leading to selective increases in alpha-MSH and carboxy-cleaved beta-endorphin (CPE-dependent POMC processing products), decreased food intake, and protection against diet-induced obesity; moderate CPE overexpression in the arcuate nucleus phenocopied these effects, placing CPE downstream of FoxO1 in hypothalamic energy balance regulation.","method":"Conditional FoxO1 knockout in POMC neurons; CPE overexpression via viral vector in arcuate nucleus; neuropeptide measurements; feeding and body weight phenotyping","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis (conditional KO) combined with gain-of-function overexpression and defined neuropeptide product measurements","pmids":["19767734"],"is_preprint":false},{"year":1999,"finding":"CPE is required for normal processing of substance P from pro-tachykinin: amidated mature SP was more than fivefold lower in all brain regions of Cpe(fat/fat) mice compared to controls, while total SP species (including processing intermediates) were unchanged, demonstrating CPE's specific role as the C-terminal basic residue-removing enzyme in SP biosynthesis.","method":"Radioimmunoassay measuring amidated SP vs. total SP forms in multiple brain regions of Cpe(fat/fat) vs. wild-type and heterozygous mice","journal":"Peptides","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — specific RIA distinguishing mature vs. intermediate forms in genetic loss-of-function model, single lab","pmids":["9700764"],"is_preprint":false},{"year":2016,"finding":"CPE inhibits Wnt3a activity by forming aggregates with Wnt3a via CPE's N-terminal sequence, leading to Wnt3a loss of function; the C-terminal Lys residue of Wnt3a is critical for its activity and important for CPE's effect on the Wnt pathway, but CPE does not act by removing this residue enzymatically. CPE and Wnt3a are co-secreted from cells.","method":"Co-secretion assays, mutagenesis of Wnt3a C-terminal Lys, co-immunoprecipitation/aggregation assays, Wnt pathway reporter assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical methods (co-secretion, mutagenesis, pathway reporter), single lab","pmids":["27375026"],"is_preprint":false},{"year":2017,"finding":"Secreted CPE (sCPE) activates mTORC1 signaling in glioma cells (detected by RPS6 phosphorylation) and inhibits glioma cell migration via negative regulation of Rac1 signaling through RPS6; mTOR inhibition or Rac1 stimulation reversed the anti-migratory effect of sCPE. sCPE also enhances glucose flux into the TCA cycle at the expense of lactate production, reducing aerobic glycolysis.","method":"Recombinant sCPE treatment of glioma cells; phospho-RPS6 Western blot; mTOR inhibitor and Rac1 activator pharmacological rescue; CPE knockdown; metabolic flux analysis","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (signaling Western blots, pharmacological epistasis, metabolic analysis, knockdown), single lab","pmids":["28978054"],"is_preprint":false},{"year":2022,"finding":"CPE is present as mRNA and protein in cancer cell-derived exosomes; exosomal CPE from high-metastatic HCC97H cells promotes proliferation and invasion of low-metastatic HCC97L cells, and CPE-shRNA-loaded exosomes suppress CPE expression along with Cyclin D1 and c-MYC in high-metastatic cells, inhibiting their proliferation.","method":"Exosome isolation and characterization; Western blot and PCR for CPE in exosomes; MTT, colony formation, and Matrigel invasion assays; CPE-shRNA exosome delivery","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple functional assays (proliferation, invasion, shRNA knockdown) but mechanism of exosomal CPE action not fully resolved at molecular level","pmids":["35328535"],"is_preprint":false},{"year":2013,"finding":"CPE promotes cell proliferation and tumorigenicity in colorectal cancer cells through downregulation of p21 and p27 and upregulation of cyclin D1, resulting in increased S-phase fraction; overexpression enhanced anchorage-independent growth in soft agar.","method":"CPE overexpression and depletion plasmids; MTT, colony formation, BrdU incorporation, flow cytometry, soft agar assays; qRT-PCR for p21, p27, cyclin D1","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple functional assays with molecular pathway readouts, single lab, no rescue experiments","pmids":["24006921"],"is_preprint":false},{"year":2014,"finding":"CPE regulates NF-κB activity in pancreatic cancer: siRNA-mediated CPE knockdown inhibited cancer cell growth, migration, and tumor growth in vivo, and directly reduced NF-κB expression; NF-κB inhibition phenocopied CPE knockdown effects, placing NF-κB downstream of CPE.","method":"siRNA knockdown of CPE; proliferation and invasion assays; in vivo xenograft; Western blot for NF-κB; NF-κB inhibitor pharmacological epistasis","journal":"Tumour biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockdown with pharmacological epistasis and in vivo validation, single lab","pmids":["25374060"],"is_preprint":false},{"year":2023,"finding":"Top-down proteomics of beta-cell-specific Cpe knockout mouse islets identified multiple novel proteoforms of improperly processed proinsulin with dibasic C-terminal residues as direct CPE substrates; carboxypeptidase D (CPD) compensates for CPE loss and maintains near-normal processing of some CPE substrates.","method":"Top-down proteomics of islets from beta-cell-specific Cpe knockout mice; quantitative comparison of hormone proteoforms","journal":"Endocrinology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — top-down proteomics with genetic KO model providing substrate-level resolution; single lab but highly rigorous method","pmids":["37967211"],"is_preprint":false},{"year":2015,"finding":"A homozygous truncating mutation of CPE (c.76_98del; p.E26RfsX68) in a human patient causes morbid obesity, intellectual disability, abnormal glucose homeostasis, and hypogonadotrophic hypogonadism with no CPE expression detected (consistent with nonsense-mediated decay), establishing that CPE is essential for peptide/hormone processing regulating body weight, metabolism, brain, and reproductive function in humans.","method":"Exome sequencing; RNA expression analysis from blood-derived RNA confirming nonsense-mediated decay; phenotypic characterization","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human genetic loss-of-function with confirmed absence of expression; single patient but recapitulates mouse model phenotypes","pmids":["26120850"],"is_preprint":false},{"year":2014,"finding":"Central Sirt1 inhibition in diet-induced obese rats increases CPE expression (via FoxO1 acetylation/phosphorylation), leading to increased alpha-MSH production from POMC processing and activation of the hypothalamic-pituitary-thyroid axis, placing CPE downstream of Sirt1/FoxO1 in the POMC processing pathway for energy expenditure regulation.","method":"Central Sirt1 inhibition (ICV injection); Western blot for CPE, FoxO1, phospho-FoxO1, acetyl-FoxO1; RIA for alpha-MSH; TRH and T3 measurements in DIO rats","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological epistasis with multiple molecular readouts, single lab, in vivo model","pmids":["25549049","24773342"],"is_preprint":false},{"year":2002,"finding":"CPE is required for normal biosynthesis of opioid peptides from prodynorphin and proenkephalin during development: Cpe(fat/fat) mice accumulate C-terminally extended forms of all three opioid peptides examined, with region-specific decreases in mature dynorphin peptides and differential alterations in Met-enkephalin levels. Loss of CPE also differentially alters mu (but not kappa) opioid receptor functional activity in select brain regions.","method":"Peptide extraction and RIA from multiple brain regions at different developmental ages; [35S]GTPgammaS binding assay for mu and kappa receptor functional activity in Cpe(fat/fat) vs. littermate controls","journal":"The Journal of pharmacology and experimental therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIA and functional receptor assays across multiple brain regions and developmental time points, single lab","pmids":["12438557"],"is_preprint":false}],"current_model":"Carboxypeptidase E (CPE) is a membrane-associated exopeptidase that removes C-terminal basic residues from prohormone processing intermediates to generate bioactive neuropeptides and peptide hormones; it also functions as a sorting receptor at the trans-Golgi network that directs prohormones into the regulated secretory pathway, acts downstream of FoxO1/Sirt1 signaling to control POMC-derived peptide production and energy balance, inhibits Wnt3a activity by forming aggregates via its N-terminal domain, activates mTORC1/RPS6 signaling to suppress glioma cell migration and aerobic glycolysis, and regulates cancer cell proliferation through cyclin D1/p21/p27 and NF-κB pathways."},"narrative":{"mechanistic_narrative":"Carboxypeptidase E (CPE) is a carboxypeptidase B-like exopeptidase concentrated in neuronal cell bodies and terminals throughout the CNS and pituitary, with highest expression in hypothalamic and pituitary neuroendocrine centers, where it serves as the terminal enzyme in neuropeptide and peptide hormone biosynthesis [PMID:2332799]. It removes C-terminal basic residues from prohormone processing intermediates: peptidomic and proteomic analyses of Cpe(fat) and beta-cell-specific knockout models show that loss of CPE causes accumulation of >100 C-terminally basic intermediates from at least 16 secretory pathway precursors—including POMC, proenkephalin, prodynorphin, protachykinin, and proinsulin—with reduced levels of the corresponding mature peptides [PMID:11481435, PMID:19014391, PMID:37967211, PMID:9700764, PMID:12438557]. Carboxypeptidase D partially compensates for CPE loss for a subset of substrates [PMID:19014391, PMID:37967211], and CPE loss also lowers PC1/PC2 convertase levels, indirectly impairing upstream endoproteolytic processing [PMID:11038363]. Independently of its enzymatic activity, CPE acts as a sorting receptor at the trans-Golgi network, binding prohormones to direct them into the regulated secretory pathway; in CPE-deficient pituitary cells POMC is missorted to the constitutive pathway [PMID:9019408]. In the hypothalamus CPE functions downstream of Sirt1/FoxO1 signaling to control POMC-derived alpha-MSH and beta-endorphin production, energy balance, and the hypothalamic-pituitary-thyroid axis [PMID:19767734, PMID:25549049, PMID:24773342]. A human homozygous truncating CPE mutation causes morbid obesity, intellectual disability, abnormal glucose homeostasis, and hypogonadotrophic hypogonadism, establishing CPE as essential for hormone processing governing body weight, metabolism, and reproduction [PMID:26120850]. Several non-canonical roles have also been documented: CPE inhibits Wnt3a by forming aggregates via its N-terminal domain without enzymatic cleavage [PMID:27375026], secreted CPE activates mTORC1/RPS6 signaling to suppress glioma migration and aerobic glycolysis [PMID:28978054], and CPE modulates cancer cell proliferation through cyclin D1/p21/p27 and NF-κB pathways [PMID:24006921, PMID:25374060].","teleology":[{"year":1990,"claim":"Established where CPE acts by mapping its anatomical distribution, linking the enzyme to neuropeptide-producing neuroendocrine centers.","evidence":"Immunocytochemistry with specific antisera across rat brain and pituitary","pmids":["2332799"],"confidence":"Medium","gaps":["Localization is anatomical, not subcellular at processing sites","Does not demonstrate enzymatic function on specific substrates"]},{"year":1997,"claim":"Resolved whether CPE has a function beyond enzymatic trimming, showing it acts as a TGN sorting receptor that routes prohormones to the regulated secretory pathway.","evidence":"Prohormone binding assays in Golgi/granule membranes plus missorting analysis in Cpe(fat) mice","pmids":["9019408"],"confidence":"High","gaps":["Structural basis of prohormone recognition not defined","Sorting role not universal across substrates (proinsulin sorting independent of CPE)"]},{"year":1997,"claim":"Separated CPE's enzymatic processing role from sorting in beta-cells, showing CPE is needed for proinsulin processing but not for regulated sorting of insulin.","evidence":"Pulse-chase, EM, ICC, and secretion assays in Cpe(fat)-derived beta-cell lines","pmids":["9348219"],"confidence":"High","gaps":["Mechanism of pro-CPE ER retention in mutant cells not fully resolved","Does not address sorting role in other cell types"]},{"year":1999,"claim":"Demonstrated CPE's substrate-specific requirement for a defined neuropeptide, establishing it as the C-terminal basic residue-removing enzyme for substance P.","evidence":"RIA distinguishing amidated mature vs. total SP in Cpe(fat/fat) brain regions","pmids":["9700764"],"confidence":"Medium","gaps":["Single substrate; relies on indirect RIA discrimination","No direct in vitro cleavage demonstration"]},{"year":2001,"claim":"Defined the breadth of CPE's role by showing it is the terminal exopeptidase for the majority of neuroendocrine peptides, and that its loss secondarily reduces convertase levels.","evidence":"Affinity-capture peptidomics with MS and RIA; Western/IHC/RIA for convertases and opioid peptides in Cpe(fat) mice","pmids":["11481435","11038363"],"confidence":"High","gaps":["Convertase reduction is correlative, mechanism of indirect effect unclear","Does not distinguish enzymatic vs. sorting contributions to each peptide deficit"]},{"year":2002,"claim":"Extended CPE's processing role to opioid peptides during development and linked peptide deficits to altered receptor signaling.","evidence":"Developmental RIA and [35S]GTPgammaS receptor functional assays across brain regions in Cpe(fat/fat) mice","pmids":["12438557"],"confidence":"Medium","gaps":["Receptor activity changes are downstream/correlative","Region- and peptide-specific effects not mechanistically explained"]},{"year":2003,"claim":"Characterized the fate of mutant pro-CPE, showing partial escape from degradation and trafficking to secretory granules, supporting a retention/sorting role even for the mutant form.","evidence":"Pulse-chase, co-localization with calnexin/PC2, and stimulated secretion in NIT3 cells","pmids":["12488357"],"confidence":"Medium","gaps":["Functional consequence of mutant trafficking unclear","Single cell-line system"]},{"year":2008,"claim":"Quantitatively confirmed CPE's global contribution to neuropeptide biosynthesis and revealed partial CPD compensation across brain regions.","evidence":"Quantitative tandem-MS peptidomics across six brain regions of Cpe(fat/fat) mice","pmids":["19014391"],"confidence":"High","gaps":["Compensation mechanism by CPD not defined","Does not resolve which deficits are sorting- vs. enzyme-dependent"]},{"year":2009,"claim":"Placed CPE in a hypothalamic regulatory circuit, showing it acts downstream of FoxO1 to control POMC-derived peptide production and energy balance.","evidence":"POMC-specific FoxO1 knockout plus arcuate CPE overexpression with feeding/weight phenotyping","pmids":["19767734"],"confidence":"High","gaps":["Direct transcriptional link between FoxO1 and CPE not fully mapped","Other FoxO1 targets may contribute"]},{"year":2013,"claim":"Implicated CPE in cancer cell proliferation, showing it drives cell-cycle progression via cyclin D1/p21/p27 in colorectal cancer.","evidence":"CPE overexpression/depletion with proliferation, cell-cycle, soft-agar assays and qRT-PCR readouts","pmids":["24006921"],"confidence":"Medium","gaps":["No rescue experiments","Molecular link from CPE to cell-cycle regulators undefined"]},{"year":2014,"claim":"Connected CPE to oncogenic NF-κB signaling in pancreatic cancer through knockdown and pharmacological epistasis.","evidence":"siRNA knockdown, proliferation/invasion assays, xenograft, and NF-κB inhibitor epistasis","pmids":["25374060"],"confidence":"Medium","gaps":["Direct molecular mechanism linking CPE to NF-κB unknown","Single cancer context"]},{"year":2014,"claim":"Extended the FoxO1 circuit upstream, showing central Sirt1 controls CPE expression to regulate POMC processing and the HPT axis.","evidence":"ICV Sirt1 inhibition with FoxO1 acetylation/phosphorylation, alpha-MSH RIA, and TRH/T3 measures in DIO rats","pmids":["25549049","24773342"],"confidence":"Medium","gaps":["Indirect pharmacological perturbation","Direct Sirt1-FoxO1-CPE molecular linkage inferred not shown"]},{"year":2015,"claim":"Established human disease relevance, showing a truncating CPE mutation causes obesity, intellectual disability, glucose dysregulation, and hypogonadism.","evidence":"Exome sequencing, NMD confirmation, and clinical phenotyping of a homozygous patient","pmids":["26120850"],"confidence":"Medium","gaps":["Single patient","Cannot dissect enzymatic vs. sorting contributions to each phenotype"]},{"year":2016,"claim":"Identified a non-enzymatic CPE function, showing it inhibits Wnt3a by N-terminal-mediated aggregation rather than cleavage.","evidence":"Co-secretion, Wnt3a C-terminal Lys mutagenesis, co-IP/aggregation, and Wnt reporter assays","pmids":["27375026"],"confidence":"Medium","gaps":["Physiological relevance of Wnt inhibition not established in vivo","Single lab biochemical system"]},{"year":2017,"claim":"Defined a secreted CPE signaling role, showing extracellular CPE activates mTORC1/RPS6 to suppress glioma migration and aerobic glycolysis.","evidence":"Recombinant sCPE treatment, phospho-RPS6 blots, mTOR/Rac1 pharmacological rescue, knockdown, and metabolic flux analysis","pmids":["28978054"],"confidence":"Medium","gaps":["Receptor/mechanism by which sCPE triggers mTORC1 unknown","Single tumor context"]},{"year":2022,"claim":"Showed CPE can be transmitted between cancer cells via exosomes to promote proliferation and invasion.","evidence":"Exosome isolation, CPE detection, proliferation/invasion assays, and CPE-shRNA exosome delivery in HCC cells","pmids":["35328535"],"confidence":"Medium","gaps":["Molecular mechanism of exosomal CPE action unresolved","Effects on cyclin D1/c-MYC correlative"]},{"year":2023,"claim":"Provided substrate-level resolution of CPE function, directly identifying improperly processed proinsulin proteoforms and confirming CPD compensation.","evidence":"Top-down proteomics of beta-cell-specific Cpe knockout islets","pmids":["37967211"],"confidence":"High","gaps":["Mechanism and regulation of CPD compensation not defined","Beta-cell context only"]},{"year":null,"claim":"How CPE's enzymatic, TGN-sorting, and extracellular signaling functions are molecularly partitioned, and how secreted/exosomal CPE engages cell-surface signaling, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model linking sorting-receptor and catalytic activities","Receptor for secreted CPE in mTORC1 activation unidentified","Mechanism of CPD functional compensation undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[3,6,8,14,17]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[3,14]},{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[0]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[0,5]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[9,10,11]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,3,6,14]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,10,16]}],"complexes":[],"partners":["WNT3A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P16870","full_name":"Carboxypeptidase E","aliases":["Carboxypeptidase H","CPH","Enkephalin convertase","Prohormone-processing carboxypeptidase"],"length_aa":476,"mass_kda":53.2,"function":"Sorting receptor that directs prohormones to the regulated secretory pathway. Also acts as a prohormone processing enzyme in neuro/endocrine cells, removing dibasic residues from the C-terminal end of peptide hormone precursors after initial endoprotease cleavage","subcellular_location":"Cytoplasmic vesicle, secretory vesicle; Cytoplasmic vesicle, secretory vesicle membrane; Secreted","url":"https://www.uniprot.org/uniprotkb/P16870/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CPE","classification":"Not Classified","n_dependent_lines":6,"n_total_lines":1208,"dependency_fraction":0.004966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PSMC3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CPE","total_profiled":1310},"omim":[{"mim_id":"620263","title":"OOCYTE-SECRETED PROTEIN 2; OOSP2","url":"https://www.omim.org/entry/620263"},{"mim_id":"619326","title":"BDV SYNDROME; BDVS","url":"https://www.omim.org/entry/619326"},{"mim_id":"617348","title":"CARBOXYPEPTIDASE X, M14 FAMILY, MEMBER 2; CPXM2","url":"https://www.omim.org/entry/617348"},{"mim_id":"610777","title":"NEUROGUIDIN; NGDN","url":"https://www.omim.org/entry/610777"},{"mim_id":"610607","title":"CYTOPLASMIC POLYADENYLATION ELEMENT-BINDING PROTEIN 4; CPEB4","url":"https://www.omim.org/entry/610607"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Centrosome","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":1047.2},{"tissue":"retina","ntpm":687.1}],"url":"https://www.proteinatlas.org/search/CPE"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P16870","domains":[{"cath_id":"3.40.630.10","chopping":"55-372","consensus_level":"high","plddt":96.5947,"start":55,"end":372},{"cath_id":"2.60.40.1120","chopping":"376-454","consensus_level":"high","plddt":97.6635,"start":376,"end":454}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P16870","model_url":"https://alphafold.ebi.ac.uk/files/AF-P16870-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P16870-F1-predicted_aligned_error_v6.png","plddt_mean":90.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CPE","jax_strain_url":"https://www.jax.org/strain/search?query=CPE"},"sequence":{"accession":"P16870","fasta_url":"https://rest.uniprot.org/uniprotkb/P16870.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P16870/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P16870"}},"corpus_meta":[{"pmid":"9019408","id":"PMC_9019408","title":"Carboxypeptidase E is a regulated secretory pathway sorting receptor: genetic obliteration leads to endocrine disorders in Cpe(fat) mice.","date":"1997","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/9019408","citation_count":387,"is_preprint":false},{"pmid":"18267074","id":"PMC_18267074","title":"A combinatorial code for CPE-mediated translational control.","date":"2008","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/18267074","citation_count":322,"is_preprint":false},{"pmid":"10749216","id":"PMC_10749216","title":"Phosphorylation of CPE binding factor by Eg2 regulates translation of c-mos mRNA.","date":"2000","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/10749216","citation_count":300,"is_preprint":false},{"pmid":"10476029","id":"PMC_10476029","title":"Inactivation of the gene (cpe) encoding Clostridium perfringens enterotoxin eliminates the ability of two cpe-positive C. perfringens type A human gastrointestinal disease isolates to affect rabbit ileal loops.","date":"1999","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/10476029","citation_count":181,"is_preprint":false},{"pmid":"32383254","id":"PMC_32383254","title":"Evaluation of SARS-CoV-2 neutralizing antibodies using a CPE-based colorimetric live virus micro-neutralization assay in human serum samples.","date":"2020","source":"Journal of medical virology","url":"https://pubmed.ncbi.nlm.nih.gov/32383254","citation_count":142,"is_preprint":false},{"pmid":"19767734","id":"PMC_19767734","title":"The obesity susceptibility gene Cpe links FoxO1 signaling in hypothalamic pro-opiomelanocortin neurons with regulation of food intake.","date":"2009","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/19767734","citation_count":134,"is_preprint":false},{"pmid":"1653174","id":"PMC_1653174","title":"Maturation-specific polyadenylation: in vitro activation by p34cdc2 and phosphorylation of a 58-kD CPE-binding protein.","date":"1991","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/1653174","citation_count":130,"is_preprint":false},{"pmid":"7783636","id":"PMC_7783636","title":"The enterotoxin gene (cpe) of Clostridium perfringens can be chromosomal or plasmid-borne.","date":"1995","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/7783636","citation_count":128,"is_preprint":false},{"pmid":"11481435","id":"PMC_11481435","title":"Identification of peptides from brain and pituitary of Cpe(fat)/Cpe(fat) mice.","date":"2001","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/11481435","citation_count":112,"is_preprint":false},{"pmid":"9422603","id":"PMC_9422603","title":"Identification and characterization of sporulation-dependent promoters upstream of the enterotoxin gene (cpe) of Clostridium perfringens.","date":"1998","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/9422603","citation_count":112,"is_preprint":false},{"pmid":"14752101","id":"PMC_14752101","title":"Cytoplasmic polyadenylation element (CPE)- and CPE-binding protein (CPEB)-independent mechanisms regulate early class maternal mRNA translational activation in Xenopus oocytes.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/14752101","citation_count":87,"is_preprint":false},{"pmid":"19201796","id":"PMC_19201796","title":"Sporulation and enterotoxin (CPE) synthesis are controlled by the sporulation-specific sigma factors SigE and SigK in Clostridium perfringens.","date":"2009","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/19201796","citation_count":86,"is_preprint":false},{"pmid":"18536713","id":"PMC_18536713","title":"Spindle-localized CPE-mediated translation controls meiotic chromosome segregation.","date":"2008","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/18536713","citation_count":78,"is_preprint":false},{"pmid":"15292123","id":"PMC_15292123","title":"The CcpA protein is necessary for efficient sporulation and enterotoxin gene (cpe) regulation in Clostridium perfringens.","date":"2004","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/15292123","citation_count":77,"is_preprint":false},{"pmid":"8757868","id":"PMC_8757868","title":"Regulated expression of Clostridium perfringens enterotoxin in naturally cpe-negative type A, B, and C isolates of C. perfringens.","date":"1996","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/8757868","citation_count":76,"is_preprint":false},{"pmid":"19014391","id":"PMC_19014391","title":"Peptidomics of Cpe(fat/fat) mouse brain regions: implications for neuropeptide processing.","date":"2008","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19014391","citation_count":75,"is_preprint":false},{"pmid":"26120850","id":"PMC_26120850","title":"Truncating Homozygous Mutation of Carboxypeptidase E (CPE) in a Morbidly Obese Female with Type 2 Diabetes Mellitus, Intellectual Disability and Hypogonadotrophic Hypogonadism.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26120850","citation_count":65,"is_preprint":false},{"pmid":"10960708","id":"PMC_10960708","title":"Detection of porcine enteroviruses by nRT-PCR: differentiation of CPE groups I-III with specific primer sets.","date":"2000","source":"Journal of virological methods","url":"https://pubmed.ncbi.nlm.nih.gov/10960708","citation_count":65,"is_preprint":false},{"pmid":"15706630","id":"PMC_15706630","title":"Relative quantitation of peptides in wild-type and Cpe(fat/fat) mouse pituitary using stable isotopic tags and mass spectrometry.","date":"2005","source":"Journal of mass spectrometry : JMS","url":"https://pubmed.ncbi.nlm.nih.gov/15706630","citation_count":63,"is_preprint":false},{"pmid":"17326053","id":"PMC_17326053","title":"Overexpression of claudin-3 and claudin-4 receptors in uterine serous papillary carcinoma: novel targets for a type-specific therapy using Clostridium perfringens enterotoxin (CPE).","date":"2007","source":"Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/17326053","citation_count":60,"is_preprint":false},{"pmid":"9348219","id":"PMC_9348219","title":"Beta-cell lines derived from transgenic Cpe(fat)/Cpe(fat) mice are defective in carboxypeptidase E and proinsulin processing.","date":"1997","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/9348219","citation_count":57,"is_preprint":false},{"pmid":"7960138","id":"PMC_7960138","title":"Expression from the Clostridium perfringens cpe promoter in C. perfringens and Bacillus subtilis.","date":"1994","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/7960138","citation_count":57,"is_preprint":false},{"pmid":"21941545","id":"PMC_21941545","title":"Use of Clostridium perfringens Enterotoxin and the Enterotoxin Receptor-Binding Domain (C-CPE) for Cancer Treatment: Opportunities and Challenges.","date":"2011","source":"Journal of toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/21941545","citation_count":55,"is_preprint":false},{"pmid":"15572367","id":"PMC_15572367","title":"Peptidomics of Cpe fat/fat mouse hypothalamus: effect of food deprivation and exercise on peptide levels.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15572367","citation_count":55,"is_preprint":false},{"pmid":"11038363","id":"PMC_11038363","title":"Impaired prohormone convertases in Cpe(fat)/Cpe(fat) mice.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11038363","citation_count":52,"is_preprint":false},{"pmid":"19567823","id":"PMC_19567823","title":"Recombinant CPE fused to tumor necrosis factor targets human ovarian cancer cells expressing the claudin-3 and claudin-4 receptors.","date":"2009","source":"Molecular cancer therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/19567823","citation_count":51,"is_preprint":false},{"pmid":"18003798","id":"PMC_18003798","title":"Clostridium perfringens type A strains carrying a plasmid-borne enterotoxin gene (genotype IS1151-cpe or IS1470-like-cpe) as a common cause of food poisoning.","date":"2007","source":"Journal of clinical microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/18003798","citation_count":51,"is_preprint":false},{"pmid":"23685873","id":"PMC_23685873","title":"Claudins overexpression in ovarian cancer: potential targets for Clostridium Perfringens Enterotoxin (CPE) based diagnosis and therapy.","date":"2013","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/23685873","citation_count":50,"is_preprint":false},{"pmid":"15071003","id":"PMC_15071003","title":"Multiplex PCR genotyping assay that distinguishes between isolates of Clostridium perfringens type A carrying a chromosomal enterotoxin gene (cpe) locus, a plasmid cpe locus with an IS1470-like sequence, or a plasmid cpe locus with an IS1151 sequence.","date":"2004","source":"Journal of clinical microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/15071003","citation_count":49,"is_preprint":false},{"pmid":"24135412","id":"PMC_24135412","title":"Evaluation of a new real-time PCR assay (Check-Direct CPE) for rapid detection of KPC, OXA-48, VIM, and NDM carbapenemases using spiked rectal swabs.","date":"2013","source":"Diagnostic microbiology and infectious disease","url":"https://pubmed.ncbi.nlm.nih.gov/24135412","citation_count":49,"is_preprint":false},{"pmid":"12117935","id":"PMC_12117935","title":"Organization of the plasmid cpe Locus in Clostridium perfringens type A isolates.","date":"2002","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/12117935","citation_count":47,"is_preprint":false},{"pmid":"26338860","id":"PMC_26338860","title":"Clinical Performance of Check-Direct CPE, a Multiplex PCR for Direct Detection of bla(KPC), bla(NDM) and/or bla(VIM), and bla(OXA)-48 from Perirectal Swabs.","date":"2015","source":"Journal of clinical microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/26338860","citation_count":44,"is_preprint":false},{"pmid":"18505809","id":"PMC_18505809","title":"Noncytotoxic Clostridium perfringens enterotoxin (CPE) variants localize CPE intestinal binding and demonstrate a relationship between CPE-induced cytotoxicity and enterotoxicity.","date":"2008","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/18505809","citation_count":43,"is_preprint":false},{"pmid":"22865060","id":"PMC_22865060","title":"A wide variety of Clostridium perfringens type A food-borne isolates that carry a chromosomal cpe gene belong to one multilocus sequence typing cluster.","date":"2012","source":"Applied and environmental microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/22865060","citation_count":42,"is_preprint":false},{"pmid":"25637518","id":"PMC_25637518","title":"Multicentre evaluation of the Check-Direct CPE® assay for direct screening of carbapenemase-producing Enterobacteriaceae from rectal swabs.","date":"2015","source":"The Journal of antimicrobial chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/25637518","citation_count":38,"is_preprint":false},{"pmid":"9878248","id":"PMC_9878248","title":"Genes for the CPE receptor (CPETR1) and the human homolog of RVP1 (CPETR2) are localized within the Williams-Beuren syndrome deletion.","date":"1998","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/9878248","citation_count":37,"is_preprint":false},{"pmid":"22575574","id":"PMC_22575574","title":"A novel method for high-throughput screening to quantify antiviral activity against viruses that induce limited CPE.","date":"2012","source":"Journal of virological methods","url":"https://pubmed.ncbi.nlm.nih.gov/22575574","citation_count":36,"is_preprint":false},{"pmid":"30579969","id":"PMC_30579969","title":"Acetic acid as a decontamination method for ICU sink drains colonized by carbapenemase-producing Enterobacteriaceae and its effect on CPE infections.","date":"2018","source":"The Journal of hospital infection","url":"https://pubmed.ncbi.nlm.nih.gov/30579969","citation_count":35,"is_preprint":false},{"pmid":"16417576","id":"PMC_16417576","title":"Altered neuropeptide processing in prefrontal cortex of Cpe (fat/fat) mice: implications for neuropeptide discovery.","date":"2006","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16417576","citation_count":35,"is_preprint":false},{"pmid":"23552466","id":"PMC_23552466","title":"Claudin-6: a novel receptor for CPE-mediated cytotoxicity in ovarian cancer.","date":"2012","source":"Oncogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/23552466","citation_count":33,"is_preprint":false},{"pmid":"29706942","id":"PMC_29706942","title":"Oral Administration of Recombinant Saccharomyces boulardii Expressing Ovalbumin-CPE Fusion Protein Induces Antibody Response in Mice.","date":"2018","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/29706942","citation_count":32,"is_preprint":false},{"pmid":"2332799","id":"PMC_2332799","title":"Carboxypeptidase E (CPE): immunocytochemical localization in the rat central nervous system and pituitary gland.","date":"1990","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/2332799","citation_count":31,"is_preprint":false},{"pmid":"20952436","id":"PMC_20952436","title":"The relevance of protein-protein interactions for p53 function: the CPE contribution.","date":"2010","source":"Protein engineering, design & selection : PEDS","url":"https://pubmed.ncbi.nlm.nih.gov/20952436","citation_count":29,"is_preprint":false},{"pmid":"23442571","id":"PMC_23442571","title":"Emergence of anxiety-like behaviours in depressive-like Cpe(fat/fat) mice.","date":"2013","source":"The international journal of neuropsychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/23442571","citation_count":29,"is_preprint":false},{"pmid":"37082099","id":"PMC_37082099","title":"Case report: Dramatic response to alectinib in a lung adenosquamous carcinoma patient harbouring a novel CPE-ALK fusion.","date":"2022","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/37082099","citation_count":29,"is_preprint":false},{"pmid":"20532170","id":"PMC_20532170","title":"Organization of the cpe locus in CPE-positive clostridium perfringens type C and D isolates.","date":"2010","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/20532170","citation_count":27,"is_preprint":false},{"pmid":"12682135","id":"PMC_12682135","title":"Development of a duplex PCR genotyping assay for distinguishing Clostridium perfringens type A isolates carrying chromosomal enterotoxin (cpe) genes from those carrying plasmid-borne enterotoxin (cpe) genes.","date":"2003","source":"Journal of clinical microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/12682135","citation_count":26,"is_preprint":false},{"pmid":"25549049","id":"PMC_25549049","title":"Central Sirt1 regulates body weight and energy expenditure along with the POMC-derived peptide α-MSH and the processing enzyme CPE production in diet-induced obese male rats.","date":"2014","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/25549049","citation_count":25,"is_preprint":false},{"pmid":"17084111","id":"PMC_17084111","title":"Electrochemical detection of short sequences related to the hepatitis B virus using MB on chitosan-modified CPE.","date":"2006","source":"Bioelectrochemistry (Amsterdam, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/17084111","citation_count":24,"is_preprint":false},{"pmid":"12488357","id":"PMC_12488357","title":"Trafficking of mutant carboxypeptidase E to secretory granules in a beta-cell line derived from Cpe(fat)/Cpe(fat) mice.","date":"2003","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/12488357","citation_count":23,"is_preprint":false},{"pmid":"9207237","id":"PMC_9207237","title":"Interleukin-8 selectively enhances cytopathic effect (CPE) induced by positive-strand RNA viruses in the human WISH cell line.","date":"1997","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/9207237","citation_count":23,"is_preprint":false},{"pmid":"31553300","id":"PMC_31553300","title":"Phylogenomic analysis of gastroenteritis-associated Clostridium perfringens in England and Wales over a 7-year period indicates distribution of clonal toxigenic strains in multiple outbreaks and extensive involvement of enterotoxin-encoding (CPE) plasmids.","date":"2019","source":"Microbial genomics","url":"https://pubmed.ncbi.nlm.nih.gov/31553300","citation_count":22,"is_preprint":false},{"pmid":"26036653","id":"PMC_26036653","title":"Claudin-binder C-CPE mutants enhance permeability of insulin across human nasal epithelial cells.","date":"2015","source":"Drug delivery","url":"https://pubmed.ncbi.nlm.nih.gov/26036653","citation_count":21,"is_preprint":false},{"pmid":"9871107","id":"PMC_9871107","title":"Evidence for Clostridium perfringens enterotoxin (CPE) inducing a mitogenic and cytokine response in vitro and a cytokine response in vivo.","date":"1999","source":"Current microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/9871107","citation_count":21,"is_preprint":false},{"pmid":"26002961","id":"PMC_26002961","title":"Synthesis of histone proteins by CPE ligation using a recombinant peptide as the C-terminal building block.","date":"2015","source":"Journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26002961","citation_count":21,"is_preprint":false},{"pmid":"35328535","id":"PMC_35328535","title":"Exosomal Carboxypeptidase E (CPE) and CPE-shRNA-Loaded Exosomes Regulate Metastatic Phenotype of Tumor Cells.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35328535","citation_count":20,"is_preprint":false},{"pmid":"8989513","id":"PMC_8989513","title":"Clostridium perfringens type A enterotoxin (CPE): more than just explosive diarrhea.","date":"1996","source":"Critical reviews in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/8989513","citation_count":20,"is_preprint":false},{"pmid":"24006921","id":"PMC_24006921","title":"Upregulation of CPE promotes cell proliferation and tumorigenicity in colorectal cancer.","date":"2013","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/24006921","citation_count":20,"is_preprint":false},{"pmid":"34503203","id":"PMC_34503203","title":"Effective Oncoleaking Treatment of Pancreatic Cancer by Claudin-Targeted Suicide Gene Therapy with Clostridium perfringens Enterotoxin (CPE).","date":"2021","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/34503203","citation_count":20,"is_preprint":false},{"pmid":"18485266","id":"PMC_18485266","title":"Spread of a large plasmid carrying the cpe gene and the tcp locus amongst Clostridium perfringens isolates from nosocomial outbreaks and sporadic cases of gastroenteritis in a geriatric hospital.","date":"2008","source":"Epidemiology and infection","url":"https://pubmed.ncbi.nlm.nih.gov/18485266","citation_count":19,"is_preprint":false},{"pmid":"32401790","id":"PMC_32401790","title":"Differentiation of Cytopathic Effects (CPE) induced by influenza virus infection using deep Convolutional Neural Networks (CNN).","date":"2020","source":"PLoS computational biology","url":"https://pubmed.ncbi.nlm.nih.gov/32401790","citation_count":17,"is_preprint":false},{"pmid":"32309697","id":"PMC_32309697","title":"Microporous Metal-Organic Framework (MOF)-Based Composite Polymer Electrolyte (CPE) Mitigating Lithium Dendrite Formation in All-Solid-State-Lithium Batteries.","date":"2020","source":"ACS omega","url":"https://pubmed.ncbi.nlm.nih.gov/32309697","citation_count":17,"is_preprint":false},{"pmid":"25374060","id":"PMC_25374060","title":"Downregulation of CPE regulates cell proliferation and chemosensitivity in pancreatic cancer.","date":"2014","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25374060","citation_count":16,"is_preprint":false},{"pmid":"19428990","id":"PMC_19428990","title":"PC2/CPE-mediated pro-protein processing in tumor cells and its differentiated cells or tissues.","date":"2009","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/19428990","citation_count":16,"is_preprint":false},{"pmid":"15364981","id":"PMC_15364981","title":"Enumeration and isolation of cpe-positive Clostridium perfringens spores from feces.","date":"2004","source":"Journal of clinical microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/15364981","citation_count":16,"is_preprint":false},{"pmid":"26188294","id":"PMC_26188294","title":"A genosensor based on CPE for study the interaction between ketamine as an anesthesia drug with DNA.","date":"2015","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/26188294","citation_count":16,"is_preprint":false},{"pmid":"22677413","id":"PMC_22677413","title":"Strong ion exchange in centrifugal partition extraction (SIX-CPE): effect of partition cell design and dimensions on purification process efficiency.","date":"2012","source":"Journal of chromatography. A","url":"https://pubmed.ncbi.nlm.nih.gov/22677413","citation_count":16,"is_preprint":false},{"pmid":"15870393","id":"PMC_15870393","title":"Genetic modifiers interact with Cpe(fat) to affect body weight, adiposity, and hyperglycemia.","date":"2005","source":"Physiological genomics","url":"https://pubmed.ncbi.nlm.nih.gov/15870393","citation_count":15,"is_preprint":false},{"pmid":"30802555","id":"PMC_30802555","title":"The prevalence of plasmid-coded cpe enterotoxin, β2 toxin, tpeL toxin, and tetracycline resistance in Clostridium perfringens strains isolated from different sources.","date":"2019","source":"Anaerobe","url":"https://pubmed.ncbi.nlm.nih.gov/30802555","citation_count":15,"is_preprint":false},{"pmid":"31952126","id":"PMC_31952126","title":"Simultaneous Determination of Six Isoflavones from Puerariae Lobatae Radix by CPE-HPLC and Effect of Puerarin on Tyrosinase Activity.","date":"2020","source":"Molecules (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/31952126","citation_count":15,"is_preprint":false},{"pmid":"23094024","id":"PMC_23094024","title":"Comparative genomic hybridization analysis shows different epidemiology of chromosomal and plasmid-borne cpe-carrying Clostridium perfringens type A.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23094024","citation_count":15,"is_preprint":false},{"pmid":"25912832","id":"PMC_25912832","title":"In vitro cytotoxicity induced by Clostridium perfringens isolate carrying a chromosomal cpe gene is exclusively dependent on sporulation and enterotoxin production.","date":"2015","source":"Microbial pathogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/25912832","citation_count":14,"is_preprint":false},{"pmid":"34525401","id":"PMC_34525401","title":"Longitudinal Genomic Characterization of Carbapenemase-producing Enterobacteriaceae (CPE) Reveals Changing Pattern of CPE Isolated in Hong Kong Hospitals.","date":"2021","source":"International journal of antimicrobial agents","url":"https://pubmed.ncbi.nlm.nih.gov/34525401","citation_count":14,"is_preprint":false},{"pmid":"23217049","id":"PMC_23217049","title":"Evaluation of progressive multifocal leukoencephalopathy treatments in a Spanish cohort of HIV-infected patients: do protease inhibitors improve survival regardless of central nervous system penetration-effectiveness (CPE) score?","date":"2012","source":"HIV medicine","url":"https://pubmed.ncbi.nlm.nih.gov/23217049","citation_count":14,"is_preprint":false},{"pmid":"12438557","id":"PMC_12438557","title":"Developmental changes in opioid peptides and their receptors in Cpe(fat)/Cpe(fat) mice lacking peptide processing enzyme carboxypeptidase E.","date":"2002","source":"The Journal of pharmacology and experimental therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/12438557","citation_count":13,"is_preprint":false},{"pmid":"28978054","id":"PMC_28978054","title":"Effects of soluble CPE on glioma cell migration are associated with mTOR activation and enhanced glucose flux.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/28978054","citation_count":12,"is_preprint":false},{"pmid":"8471071","id":"PMC_8471071","title":"Mechanism of resistance to cyclopentenyl cytosine (CPE-C) in Molt-4 lymphoblasts.","date":"1993","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/8471071","citation_count":12,"is_preprint":false},{"pmid":"27022469","id":"PMC_27022469","title":"Claudin-4 binder C-CPE 194 enhances effects of anticancer agents on pancreatic cancer cell lines via a MAPK pathway.","date":"2015","source":"Pharmacology research & perspectives","url":"https://pubmed.ncbi.nlm.nih.gov/27022469","citation_count":12,"is_preprint":false},{"pmid":"28265741","id":"PMC_28265741","title":"The pleiotropic vegetative and sexual development phenotypes of Neurospora crassa arise from double mutants of the calcium signaling genes plc-1, splA2, and cpe-1.","date":"2017","source":"Current genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28265741","citation_count":12,"is_preprint":false},{"pmid":"24434005","id":"PMC_24434005","title":"Folding and stability studies on C-PE and its natural N-terminal truncant.","date":"2014","source":"Archives of biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/24434005","citation_count":12,"is_preprint":false},{"pmid":"24773342","id":"PMC_24773342","title":"Central Sirt1 regulates body weight and energy expenditure along with the POMC-derived peptide α-MSH and the processing enzyme CPE production in diet-induced obese male rats.","date":"2014","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/24773342","citation_count":12,"is_preprint":false},{"pmid":"3765819","id":"PMC_3765819","title":"Dominance of the CPE(+) phenotype in hybrid Aedes albopictus cells infected with Sindbis virus.","date":"1986","source":"Virus research","url":"https://pubmed.ncbi.nlm.nih.gov/3765819","citation_count":12,"is_preprint":false},{"pmid":"29702356","id":"PMC_29702356","title":"Identification of CPE and GAIT elements in 3'UTR of macrophage migration inhibitory factor (MIF) involved in inflammatory response induced by LPS in Ciona robusta.","date":"2018","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/29702356","citation_count":11,"is_preprint":false},{"pmid":"15532984","id":"PMC_15532984","title":"PCR identification of the plasmid-borne enterotoxin gene (cpe) in Clostridium perfringens strains isolated from food poisoning outbreaks.","date":"2004","source":"International journal of medical microbiology : IJMM","url":"https://pubmed.ncbi.nlm.nih.gov/15532984","citation_count":11,"is_preprint":false},{"pmid":"12667923","id":"PMC_12667923","title":"Study of interactions between actinomycin D and DNA on carbon paste electrode (CPE) and on the hanging mercury drop (HMDE) surface.","date":"2003","source":"Journal of pharmaceutical and biomedical analysis","url":"https://pubmed.ncbi.nlm.nih.gov/12667923","citation_count":11,"is_preprint":false},{"pmid":"37967211","id":"PMC_37967211","title":"Top-Down Proteomics of Mouse Islets With Beta Cell CPE Deletion Reveals Molecular Details in Prohormone Processing.","date":"2023","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/37967211","citation_count":10,"is_preprint":false},{"pmid":"36549463","id":"PMC_36549463","title":"Prevalence of cpe-positive Clostridium perfringens in surface-attached soil of commercially available potatoes and its significance as a potential source of food poisoning.","date":"2022","source":"Anaerobe","url":"https://pubmed.ncbi.nlm.nih.gov/36549463","citation_count":10,"is_preprint":false},{"pmid":"10657504","id":"PMC_10657504","title":"Altered biosynthesis and secretion of pro-opiomelanocortin in the intermediate and anterior pituitary of carboxypeptidase E-deficient, Cpe(fat)/ Cpe(fat)mice.","date":"1999","source":"Neuropeptides","url":"https://pubmed.ncbi.nlm.nih.gov/10657504","citation_count":10,"is_preprint":false},{"pmid":"25461607","id":"PMC_25461607","title":"Differential outgrowth potential of Clostridium perfringens food-borne isolates with various cpe-genotypes in vacuum-packed ground beef during storage at 12°C.","date":"2014","source":"International journal of food microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/25461607","citation_count":9,"is_preprint":false},{"pmid":"19786034","id":"PMC_19786034","title":"Neutralizing antibodies against IFN beta in patients with multiple sclerosis: a comparative study of two cytopathic effect tests (CPE) for their detection.","date":"2009","source":"Journal of immunological methods","url":"https://pubmed.ncbi.nlm.nih.gov/19786034","citation_count":9,"is_preprint":false},{"pmid":"1723149","id":"PMC_1723149","title":"Identification of a common Plasmodium epitope (CPE) recognised by a pan-specific inhibitory monoclonal antibody.","date":"1991","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/1723149","citation_count":9,"is_preprint":false},{"pmid":"35347588","id":"PMC_35347588","title":"CHIKV strains Brazil (wt) and Ross (lab-adapted) differ with regard to cell host range and antiviral sensitivity and show CPE in human glioblastoma cell lines U138 and U251.","date":"2022","source":"Virus genes","url":"https://pubmed.ncbi.nlm.nih.gov/35347588","citation_count":8,"is_preprint":false},{"pmid":"27375026","id":"PMC_27375026","title":"Carboxypeptidase E (CPE) inhibits the secretion and activity of Wnt3a.","date":"2016","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/27375026","citation_count":8,"is_preprint":false},{"pmid":"27533488","id":"PMC_27533488","title":"An optimized work-flow to reduce time-to-detection of carbapenemase-producing Enterobacteriaceae (CPE) using direct testing from rectal swabs.","date":"2016","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/27533488","citation_count":6,"is_preprint":false},{"pmid":"9700764","id":"PMC_9700764","title":"Reduced levels of substance P in the brains of Cpe(fat)/Cpe(fat) mice.","date":"1998","source":"Peptides","url":"https://pubmed.ncbi.nlm.nih.gov/9700764","citation_count":6,"is_preprint":false},{"pmid":"1333832","id":"PMC_1333832","title":"Evaluation of the shell vial pre-CPE method using monoclonal antibodies for the diagnosis of human cytomegalovirus infection in the field of pediatrics.","date":"1992","source":"In vivo (Athens, Greece)","url":"https://pubmed.ncbi.nlm.nih.gov/1333832","citation_count":6,"is_preprint":false},{"pmid":"35340224","id":"PMC_35340224","title":"CPE Regulates Proliferation and Apoptosis of Primary Myocardial Cells Mediated by Ischemia and Hypoxia Injury.","date":"2022","source":"Journal of healthcare engineering","url":"https://pubmed.ncbi.nlm.nih.gov/35340224","citation_count":5,"is_preprint":false},{"pmid":"34830170","id":"PMC_34830170","title":"Ablation of Red Stable Transfected Claudin Expressing Canine Prostate Adenocarcinoma and Transitional Cell Carcinoma Cell Lines by C-CPE Gold-Nanoparticle-Mediated Laser Intervention.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34830170","citation_count":5,"is_preprint":false},{"pmid":"40458709","id":"PMC_40458709","title":"First genomic analysis of a Clostridium perfringens strain carrying both the cpe and netB genes and the proposal of an amended toxin-based typing scheme.","date":"2025","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/40458709","citation_count":5,"is_preprint":false},{"pmid":"26072402","id":"PMC_26072402","title":"Oncoleaking: Use of the Pore-Forming Clostridium perfringens Enterotoxin (CPE) for Suicide Gene Therapy.","date":"2015","source":"Methods in molecular biology (Clifton, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/26072402","citation_count":5,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49976,"output_tokens":4698,"usd":0.110199,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12946,"output_tokens":4875,"usd":0.093302,"stage2_stop_reason":"end_turn"},"total_usd":0.203501,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"Membrane-associated carboxypeptidase E (CPE) functions as a sorting receptor at the trans-Golgi network for regulated secretory pathway proteins: CPE specifically bound prohormones (but not constitutively secreted proteins) in pituitary Golgi-enriched and secretory granule membranes, and in Cpe(fat) mice lacking CPE, pro-opiomelanocortin was missorted to the constitutive pathway and secreted in an unregulated manner.\",\n      \"method\": \"Biochemical binding assays with pituitary Golgi-enriched and secretory granule membrane fractions; in vivo missecretion analysis in Cpe(fat) mutant mice\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding assays combined with in vivo genetic loss-of-function demonstrating missorted secretion; replicated across multiple prohormone substrates\",\n      \"pmids\": [\"9019408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"CPE is required for normal proinsulin processing in pancreatic beta-cells: beta-cell lines from Cpe(fat)/Cpe(fat) mice accumulate pro-CPE (not mature CPE) in an ER-like compartment and show defective proinsulin processing, with enlarged electron-lucent granules observed by electron microscopy. Notably, insulin/proinsulin secretion remains regulated (stimulated by secretagogues), indicating CPE is not required for sorting proinsulin to the regulated pathway.\",\n      \"method\": \"Pulse-chase metabolic labeling, immunocytochemistry, electron microscopy, secretion assays in Cpe(fat)/Cpe(fat)-derived NIT-2/NIT-3 beta-cell lines\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (EM, ICC, biochemical assays) in isogenic cell lines\",\n      \"pmids\": [\"9348219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"CPE (carboxypeptidase E) is a carboxypeptidase B-like enzyme localized in neuronal cell bodies and terminals throughout the rat CNS and pituitary, with highest concentration in hypothalamic nuclei (median eminence, supraoptic, paraventricular, suprachiasmatic), posterior pituitary, intermediate pituitary melanotropes, and hippocampal pyramidal cells, consistent with a role in neuropeptide biosynthesis.\",\n      \"method\": \"Immunocytochemistry using specific polyclonal antisera to purified CPE enzyme in rat brain sections\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — detailed immunolocalization across multiple brain regions with specific antisera, single lab but comprehensive anatomical mapping\",\n      \"pmids\": [\"2332799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"CPE activity is required for normal biosynthesis of the majority of neuroendocrine peptides: peptidomic analysis of Cpe(fat/fat) mouse brain and pituitary identified over 100 peptides accumulating as C-terminally basic processing intermediates from 16 secretory pathway proteins including proenkephalin, POMC, protachykinins, and chromogranins, demonstrating CPE's broad substrate scope as the terminal exopeptidase.\",\n      \"method\": \"Affinity chromatography on anhydrotrypsin resin followed by mass spectrometry peptide identification; radioimmunoassay validation in wild-type mice\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mass spectrometry-based peptidomics with RIA validation across multiple substrates in genetic loss-of-function model\",\n      \"pmids\": [\"11481435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Loss of CPE activity in Cpe(fat) mice leads to reduced levels of PC1 and PC2 prohormone convertases in brain and pituitary, resulting in decreased alpha-MSH, altered beta-endorphin processing, and increased dynorphin A-17, indicating CPE activity indirectly supports endoproteolytic processing by maintaining normal convertase levels.\",\n      \"method\": \"Western blot and immunohistochemistry for PC1, PC2 in multiple brain regions; radioimmunoassay for opioid peptides in Cpe(fat) vs. wild-type mice\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Western blot, IHC, RIA) in genetic model, single lab\",\n      \"pmids\": [\"11038363\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Mutant CPE (pro-CPE202) from Cpe(fat)/Cpe(fat) mice has a half-life of ~3 h in beta-cells, with up to 45% escaping proteasomal degradation and trafficking to PC2-containing secretory granules (post-Golgi regulated secretory pathway), where it is secreted in a stimulated manner, supporting a potential sorting/retention receptor role even for the mutant form.\",\n      \"method\": \"Pulse-chase experiments, double-label immunofluorescence microscopy with calnexin and PC2 markers, stimulated secretion assay with glucagon-like peptide-1 in NIT3 cells\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (pulse-chase, co-localization, functional secretion assay), single lab\",\n      \"pmids\": [\"12488357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Quantitative peptidomics of six brain regions of Cpe(fat/fat) mice demonstrated that CPE contributes to biosynthesis of the majority of neuropeptides; most secretory pathway peptides were greatly reduced while C-terminally basic processing intermediates were elevated, with partial compensation by carboxypeptidase D for a subset of peptides.\",\n      \"method\": \"Quantitative peptidomics with tandem mass spectrometry comparing six brain regions of Cpe(fat/fat) vs. wild-type mice\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — comprehensive quantitative MS across 6 brain regions in genetic model, replicates and extends earlier peptidomics findings\",\n      \"pmids\": [\"19014391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"FoxO1 ablation in POMC neurons increases CPE expression, leading to selective increases in alpha-MSH and carboxy-cleaved beta-endorphin (CPE-dependent POMC processing products), decreased food intake, and protection against diet-induced obesity; moderate CPE overexpression in the arcuate nucleus phenocopied these effects, placing CPE downstream of FoxO1 in hypothalamic energy balance regulation.\",\n      \"method\": \"Conditional FoxO1 knockout in POMC neurons; CPE overexpression via viral vector in arcuate nucleus; neuropeptide measurements; feeding and body weight phenotyping\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis (conditional KO) combined with gain-of-function overexpression and defined neuropeptide product measurements\",\n      \"pmids\": [\"19767734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"CPE is required for normal processing of substance P from pro-tachykinin: amidated mature SP was more than fivefold lower in all brain regions of Cpe(fat/fat) mice compared to controls, while total SP species (including processing intermediates) were unchanged, demonstrating CPE's specific role as the C-terminal basic residue-removing enzyme in SP biosynthesis.\",\n      \"method\": \"Radioimmunoassay measuring amidated SP vs. total SP forms in multiple brain regions of Cpe(fat/fat) vs. wild-type and heterozygous mice\",\n      \"journal\": \"Peptides\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — specific RIA distinguishing mature vs. intermediate forms in genetic loss-of-function model, single lab\",\n      \"pmids\": [\"9700764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CPE inhibits Wnt3a activity by forming aggregates with Wnt3a via CPE's N-terminal sequence, leading to Wnt3a loss of function; the C-terminal Lys residue of Wnt3a is critical for its activity and important for CPE's effect on the Wnt pathway, but CPE does not act by removing this residue enzymatically. CPE and Wnt3a are co-secreted from cells.\",\n      \"method\": \"Co-secretion assays, mutagenesis of Wnt3a C-terminal Lys, co-immunoprecipitation/aggregation assays, Wnt pathway reporter assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical methods (co-secretion, mutagenesis, pathway reporter), single lab\",\n      \"pmids\": [\"27375026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Secreted CPE (sCPE) activates mTORC1 signaling in glioma cells (detected by RPS6 phosphorylation) and inhibits glioma cell migration via negative regulation of Rac1 signaling through RPS6; mTOR inhibition or Rac1 stimulation reversed the anti-migratory effect of sCPE. sCPE also enhances glucose flux into the TCA cycle at the expense of lactate production, reducing aerobic glycolysis.\",\n      \"method\": \"Recombinant sCPE treatment of glioma cells; phospho-RPS6 Western blot; mTOR inhibitor and Rac1 activator pharmacological rescue; CPE knockdown; metabolic flux analysis\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (signaling Western blots, pharmacological epistasis, metabolic analysis, knockdown), single lab\",\n      \"pmids\": [\"28978054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CPE is present as mRNA and protein in cancer cell-derived exosomes; exosomal CPE from high-metastatic HCC97H cells promotes proliferation and invasion of low-metastatic HCC97L cells, and CPE-shRNA-loaded exosomes suppress CPE expression along with Cyclin D1 and c-MYC in high-metastatic cells, inhibiting their proliferation.\",\n      \"method\": \"Exosome isolation and characterization; Western blot and PCR for CPE in exosomes; MTT, colony formation, and Matrigel invasion assays; CPE-shRNA exosome delivery\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple functional assays (proliferation, invasion, shRNA knockdown) but mechanism of exosomal CPE action not fully resolved at molecular level\",\n      \"pmids\": [\"35328535\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CPE promotes cell proliferation and tumorigenicity in colorectal cancer cells through downregulation of p21 and p27 and upregulation of cyclin D1, resulting in increased S-phase fraction; overexpression enhanced anchorage-independent growth in soft agar.\",\n      \"method\": \"CPE overexpression and depletion plasmids; MTT, colony formation, BrdU incorporation, flow cytometry, soft agar assays; qRT-PCR for p21, p27, cyclin D1\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple functional assays with molecular pathway readouts, single lab, no rescue experiments\",\n      \"pmids\": [\"24006921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CPE regulates NF-κB activity in pancreatic cancer: siRNA-mediated CPE knockdown inhibited cancer cell growth, migration, and tumor growth in vivo, and directly reduced NF-κB expression; NF-κB inhibition phenocopied CPE knockdown effects, placing NF-κB downstream of CPE.\",\n      \"method\": \"siRNA knockdown of CPE; proliferation and invasion assays; in vivo xenograft; Western blot for NF-κB; NF-κB inhibitor pharmacological epistasis\",\n      \"journal\": \"Tumour biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockdown with pharmacological epistasis and in vivo validation, single lab\",\n      \"pmids\": [\"25374060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Top-down proteomics of beta-cell-specific Cpe knockout mouse islets identified multiple novel proteoforms of improperly processed proinsulin with dibasic C-terminal residues as direct CPE substrates; carboxypeptidase D (CPD) compensates for CPE loss and maintains near-normal processing of some CPE substrates.\",\n      \"method\": \"Top-down proteomics of islets from beta-cell-specific Cpe knockout mice; quantitative comparison of hormone proteoforms\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — top-down proteomics with genetic KO model providing substrate-level resolution; single lab but highly rigorous method\",\n      \"pmids\": [\"37967211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"A homozygous truncating mutation of CPE (c.76_98del; p.E26RfsX68) in a human patient causes morbid obesity, intellectual disability, abnormal glucose homeostasis, and hypogonadotrophic hypogonadism with no CPE expression detected (consistent with nonsense-mediated decay), establishing that CPE is essential for peptide/hormone processing regulating body weight, metabolism, brain, and reproductive function in humans.\",\n      \"method\": \"Exome sequencing; RNA expression analysis from blood-derived RNA confirming nonsense-mediated decay; phenotypic characterization\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human genetic loss-of-function with confirmed absence of expression; single patient but recapitulates mouse model phenotypes\",\n      \"pmids\": [\"26120850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Central Sirt1 inhibition in diet-induced obese rats increases CPE expression (via FoxO1 acetylation/phosphorylation), leading to increased alpha-MSH production from POMC processing and activation of the hypothalamic-pituitary-thyroid axis, placing CPE downstream of Sirt1/FoxO1 in the POMC processing pathway for energy expenditure regulation.\",\n      \"method\": \"Central Sirt1 inhibition (ICV injection); Western blot for CPE, FoxO1, phospho-FoxO1, acetyl-FoxO1; RIA for alpha-MSH; TRH and T3 measurements in DIO rats\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological epistasis with multiple molecular readouts, single lab, in vivo model\",\n      \"pmids\": [\"25549049\", \"24773342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"CPE is required for normal biosynthesis of opioid peptides from prodynorphin and proenkephalin during development: Cpe(fat/fat) mice accumulate C-terminally extended forms of all three opioid peptides examined, with region-specific decreases in mature dynorphin peptides and differential alterations in Met-enkephalin levels. Loss of CPE also differentially alters mu (but not kappa) opioid receptor functional activity in select brain regions.\",\n      \"method\": \"Peptide extraction and RIA from multiple brain regions at different developmental ages; [35S]GTPgammaS binding assay for mu and kappa receptor functional activity in Cpe(fat/fat) vs. littermate controls\",\n      \"journal\": \"The Journal of pharmacology and experimental therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIA and functional receptor assays across multiple brain regions and developmental time points, single lab\",\n      \"pmids\": [\"12438557\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Carboxypeptidase E (CPE) is a membrane-associated exopeptidase that removes C-terminal basic residues from prohormone processing intermediates to generate bioactive neuropeptides and peptide hormones; it also functions as a sorting receptor at the trans-Golgi network that directs prohormones into the regulated secretory pathway, acts downstream of FoxO1/Sirt1 signaling to control POMC-derived peptide production and energy balance, inhibits Wnt3a activity by forming aggregates via its N-terminal domain, activates mTORC1/RPS6 signaling to suppress glioma cell migration and aerobic glycolysis, and regulates cancer cell proliferation through cyclin D1/p21/p27 and NF-κB pathways.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"Carboxypeptidase E (CPE) is a carboxypeptidase B-like exopeptidase concentrated in neuronal cell bodies and terminals throughout the CNS and pituitary, with highest expression in hypothalamic and pituitary neuroendocrine centers, where it serves as the terminal enzyme in neuropeptide and peptide hormone biosynthesis [#2]. It removes C-terminal basic residues from prohormone processing intermediates: peptidomic and proteomic analyses of Cpe(fat) and beta-cell-specific knockout models show that loss of CPE causes accumulation of >100 C-terminally basic intermediates from at least 16 secretory pathway precursors—including POMC, proenkephalin, prodynorphin, protachykinin, and proinsulin—with reduced levels of the corresponding mature peptides [#3, #6, #14, #8, #17]. Carboxypeptidase D partially compensates for CPE loss for a subset of substrates [#6, #14], and CPE loss also lowers PC1/PC2 convertase levels, indirectly impairing upstream endoproteolytic processing [#4]. Independently of its enzymatic activity, CPE acts as a sorting receptor at the trans-Golgi network, binding prohormones to direct them into the regulated secretory pathway; in CPE-deficient pituitary cells POMC is missorted to the constitutive pathway [#0]. In the hypothalamus CPE functions downstream of Sirt1/FoxO1 signaling to control POMC-derived alpha-MSH and beta-endorphin production, energy balance, and the hypothalamic-pituitary-thyroid axis [#7, #16]. A human homozygous truncating CPE mutation causes morbid obesity, intellectual disability, abnormal glucose homeostasis, and hypogonadotrophic hypogonadism, establishing CPE as essential for hormone processing governing body weight, metabolism, and reproduction [#15]. Several non-canonical roles have also been documented: CPE inhibits Wnt3a by forming aggregates via its N-terminal domain without enzymatic cleavage [#9], secreted CPE activates mTORC1/RPS6 signaling to suppress glioma migration and aerobic glycolysis [#10], and CPE modulates cancer cell proliferation through cyclin D1/p21/p27 and NF-\\u03baB pathways [#12, #13].\",\n  \"teleology\": [\n    {\n      \"year\": 1990,\n      \"claim\": \"Established where CPE acts by mapping its anatomical distribution, linking the enzyme to neuropeptide-producing neuroendocrine centers.\",\n      \"evidence\": \"Immunocytochemistry with specific antisera across rat brain and pituitary\",\n      \"pmids\": [\"2332799\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Localization is anatomical, not subcellular at processing sites\", \"Does not demonstrate enzymatic function on specific substrates\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Resolved whether CPE has a function beyond enzymatic trimming, showing it acts as a TGN sorting receptor that routes prohormones to the regulated secretory pathway.\",\n      \"evidence\": \"Prohormone binding assays in Golgi/granule membranes plus missorting analysis in Cpe(fat) mice\",\n      \"pmids\": [\"9019408\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of prohormone recognition not defined\", \"Sorting role not universal across substrates (proinsulin sorting independent of CPE)\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Separated CPE's enzymatic processing role from sorting in beta-cells, showing CPE is needed for proinsulin processing but not for regulated sorting of insulin.\",\n      \"evidence\": \"Pulse-chase, EM, ICC, and secretion assays in Cpe(fat)-derived beta-cell lines\",\n      \"pmids\": [\"9348219\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of pro-CPE ER retention in mutant cells not fully resolved\", \"Does not address sorting role in other cell types\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Demonstrated CPE's substrate-specific requirement for a defined neuropeptide, establishing it as the C-terminal basic residue-removing enzyme for substance P.\",\n      \"evidence\": \"RIA distinguishing amidated mature vs. total SP in Cpe(fat/fat) brain regions\",\n      \"pmids\": [\"9700764\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single substrate; relies on indirect RIA discrimination\", \"No direct in vitro cleavage demonstration\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defined the breadth of CPE's role by showing it is the terminal exopeptidase for the majority of neuroendocrine peptides, and that its loss secondarily reduces convertase levels.\",\n      \"evidence\": \"Affinity-capture peptidomics with MS and RIA; Western/IHC/RIA for convertases and opioid peptides in Cpe(fat) mice\",\n      \"pmids\": [\"11481435\", \"11038363\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Convertase reduction is correlative, mechanism of indirect effect unclear\", \"Does not distinguish enzymatic vs. sorting contributions to each peptide deficit\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Extended CPE's processing role to opioid peptides during development and linked peptide deficits to altered receptor signaling.\",\n      \"evidence\": \"Developmental RIA and [35S]GTPgammaS receptor functional assays across brain regions in Cpe(fat/fat) mice\",\n      \"pmids\": [\"12438557\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor activity changes are downstream/correlative\", \"Region- and peptide-specific effects not mechanistically explained\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Characterized the fate of mutant pro-CPE, showing partial escape from degradation and trafficking to secretory granules, supporting a retention/sorting role even for the mutant form.\",\n      \"evidence\": \"Pulse-chase, co-localization with calnexin/PC2, and stimulated secretion in NIT3 cells\",\n      \"pmids\": [\"12488357\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of mutant trafficking unclear\", \"Single cell-line system\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Quantitatively confirmed CPE's global contribution to neuropeptide biosynthesis and revealed partial CPD compensation across brain regions.\",\n      \"evidence\": \"Quantitative tandem-MS peptidomics across six brain regions of Cpe(fat/fat) mice\",\n      \"pmids\": [\"19014391\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Compensation mechanism by CPD not defined\", \"Does not resolve which deficits are sorting- vs. enzyme-dependent\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Placed CPE in a hypothalamic regulatory circuit, showing it acts downstream of FoxO1 to control POMC-derived peptide production and energy balance.\",\n      \"evidence\": \"POMC-specific FoxO1 knockout plus arcuate CPE overexpression with feeding/weight phenotyping\",\n      \"pmids\": [\"19767734\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional link between FoxO1 and CPE not fully mapped\", \"Other FoxO1 targets may contribute\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Implicated CPE in cancer cell proliferation, showing it drives cell-cycle progression via cyclin D1/p21/p27 in colorectal cancer.\",\n      \"evidence\": \"CPE overexpression/depletion with proliferation, cell-cycle, soft-agar assays and qRT-PCR readouts\",\n      \"pmids\": [\"24006921\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No rescue experiments\", \"Molecular link from CPE to cell-cycle regulators undefined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connected CPE to oncogenic NF-\\u03baB signaling in pancreatic cancer through knockdown and pharmacological epistasis.\",\n      \"evidence\": \"siRNA knockdown, proliferation/invasion assays, xenograft, and NF-\\u03baB inhibitor epistasis\",\n      \"pmids\": [\"25374060\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular mechanism linking CPE to NF-\\u03baB unknown\", \"Single cancer context\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extended the FoxO1 circuit upstream, showing central Sirt1 controls CPE expression to regulate POMC processing and the HPT axis.\",\n      \"evidence\": \"ICV Sirt1 inhibition with FoxO1 acetylation/phosphorylation, alpha-MSH RIA, and TRH/T3 measures in DIO rats\",\n      \"pmids\": [\"25549049\", \"24773342\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Indirect pharmacological perturbation\", \"Direct Sirt1-FoxO1-CPE molecular linkage inferred not shown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established human disease relevance, showing a truncating CPE mutation causes obesity, intellectual disability, glucose dysregulation, and hypogonadism.\",\n      \"evidence\": \"Exome sequencing, NMD confirmation, and clinical phenotyping of a homozygous patient\",\n      \"pmids\": [\"26120850\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single patient\", \"Cannot dissect enzymatic vs. sorting contributions to each phenotype\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified a non-enzymatic CPE function, showing it inhibits Wnt3a by N-terminal-mediated aggregation rather than cleavage.\",\n      \"evidence\": \"Co-secretion, Wnt3a C-terminal Lys mutagenesis, co-IP/aggregation, and Wnt reporter assays\",\n      \"pmids\": [\"27375026\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological relevance of Wnt inhibition not established in vivo\", \"Single lab biochemical system\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined a secreted CPE signaling role, showing extracellular CPE activates mTORC1/RPS6 to suppress glioma migration and aerobic glycolysis.\",\n      \"evidence\": \"Recombinant sCPE treatment, phospho-RPS6 blots, mTOR/Rac1 pharmacological rescue, knockdown, and metabolic flux analysis\",\n      \"pmids\": [\"28978054\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor/mechanism by which sCPE triggers mTORC1 unknown\", \"Single tumor context\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed CPE can be transmitted between cancer cells via exosomes to promote proliferation and invasion.\",\n      \"evidence\": \"Exosome isolation, CPE detection, proliferation/invasion assays, and CPE-shRNA exosome delivery in HCC cells\",\n      \"pmids\": [\"35328535\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of exosomal CPE action unresolved\", \"Effects on cyclin D1/c-MYC correlative\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Provided substrate-level resolution of CPE function, directly identifying improperly processed proinsulin proteoforms and confirming CPD compensation.\",\n      \"evidence\": \"Top-down proteomics of beta-cell-specific Cpe knockout islets\",\n      \"pmids\": [\"37967211\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism and regulation of CPD compensation not defined\", \"Beta-cell context only\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CPE's enzymatic, TGN-sorting, and extracellular signaling functions are molecularly partitioned, and how secreted/exosomal CPE engages cell-surface signaling, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model linking sorting-receptor and catalytic activities\", \"Receptor for secreted CPE in mTORC1 activation unidentified\", \"Mechanism of CPD functional compensation undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [3, 6, 8, 14, 17]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [3, 14]},\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [9, 10, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 3, 6, 14]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 10, 16]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"WNT3A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}