{"gene":"CPE","run_date":"2026-04-28T17:28:53","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, binding prohormones (including pro-opiomelanocortin) to direct them into secretory granules. In Cpe(fat) mutant mice lacking CPE, POMC is missorted to the constitutive secretory pathway and secreted in an unregulated manner.","method":"Biochemical fractionation of pituitary Golgi-enriched and secretory granule membranes, binding assays with prohormones, and genetic loss-of-function (Cpe(fat) mice) with secretory pathway readout","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (binding assay, fractionation, genetic KO with defined secretory phenotype); foundational paper with 385 citations","pmids":["9019408"],"is_preprint":false},{"year":1990,"finding":"CPE (carboxypeptidase E/enkephalin convertase) is localized by immunocytochemistry to neuronal cell bodies and terminals throughout the rat CNS, with highest concentrations in the hypothalamus (median eminence, supraoptic, paraventricular, suprachiasmatic nuclei), posterior pituitary, intermediate pituitary melanotropes, hippocampal pyramidal cells, and amygdala—distribution matching that of neuropeptides.","method":"Immunocytochemistry with specific polyclonal antisera against purified CPE in rat CNS sections","journal":"The Journal of Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization experiment; single lab, single method but spatially detailed","pmids":["2332799"],"is_preprint":false},{"year":2001,"finding":"Carboxypeptidase E is required for the biosynthesis of the majority of neuropeptides in mouse brain and pituitary; Cpe(fat/fat) mice lacking CPE activity accumulate peptide processing intermediates with C-terminal basic residues, and levels of over 100 secretory pathway peptides (from proenkephalin, POMC, protachykinins, chromogranins, secretogranin II) are drastically reduced.","method":"Anhydrotrypsin affinity chromatography to isolate C-terminal basic residue-containing intermediates from Cpe(fat/fat) mouse brain; mass spectrometry identification; RIA validation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (affinity purification, MS, RIA) in Cpe loss-of-function model; replicated across subsequent peptidomics studies","pmids":["11481435"],"is_preprint":false},{"year":2001,"finding":"Loss of CPE activity in Cpe(fat) mice leads to secondary decreases in prohormone convertase PC1 and PC2 levels in brain regions and pituitary, resulting in altered processing of neuropeptides including dynorphin A-17, beta-endorphin, and alpha-MSH that are involved in feeding behavior and body weight regulation.","method":"Western blot and immunoassay for PC1, PC2, and neuropeptides in Cpe(fat) vs. wild-type mouse brain regions","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — clean loss-of-function model with defined molecular phenotype; single lab, two methods","pmids":["11038363"],"is_preprint":false},{"year":1997,"finding":"The Cpe(fat) point mutation (Ser202Pro) in the CPE coding region results in production of pro-CPE that is catalytically inactive and unstable; in beta-cell lines from Cpe(fat/fat) mice (NIT-2, NIT-3), pro-CPE accumulates in an ER-like compartment and proinsulin processing is defective. Granule morphology is altered (enlarged, electron-lucent). CPE activity is not required for sorting proinsulin into the regulated secretory pathway, as secretion remains stimulable.","method":"Beta-cell lines from Cpe(fat/fat) mice; Western blot for pro-CPE and mature CPE; electron microscopy; immunocytochemistry; pulse-chase secretion assays with secretagogues","journal":"Endocrinology","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (EM, ICC, Western blot, secretion assay) in defined mutant cell lines","pmids":["9348219"],"is_preprint":false},{"year":2003,"finding":"Mutant CPE (from Cpe(fat/fat) mice) has a half-life of ~3 h in NIT3 beta-cells; up to 45% escapes proteasomal degradation and traffics to prohormone convertase 2-containing secretory granules, where it is secreted in a regulated manner upon glucagon-like peptide-1 stimulation, supporting a role for CPE as a sorting/retention receptor in granule trafficking.","method":"Pulse-chase experiments in NIT3 cells; double-label immunofluorescence microscopy; secretion assay with GLP-1 stimulation","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 — pulse-chase, co-localization, secretion assay; single lab, multiple orthogonal methods","pmids":["12488357"],"is_preprint":false},{"year":2009,"finding":"FoxO1 ablation in POMC neurons increases CPE expression in the hypothalamus, leading to selective increases of alpha-MSH and carboxy-cleaved beta-endorphin (CPE-dependent POMC processing products), resulting in decreased food intake. Moderate CPE overexpression in the arcuate nucleus phenocopies FoxO1 deletion effects on food intake, placing CPE downstream of FoxO1 in the hypothalamic energy-balance circuit.","method":"Conditional Pomc-Foxo1 knockout mice; CPE overexpression in arcuate nucleus via viral vector; measurement of alpha-MSH and beta-endorphin forms; food intake and body weight measurements","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis (conditional KO + gain-of-function) with defined neuropeptide and behavioral phenotypes; replicated across multiple experiments","pmids":["19767734"],"is_preprint":false},{"year":2016,"finding":"CPE inhibits the secretion and activity of Wnt3a ligand. CPE and Wnt3a are co-secreted from cells; CPE forms aggregates with Wnt3a through its N-terminal sequence, inducing possible ER stress and causing loss of Wnt3a function, thereby negatively regulating the canonical Wnt signaling pathway. The C-terminal Lys residue of Wnt3a is critical for its activity, but CPE does not act by removing this residue.","method":"Co-secretion experiments, co-immunoprecipitation/aggregation assays, Wnt pathway reporter assays, CPE N-terminal deletion and Wnt3a C-terminal mutagenesis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2–3 — multiple mechanistic methods (co-secretion, aggregation, mutagenesis, reporter assay); single lab","pmids":["27375026"],"is_preprint":false},{"year":2017,"finding":"Secreted CPE (sCPE) activates mTORC1 signaling in glioma cells (detected by phosphorylation of RPS6) and reduces glioma cell migration via negative regulation of Rac1 signaling downstream of RPS6. CPE knockdown decreases active RPS6 and increases GBM cell motility. sCPE also shifts glucose metabolism away from aerobic glycolysis toward the TCA cycle.","method":"Recombinant sCPE treatment of glioma cell lines; CPE shRNA knockdown; phospho-protein Western blot (RPS6, Rac1); mTOR inhibitor experiments; glucose flux metabolic assays","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2–3 — gain- and loss-of-function with pathway inhibitor confirmation; single lab","pmids":["28978054"],"is_preprint":false},{"year":1998,"finding":"CPE is required for normal proteolytic processing of protachykinin to mature amidated substance P (SP) in the brain. Cpe(fat/fat) mice have more than fivefold lower levels of fully processed amidated SP in all brain regions tested compared to controls, while total SP species are unchanged, consistent with CPE acting as the final C-terminal basic residue-removing exopeptidase in SP biosynthesis.","method":"Radioimmunoassay for amidated SP and 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 — defined loss-of-function mouse model with quantitative peptide measurements; single lab","pmids":["9700764"],"is_preprint":false},{"year":2008,"finding":"Quantitative peptidomics in six brain regions of Cpe(fat/fat) mice reveals that CPE contributes to production of the majority of neuropeptides; most secretory pathway peptides are greatly reduced in CPE-null mice, while processing intermediates with C-terminal Lys/Arg are elevated. Some peptides are only partially reduced, indicating that carboxypeptidase D can partially compensate.","method":"Tandem mass spectrometry peptidomics with quantitative comparison of Cpe(fat/fat) vs. wild-type mouse brain regions (amygdala, hippocampus, hypothalamus, prefrontal cortex, striatum, thalamus)","journal":"Journal of neurochemistry","confidence":"High","confidence_rationale":"Tier 1 — quantitative mass spectrometry across six brain regions with defined loss-of-function model; replicated findings across multiple peptidomics studies","pmids":["19014391"],"is_preprint":false},{"year":2023,"finding":"Top-down proteomics of beta-cell-specific Cpe knockout mouse islets demonstrates that CPE processes proinsulin by removing C-terminal basic residues and identifies novel proteoforms as CPE substrates; some known substrates remain at near-normal levels, showing that carboxypeptidase D (CPD) can compensate for CPE loss in the pancreatic islet.","method":"Top-down proteomics of pancreatic islets from beta-cell-specific Cpe conditional knockout mice; quantitative proteoform analysis","journal":"Endocrinology","confidence":"High","confidence_rationale":"Tier 1 — top-down proteomics in conditional KO with comprehensive proteoform quantitation; rigorous characterization of CPE substrates","pmids":["37967211"],"is_preprint":false},{"year":2015,"finding":"A homozygous truncating mutation in human CPE (c.76_98del; p.E26RfsX68) causing loss of CPE expression (nonsense-mediated decay) results in morbid obesity, intellectual disability, type 2 diabetes, and hypogonadotrophic hypogonadism in a human patient, recapitulating the Cpe(fat/fat) and Cpe knockout mouse phenotypes and confirming CPE's role as a peptide/hormone-processing enzyme essential for body weight, metabolism, and reproductive/brain function in humans.","method":"Exome sequencing; RNA expression analysis from whole blood; phenotypic characterization","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — human loss-of-function genetic variant with molecular validation (NMD confirmed); single case but strong mechanistic parallel to mouse models","pmids":["26120850"],"is_preprint":false},{"year":2022,"finding":"CPE protein and mRNA are present within exosomes secreted from cancer cells; exosomal CPE from high-metastatic HCC cells promotes proliferation and invasion of low-metastatic HCC cells. CPE-shRNA-loaded exosomes suppress CPE expression in high-metastatic HCC cells and reduce proliferation via suppression of Cyclin D1 and c-MYC.","method":"Exosome isolation from cancer cell supernatants and patient sera; Western blot and PCR for CPE; cell proliferation (MTT, colony formation) and invasion (Matrigel) assays; shRNA knockdown via exosome delivery","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2–3 — gain- and loss-of-function with defined proliferation and invasion phenotypes; single lab","pmids":["35328535"],"is_preprint":false},{"year":2014,"finding":"Central inhibition of Sirt1 in diet-induced obese rats increases CPE expression in the hypothalamus via an acetylated/phosphorylated FoxO1-mediated increase in POMC, leading to greater production of alpha-MSH, elevated TRH and thyroid hormone (T3), and increased energy expenditure, placing CPE as a downstream effector of the Sirt1-FoxO1-POMC axis.","method":"Intracerebroventricular Sirt1 inhibitor injection in DIO rats; Western blot and immunoassay for CPE, alpha-MSH, FoxO1 modifications, and thyroid hormones","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo pharmacological intervention with molecular pathway readout; replicated in two publications (PMIDs 25549049 and 24773342)","pmids":["25549049","24773342"],"is_preprint":false}],"current_model":"Carboxypeptidase E (CPE) is a multifunctional enzyme that acts primarily as a regulated secretory pathway sorting receptor at the trans-Golgi network—binding prohormones to direct them into secretory granules—and as a carboxypeptidase B-like exopeptidase that removes C-terminal basic residues from prohormone processing intermediates to generate mature bioactive neuropeptides and peptide hormones (e.g., POMC-derived alpha-MSH, enkephalins, substance P, insulin); it additionally functions as a secreted signaling protein that activates mTORC1/RPS6 to suppress glioma cell migration, inhibits Wnt3a secretion and activity through N-terminal-mediated aggregation, and serves downstream of the FoxO1-POMC axis in hypothalamic energy balance regulation."},"narrative":{"teleology":[{"year":1990,"claim":"Establishing where CPE acts: immunocytochemistry revealed CPE protein concentrated in hypothalamic nuclei, pituitary, hippocampus, and amygdala—matching neuropeptide-rich regions and implying CPE functions in neuropeptide-producing neurons.","evidence":"Immunocytochemistry with specific antisera on rat CNS sections","pmids":["2332799"],"confidence":"Medium","gaps":["Single method (immunocytochemistry) without functional readout","Subcellular compartment identity not resolved at EM level in this study"]},{"year":1997,"claim":"CPE was shown to have a dual function—both enzymatic and non-enzymatic—when it was identified as a trans-Golgi network sorting receptor that binds prohormones and directs them into regulated secretory granules; in Cpe(fat) mutant mice, POMC was missorted to the constitutive pathway. Simultaneously, the Ser202Pro mutation was shown to render CPE catalytically inactive and unstable, causing proinsulin processing defects in beta-cells without abolishing regulated secretion per se.","evidence":"Biochemical fractionation and binding assays on pituitary Golgi membranes; Cpe(fat) mouse model; beta-cell lines with EM, Western blot, pulse-chase secretion assays","pmids":["9019408","9348219"],"confidence":"High","gaps":["Structural basis for prohormone recognition by CPE not determined","Whether sorting and enzymatic functions are separable at the domain level remained unclear"]},{"year":1998,"claim":"CPE's enzymatic role was extended to specific neuropeptides when Cpe(fat) mice were shown to have fivefold reduced amidated substance P across all brain regions, confirming CPE as the rate-limiting C-terminal exopeptidase in protachykinin processing.","evidence":"Radioimmunoassay for amidated and total SP forms in Cpe(fat/fat) vs. control mouse brain","pmids":["9700764"],"confidence":"Medium","gaps":["Whether other carboxypeptidases partially compensate for SP processing was not assessed"]},{"year":2001,"claim":"The scope of CPE's enzymatic activity was revealed to be genome-wide: mass spectrometry of Cpe(fat) mouse brains identified >100 secretory peptides drastically reduced, with accumulation of C-terminal basic-residue intermediates, establishing CPE as the principal neuropeptide-maturing carboxypeptidase. Loss of CPE also secondarily decreased prohormone convertases PC1 and PC2.","evidence":"Anhydrotrypsin affinity chromatography, mass spectrometry, and RIA in Cpe(fat/fat) brain; Western blot for PC1/PC2","pmids":["11481435","11038363"],"confidence":"High","gaps":["Degree of compensation by carboxypeptidase D not yet quantified","Mechanism of secondary PC1/PC2 decrease unknown"]},{"year":2003,"claim":"Pulse-chase studies showed that even mutant CPE traffics to secretory granules and is secreted in a regulated manner upon GLP-1 stimulation, supporting the model that CPE serves as a sorting/retention receptor independent of its catalytic activity.","evidence":"Pulse-chase, double-label immunofluorescence, and GLP-1-stimulated secretion assays in NIT3 beta-cells","pmids":["12488357"],"confidence":"Medium","gaps":["Only examined in mutant CPE context; sorting contribution of wild-type CPE not directly measured by pulse-chase"]},{"year":2008,"claim":"Quantitative peptidomics across six brain regions confirmed CPE as the dominant neuropeptide-maturing carboxypeptidase but also demonstrated that carboxypeptidase D partially compensates for CPE loss for a subset of peptides.","evidence":"Tandem mass spectrometry peptidomics comparing Cpe(fat/fat) vs. wild-type across amygdala, hippocampus, hypothalamus, prefrontal cortex, striatum, thalamus","pmids":["19014391"],"confidence":"High","gaps":["Quantitative contribution of CPD vs. CPE not determined on a per-substrate basis","Peripheral peptidome not assessed"]},{"year":2009,"claim":"CPE was placed in the hypothalamic energy-balance circuit when FoxO1 ablation in POMC neurons was shown to upregulate CPE, increasing alpha-MSH production and reducing food intake; viral overexpression of CPE in the arcuate nucleus phenocopied this effect.","evidence":"Conditional Pomc-Foxo1 KO mice; AAV-CPE overexpression in arcuate nucleus; neuropeptide measurements and food intake/body weight phenotyping","pmids":["19767734"],"confidence":"High","gaps":["Direct transcriptional mechanism linking FoxO1 to CPE promoter not shown","Whether CPE's sorting or enzymatic function is more important for energy balance not distinguished"]},{"year":2014,"claim":"The FoxO1-CPE axis was further elaborated: Sirt1 inhibition in hypothalamus increased CPE expression via acetylated/phosphorylated FoxO1, boosting alpha-MSH, TRH, and T3, thereby increasing energy expenditure.","evidence":"Intracerebroventricular Sirt1 inhibitor in diet-induced obese rats; Western blot and immunoassay","pmids":["25549049","24773342"],"confidence":"Medium","gaps":["Pharmacological approach; genetic confirmation of Sirt1-CPE link not performed","Direct binding of FoxO1 to CPE regulatory elements not demonstrated"]},{"year":2015,"claim":"A homozygous truncating CPE mutation in a human patient confirmed CPE's essential role in humans, causing morbid obesity, type 2 diabetes, intellectual disability, and hypogonadotrophic hypogonadism—recapitulating the mouse phenotype.","evidence":"Exome sequencing; RNA analysis confirming nonsense-mediated decay; clinical phenotyping","pmids":["26120850"],"confidence":"Medium","gaps":["Single case report; additional human families needed for full penetrance assessment","Specific peptide processing defects not measured in patient tissues"]},{"year":2016,"claim":"A non-enzymatic extracellular function of CPE was revealed: CPE inhibits Wnt3a secretion and activity by forming aggregates with Wnt3a through its N-terminal domain, independent of carboxypeptidase activity.","evidence":"Co-secretion experiments, co-immunoprecipitation/aggregation assays, Wnt reporter assays, N-terminal deletion and Wnt3a mutagenesis","pmids":["27375026"],"confidence":"Medium","gaps":["Physiological context for CPE-Wnt3a interaction unclear","Single lab; in vivo relevance not tested","Structural basis of N-terminal aggregation unknown"]},{"year":2017,"claim":"Secreted CPE was found to activate mTORC1/RPS6 signaling and suppress Rac1-dependent glioma cell migration, revealing a signaling function for sCPE distinct from its carboxypeptidase activity.","evidence":"Recombinant sCPE treatment and shRNA knockdown in glioma cell lines; phospho-protein blots; mTOR inhibitor rescue; metabolic flux assays","pmids":["28978054"],"confidence":"Medium","gaps":["Receptor for sCPE on glioma cells not identified","In vivo anti-tumor effect not demonstrated","Whether enzymatic activity contributes to signaling function not fully excluded"]},{"year":2023,"claim":"Top-down proteomics of beta-cell-specific Cpe knockout islets confirmed CPE as the principal proinsulin carboxypeptidase and identified novel proteoform substrates, while showing CPD can compensate for some substrates in the islet.","evidence":"Top-down proteomics of pancreatic islets from beta-cell-specific Cpe conditional KO mice","pmids":["37967211"],"confidence":"High","gaps":["Full substrate specificity rules (CPE vs. CPD preference) not derived","Processing kinetics not measured"]},{"year":null,"claim":"The receptor or binding partner that transduces the signaling functions of secreted CPE (activation of mTORC1, inhibition of Wnt) has not been identified, and the structural basis for CPE's dual enzymatic/sorting-receptor activities remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No crystal structure of full-length CPE","Cell-surface receptor for secreted CPE unknown","Relative in vivo contributions of enzymatic vs. sorting vs. signaling functions not dissected with separation-of-function mutants"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,4,9,10,11]},{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[0,5]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[7,8]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[0]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[0,4,5]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[7,8,13]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,2,4,9,10,11]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,5]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,8]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[1,2,6]}],"complexes":[],"partners":["POMC","WNT3A","PCSK1","PCSK2","CPD","FOXO1"],"other_free_text":[]},"mechanistic_narrative":"Carboxypeptidase E (CPE) is a carboxypeptidase B-like exopeptidase and regulated secretory pathway sorting receptor essential for the biosynthesis of the majority of neuropeptides and peptide hormones. As an exopeptidase, CPE removes C-terminal basic residues (Lys/Arg) from prohormone processing intermediates to generate mature bioactive peptides including alpha-MSH, beta-endorphin, enkephalins, substance P, and insulin; loss of CPE activity causes accumulation of unprocessed intermediates across the brain and pancreatic islets, with carboxypeptidase D providing only partial compensation [PMID:11481435, PMID:19014391, PMID:37967211, PMID:9700764]. As a membrane-associated sorting receptor at the trans-Golgi network, CPE binds prohormones such as POMC and directs them into regulated secretory granules; in Cpe-null mice POMC is missorted to the constitutive pathway [PMID:9019408, PMID:12488357]. CPE also functions as a secreted signaling molecule that activates mTORC1/RPS6 to suppress glioma cell migration [PMID:28978054] and inhibits Wnt3a secretion and activity through N-terminal-mediated aggregation [PMID:27375026]; in the hypothalamus, CPE acts downstream of the FoxO1-POMC axis to promote alpha-MSH production and regulate energy balance [PMID:19767734, PMID:25549049]. Homozygous loss-of-function mutation in human CPE causes morbid obesity, type 2 diabetes, intellectual disability, and hypogonadotrophic hypogonadism [PMID:26120850]."},"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":385,"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":320,"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":139,"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":133,"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":"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":"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 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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":"27151665","id":"PMC_27151665","title":"SiO2 nanoparticles modified CPE as a biosensor for determination of i-motif DNA/Tamoxifen interaction.","date":"2016","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/27151665","citation_count":5,"is_preprint":false},{"pmid":"34029697","id":"PMC_34029697","title":"In silico analysis of non-synonymous missense SNPs (nsSNPs) in CPE, GNAS genes and experimental validation in type II diabetes mellitus through Next Generation Sequencing.","date":"2021","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/34029697","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":48938,"output_tokens":4070,"usd":0.103932},"stage2":{"model":"claude-opus-4-6","input_tokens":7488,"output_tokens":3334,"usd":0.181185},"total_usd":0.285117,"stage1_batch_id":"msgbatch_011kfMfE81o6CTcyhVUqumuW","stage2_batch_id":"msgbatch_01DTputS6WNkH745x1nVSoBo","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, binding prohormones (including pro-opiomelanocortin) to direct them into secretory granules. In Cpe(fat) mutant mice lacking CPE, POMC is missorted to the constitutive secretory pathway and secreted in an unregulated manner.\",\n      \"method\": \"Biochemical fractionation of pituitary Golgi-enriched and secretory granule membranes, binding assays with prohormones, and genetic loss-of-function (Cpe(fat) mice) with secretory pathway readout\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (binding assay, fractionation, genetic KO with defined secretory phenotype); foundational paper with 385 citations\",\n      \"pmids\": [\"9019408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"CPE (carboxypeptidase E/enkephalin convertase) is localized by immunocytochemistry to neuronal cell bodies and terminals throughout the rat CNS, with highest concentrations in the hypothalamus (median eminence, supraoptic, paraventricular, suprachiasmatic nuclei), posterior pituitary, intermediate pituitary melanotropes, hippocampal pyramidal cells, and amygdala—distribution matching that of neuropeptides.\",\n      \"method\": \"Immunocytochemistry with specific polyclonal antisera against purified CPE in rat CNS sections\",\n      \"journal\": \"The Journal of Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiment; single lab, single method but spatially detailed\",\n      \"pmids\": [\"2332799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Carboxypeptidase E is required for the biosynthesis of the majority of neuropeptides in mouse brain and pituitary; Cpe(fat/fat) mice lacking CPE activity accumulate peptide processing intermediates with C-terminal basic residues, and levels of over 100 secretory pathway peptides (from proenkephalin, POMC, protachykinins, chromogranins, secretogranin II) are drastically reduced.\",\n      \"method\": \"Anhydrotrypsin affinity chromatography to isolate C-terminal basic residue-containing intermediates from Cpe(fat/fat) mouse brain; mass spectrometry identification; RIA validation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (affinity purification, MS, RIA) in Cpe loss-of-function model; replicated across subsequent peptidomics studies\",\n      \"pmids\": [\"11481435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Loss of CPE activity in Cpe(fat) mice leads to secondary decreases in prohormone convertase PC1 and PC2 levels in brain regions and pituitary, resulting in altered processing of neuropeptides including dynorphin A-17, beta-endorphin, and alpha-MSH that are involved in feeding behavior and body weight regulation.\",\n      \"method\": \"Western blot and immunoassay for PC1, PC2, and neuropeptides in Cpe(fat) vs. wild-type mouse brain regions\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean loss-of-function model with defined molecular phenotype; single lab, two methods\",\n      \"pmids\": [\"11038363\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The Cpe(fat) point mutation (Ser202Pro) in the CPE coding region results in production of pro-CPE that is catalytically inactive and unstable; in beta-cell lines from Cpe(fat/fat) mice (NIT-2, NIT-3), pro-CPE accumulates in an ER-like compartment and proinsulin processing is defective. Granule morphology is altered (enlarged, electron-lucent). CPE activity is not required for sorting proinsulin into the regulated secretory pathway, as secretion remains stimulable.\",\n      \"method\": \"Beta-cell lines from Cpe(fat/fat) mice; Western blot for pro-CPE and mature CPE; electron microscopy; immunocytochemistry; pulse-chase secretion assays with secretagogues\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (EM, ICC, Western blot, secretion assay) in defined mutant cell lines\",\n      \"pmids\": [\"9348219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Mutant CPE (from Cpe(fat/fat) mice) has a half-life of ~3 h in NIT3 beta-cells; up to 45% escapes proteasomal degradation and traffics to prohormone convertase 2-containing secretory granules, where it is secreted in a regulated manner upon glucagon-like peptide-1 stimulation, supporting a role for CPE as a sorting/retention receptor in granule trafficking.\",\n      \"method\": \"Pulse-chase experiments in NIT3 cells; double-label immunofluorescence microscopy; secretion assay with GLP-1 stimulation\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pulse-chase, co-localization, secretion assay; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"12488357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"FoxO1 ablation in POMC neurons increases CPE expression in the hypothalamus, leading to selective increases of alpha-MSH and carboxy-cleaved beta-endorphin (CPE-dependent POMC processing products), resulting in decreased food intake. Moderate CPE overexpression in the arcuate nucleus phenocopies FoxO1 deletion effects on food intake, placing CPE downstream of FoxO1 in the hypothalamic energy-balance circuit.\",\n      \"method\": \"Conditional Pomc-Foxo1 knockout mice; CPE overexpression in arcuate nucleus via viral vector; measurement of alpha-MSH and beta-endorphin forms; food intake and body weight measurements\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis (conditional KO + gain-of-function) with defined neuropeptide and behavioral phenotypes; replicated across multiple experiments\",\n      \"pmids\": [\"19767734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CPE inhibits the secretion and activity of Wnt3a ligand. CPE and Wnt3a are co-secreted from cells; CPE forms aggregates with Wnt3a through its N-terminal sequence, inducing possible ER stress and causing loss of Wnt3a function, thereby negatively regulating the canonical Wnt signaling pathway. The C-terminal Lys residue of Wnt3a is critical for its activity, but CPE does not act by removing this residue.\",\n      \"method\": \"Co-secretion experiments, co-immunoprecipitation/aggregation assays, Wnt pathway reporter assays, CPE N-terminal deletion and Wnt3a C-terminal mutagenesis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — multiple mechanistic methods (co-secretion, aggregation, mutagenesis, reporter assay); 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 phosphorylation of RPS6) and reduces glioma cell migration via negative regulation of Rac1 signaling downstream of RPS6. CPE knockdown decreases active RPS6 and increases GBM cell motility. sCPE also shifts glucose metabolism away from aerobic glycolysis toward the TCA cycle.\",\n      \"method\": \"Recombinant sCPE treatment of glioma cell lines; CPE shRNA knockdown; phospho-protein Western blot (RPS6, Rac1); mTOR inhibitor experiments; glucose flux metabolic assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — gain- and loss-of-function with pathway inhibitor confirmation; single lab\",\n      \"pmids\": [\"28978054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"CPE is required for normal proteolytic processing of protachykinin to mature amidated substance P (SP) in the brain. Cpe(fat/fat) mice have more than fivefold lower levels of fully processed amidated SP in all brain regions tested compared to controls, while total SP species are unchanged, consistent with CPE acting as the final C-terminal basic residue-removing exopeptidase in SP biosynthesis.\",\n      \"method\": \"Radioimmunoassay for amidated SP and 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 — defined loss-of-function mouse model with quantitative peptide measurements; single lab\",\n      \"pmids\": [\"9700764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Quantitative peptidomics in six brain regions of Cpe(fat/fat) mice reveals that CPE contributes to production of the majority of neuropeptides; most secretory pathway peptides are greatly reduced in CPE-null mice, while processing intermediates with C-terminal Lys/Arg are elevated. Some peptides are only partially reduced, indicating that carboxypeptidase D can partially compensate.\",\n      \"method\": \"Tandem mass spectrometry peptidomics with quantitative comparison of Cpe(fat/fat) vs. wild-type mouse brain regions (amygdala, hippocampus, hypothalamus, prefrontal cortex, striatum, thalamus)\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — quantitative mass spectrometry across six brain regions with defined loss-of-function model; replicated findings across multiple peptidomics studies\",\n      \"pmids\": [\"19014391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Top-down proteomics of beta-cell-specific Cpe knockout mouse islets demonstrates that CPE processes proinsulin by removing C-terminal basic residues and identifies novel proteoforms as CPE substrates; some known substrates remain at near-normal levels, showing that carboxypeptidase D (CPD) can compensate for CPE loss in the pancreatic islet.\",\n      \"method\": \"Top-down proteomics of pancreatic islets from beta-cell-specific Cpe conditional knockout mice; quantitative proteoform analysis\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — top-down proteomics in conditional KO with comprehensive proteoform quantitation; rigorous characterization of CPE substrates\",\n      \"pmids\": [\"37967211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"A homozygous truncating mutation in human CPE (c.76_98del; p.E26RfsX68) causing loss of CPE expression (nonsense-mediated decay) results in morbid obesity, intellectual disability, type 2 diabetes, and hypogonadotrophic hypogonadism in a human patient, recapitulating the Cpe(fat/fat) and Cpe knockout mouse phenotypes and confirming CPE's role as a peptide/hormone-processing enzyme essential for body weight, metabolism, and reproductive/brain function in humans.\",\n      \"method\": \"Exome sequencing; RNA expression analysis from whole blood; phenotypic characterization\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — human loss-of-function genetic variant with molecular validation (NMD confirmed); single case but strong mechanistic parallel to mouse models\",\n      \"pmids\": [\"26120850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CPE protein and mRNA are present within exosomes secreted from cancer cells; exosomal CPE from high-metastatic HCC cells promotes proliferation and invasion of low-metastatic HCC cells. CPE-shRNA-loaded exosomes suppress CPE expression in high-metastatic HCC cells and reduce proliferation via suppression of Cyclin D1 and c-MYC.\",\n      \"method\": \"Exosome isolation from cancer cell supernatants and patient sera; Western blot and PCR for CPE; cell proliferation (MTT, colony formation) and invasion (Matrigel) assays; shRNA knockdown via exosome delivery\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — gain- and loss-of-function with defined proliferation and invasion phenotypes; single lab\",\n      \"pmids\": [\"35328535\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Central inhibition of Sirt1 in diet-induced obese rats increases CPE expression in the hypothalamus via an acetylated/phosphorylated FoxO1-mediated increase in POMC, leading to greater production of alpha-MSH, elevated TRH and thyroid hormone (T3), and increased energy expenditure, placing CPE as a downstream effector of the Sirt1-FoxO1-POMC axis.\",\n      \"method\": \"Intracerebroventricular Sirt1 inhibitor injection in DIO rats; Western blot and immunoassay for CPE, alpha-MSH, FoxO1 modifications, and thyroid hormones\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo pharmacological intervention with molecular pathway readout; replicated in two publications (PMIDs 25549049 and 24773342)\",\n      \"pmids\": [\"25549049\", \"24773342\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Carboxypeptidase E (CPE) is a multifunctional enzyme that acts primarily as a regulated secretory pathway sorting receptor at the trans-Golgi network—binding prohormones to direct them into secretory granules—and as a carboxypeptidase B-like exopeptidase that removes C-terminal basic residues from prohormone processing intermediates to generate mature bioactive neuropeptides and peptide hormones (e.g., POMC-derived alpha-MSH, enkephalins, substance P, insulin); it additionally functions as a secreted signaling protein that activates mTORC1/RPS6 to suppress glioma cell migration, inhibits Wnt3a secretion and activity through N-terminal-mediated aggregation, and serves downstream of the FoxO1-POMC axis in hypothalamic energy balance regulation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"Carboxypeptidase E (CPE) is a carboxypeptidase B-like exopeptidase and regulated secretory pathway sorting receptor essential for the biosynthesis of the majority of neuropeptides and peptide hormones. As an exopeptidase, CPE removes C-terminal basic residues (Lys/Arg) from prohormone processing intermediates to generate mature bioactive peptides including alpha-MSH, beta-endorphin, enkephalins, substance P, and insulin; loss of CPE activity causes accumulation of unprocessed intermediates across the brain and pancreatic islets, with carboxypeptidase D providing only partial compensation [PMID:11481435, PMID:19014391, PMID:37967211, PMID:9700764]. As a membrane-associated sorting receptor at the trans-Golgi network, CPE binds prohormones such as POMC and directs them into regulated secretory granules; in Cpe-null mice POMC is missorted to the constitutive pathway [PMID:9019408, PMID:12488357]. CPE also functions as a secreted signaling molecule that activates mTORC1/RPS6 to suppress glioma cell migration [PMID:28978054] and inhibits Wnt3a secretion and activity through N-terminal-mediated aggregation [PMID:27375026]; in the hypothalamus, CPE acts downstream of the FoxO1-POMC axis to promote alpha-MSH production and regulate energy balance [PMID:19767734, PMID:25549049]. Homozygous loss-of-function mutation in human CPE causes morbid obesity, type 2 diabetes, intellectual disability, and hypogonadotrophic hypogonadism [PMID:26120850].\",\n  \"teleology\": [\n    {\n      \"year\": 1990,\n      \"claim\": \"Establishing where CPE acts: immunocytochemistry revealed CPE protein concentrated in hypothalamic nuclei, pituitary, hippocampus, and amygdala—matching neuropeptide-rich regions and implying CPE functions in neuropeptide-producing neurons.\",\n      \"evidence\": \"Immunocytochemistry with specific antisera on rat CNS sections\",\n      \"pmids\": [\"2332799\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single method (immunocytochemistry) without functional readout\", \"Subcellular compartment identity not resolved at EM level in this study\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"CPE was shown to have a dual function—both enzymatic and non-enzymatic—when it was identified as a trans-Golgi network sorting receptor that binds prohormones and directs them into regulated secretory granules; in Cpe(fat) mutant mice, POMC was missorted to the constitutive pathway. Simultaneously, the Ser202Pro mutation was shown to render CPE catalytically inactive and unstable, causing proinsulin processing defects in beta-cells without abolishing regulated secretion per se.\",\n      \"evidence\": \"Biochemical fractionation and binding assays on pituitary Golgi membranes; Cpe(fat) mouse model; beta-cell lines with EM, Western blot, pulse-chase secretion assays\",\n      \"pmids\": [\"9019408\", \"9348219\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for prohormone recognition by CPE not determined\", \"Whether sorting and enzymatic functions are separable at the domain level remained unclear\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"CPE's enzymatic role was extended to specific neuropeptides when Cpe(fat) mice were shown to have fivefold reduced amidated substance P across all brain regions, confirming CPE as the rate-limiting C-terminal exopeptidase in protachykinin processing.\",\n      \"evidence\": \"Radioimmunoassay for amidated and total SP forms in Cpe(fat/fat) vs. control mouse brain\",\n      \"pmids\": [\"9700764\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether other carboxypeptidases partially compensate for SP processing was not assessed\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"The scope of CPE's enzymatic activity was revealed to be genome-wide: mass spectrometry of Cpe(fat) mouse brains identified >100 secretory peptides drastically reduced, with accumulation of C-terminal basic-residue intermediates, establishing CPE as the principal neuropeptide-maturing carboxypeptidase. Loss of CPE also secondarily decreased prohormone convertases PC1 and PC2.\",\n      \"evidence\": \"Anhydrotrypsin affinity chromatography, mass spectrometry, and RIA in Cpe(fat/fat) brain; Western blot for PC1/PC2\",\n      \"pmids\": [\"11481435\", \"11038363\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Degree of compensation by carboxypeptidase D not yet quantified\", \"Mechanism of secondary PC1/PC2 decrease unknown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Pulse-chase studies showed that even mutant CPE traffics to secretory granules and is secreted in a regulated manner upon GLP-1 stimulation, supporting the model that CPE serves as a sorting/retention receptor independent of its catalytic activity.\",\n      \"evidence\": \"Pulse-chase, double-label immunofluorescence, and GLP-1-stimulated secretion assays in NIT3 beta-cells\",\n      \"pmids\": [\"12488357\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Only examined in mutant CPE context; sorting contribution of wild-type CPE not directly measured by pulse-chase\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Quantitative peptidomics across six brain regions confirmed CPE as the dominant neuropeptide-maturing carboxypeptidase but also demonstrated that carboxypeptidase D partially compensates for CPE loss for a subset of peptides.\",\n      \"evidence\": \"Tandem mass spectrometry peptidomics comparing Cpe(fat/fat) vs. wild-type across amygdala, hippocampus, hypothalamus, prefrontal cortex, striatum, thalamus\",\n      \"pmids\": [\"19014391\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative contribution of CPD vs. CPE not determined on a per-substrate basis\", \"Peripheral peptidome not assessed\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"CPE was placed in the hypothalamic energy-balance circuit when FoxO1 ablation in POMC neurons was shown to upregulate CPE, increasing alpha-MSH production and reducing food intake; viral overexpression of CPE in the arcuate nucleus phenocopied this effect.\",\n      \"evidence\": \"Conditional Pomc-Foxo1 KO mice; AAV-CPE overexpression in arcuate nucleus; neuropeptide measurements and food intake/body weight phenotyping\",\n      \"pmids\": [\"19767734\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional mechanism linking FoxO1 to CPE promoter not shown\", \"Whether CPE's sorting or enzymatic function is more important for energy balance not distinguished\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"The FoxO1-CPE axis was further elaborated: Sirt1 inhibition in hypothalamus increased CPE expression via acetylated/phosphorylated FoxO1, boosting alpha-MSH, TRH, and T3, thereby increasing energy expenditure.\",\n      \"evidence\": \"Intracerebroventricular Sirt1 inhibitor in diet-induced obese rats; Western blot and immunoassay\",\n      \"pmids\": [\"25549049\", \"24773342\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Pharmacological approach; genetic confirmation of Sirt1-CPE link not performed\", \"Direct binding of FoxO1 to CPE regulatory elements not demonstrated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"A homozygous truncating CPE mutation in a human patient confirmed CPE's essential role in humans, causing morbid obesity, type 2 diabetes, intellectual disability, and hypogonadotrophic hypogonadism—recapitulating the mouse phenotype.\",\n      \"evidence\": \"Exome sequencing; RNA analysis confirming nonsense-mediated decay; clinical phenotyping\",\n      \"pmids\": [\"26120850\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single case report; additional human families needed for full penetrance assessment\", \"Specific peptide processing defects not measured in patient tissues\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"A non-enzymatic extracellular function of CPE was revealed: CPE inhibits Wnt3a secretion and activity by forming aggregates with Wnt3a through its N-terminal domain, independent of carboxypeptidase activity.\",\n      \"evidence\": \"Co-secretion experiments, co-immunoprecipitation/aggregation assays, Wnt reporter assays, N-terminal deletion and Wnt3a mutagenesis\",\n      \"pmids\": [\"27375026\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological context for CPE-Wnt3a interaction unclear\", \"Single lab; in vivo relevance not tested\", \"Structural basis of N-terminal aggregation unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Secreted CPE was found to activate mTORC1/RPS6 signaling and suppress Rac1-dependent glioma cell migration, revealing a signaling function for sCPE distinct from its carboxypeptidase activity.\",\n      \"evidence\": \"Recombinant sCPE treatment and shRNA knockdown in glioma cell lines; phospho-protein blots; mTOR inhibitor rescue; metabolic flux assays\",\n      \"pmids\": [\"28978054\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor for sCPE on glioma cells not identified\", \"In vivo anti-tumor effect not demonstrated\", \"Whether enzymatic activity contributes to signaling function not fully excluded\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Top-down proteomics of beta-cell-specific Cpe knockout islets confirmed CPE as the principal proinsulin carboxypeptidase and identified novel proteoform substrates, while showing CPD can compensate for some substrates in the islet.\",\n      \"evidence\": \"Top-down proteomics of pancreatic islets from beta-cell-specific Cpe conditional KO mice\",\n      \"pmids\": [\"37967211\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full substrate specificity rules (CPE vs. CPD preference) not derived\", \"Processing kinetics not measured\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The receptor or binding partner that transduces the signaling functions of secreted CPE (activation of mTORC1, inhibition of Wnt) has not been identified, and the structural basis for CPE's dual enzymatic/sorting-receptor activities remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal structure of full-length CPE\", \"Cell-surface receptor for secreted CPE unknown\", \"Relative in vivo contributions of enzymatic vs. sorting vs. signaling functions not dissected with separation-of-function mutants\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 4, 9, 10, 11]},\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [7, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [0, 4, 5]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [7, 8, 13]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 2, 4, 9, 10, 11]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 8]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [1, 2, 6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"POMC\",\n      \"WNT3A\",\n      \"PCSK1\",\n      \"PCSK2\",\n      \"CPD\",\n      \"FOXO1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}