{"gene":"VPS37A","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2004,"finding":"HCRP1/hVps37A is a subunit of mammalian ESCRT-I, interacting with Tsg101 (via its mod(r) domain), hVps28, and their upstream regulator Hrs. It cofractionates with Tsg101 and hVps28 by size exclusion chromatography and colocalizes with hVps28 on LAMP1-positive endosomes. siRNA depletion of HCRP1 strongly retards EGF receptor degradation, while depletion of Tsg101 reduces cellular levels of hVps28 and HCRP1 (but not vice versa).","method":"Co-immunoprecipitation, size exclusion chromatography, colocalization by immunofluorescence, siRNA knockdown with EGFR degradation assay","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, biochemical fractionation, colocalization, and functional siRNA knockdown with defined receptor-sorting phenotype; foundational paper independently replicated by subsequent studies","pmids":["15240819"],"is_preprint":false},{"year":2004,"finding":"The mod(r) domain of hVps37A (HCRP1) is required for its interaction with Tsg101 and is shared with paralogs hVps37B and hVps37C.","method":"Co-immunoprecipitation with domain-mapping constructs","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mapping by Co-IP in single lab with clear functional context","pmids":["15240819"],"is_preprint":false},{"year":2019,"finding":"VPS37A is a critical component for phagophore closure (autophagosome completion). It localizes to the phagophore via its N-terminal ubiquitin E2 variant (UEV)-like domain, which is required for autophagosome completion but dispensable for ESCRT-I complex formation and EGFR degradation in the MVB pathway. Loss of VPS37A abrogates phagophore recruitment of the ESCRT-I subunit VPS28 and the ESCRT-III subunit CHMP2A. Inhibition of membrane closure (by CHMP2A depletion or VPS4 inhibition) causes VPS37A accumulation on the phagophore.","method":"Genome-wide CRISPR screen (FACS-based HaloTag-LC3 autophagosome completion assay), live-cell imaging/localization, domain-deletion mutants, siRNA knockdown with defined phagophore-closure phenotype","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide unbiased CRISPR screen followed by mechanistic validation with domain mutants, localization studies, and epistasis experiments in single rigorous study","pmids":["31519728"],"is_preprint":false},{"year":2019,"finding":"The N-terminal UEV-like domain of VPS37A is dispensable for ESCRT-I complex formation and for EGFR degradation in the MVB pathway, but is specifically required for phagophore closure, establishing a functional separation between VPS37A's roles in endosomal sorting and autophagosome closure.","method":"Domain-deletion mutants complementing VPS37A-KO cells, EGFR degradation assay, autophagosome completion assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — domain mutagenesis with two distinct functional readouts in same study","pmids":["31519728"],"is_preprint":false},{"year":2022,"finding":"Vps37a controls glucagon receptor (Gcgr) localization by preventing its accumulation in endosomes. Hepatocyte-specific knockdown of Vps37a causes endosomal accumulation of Gcgr, resulting in overactivation of the cAMP/PKA/p-CREB signaling pathway and increased gluconeogenesis, without affecting β-oxidation. Shifting the receptor back to the plasma membrane rescues differential signaling, indicating that Vps37a uncouples glucose production from lipid usage downstream of Gcgr by controlling receptor spatiotemporal localization.","method":"Hepatocyte-specific siRNA knockdown in vivo, Cy5-glucagon agonist trafficking assay, cAMP/PKA/p-CREB signaling readouts, plasma-membrane targeting rescue experiment","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo hepatocyte-specific KD with receptor-localization tracking, signaling pathway readouts, and mechanistic rescue; single lab but multiple orthogonal methods","pmids":["36243006"],"is_preprint":false},{"year":2024,"finding":"The UEV-like (UEVL) β-strand region (residues 43–139) of VPS37A is required for autophagosome closure in vivo. Mice homozygous for a VPS37A UEVL mutation (Δ43-139) show impaired bulk autophagic flux, p62/SQSTM1 and ubiquitinated protein accumulation, neuronal dysfunction, growth retardation, antioxidant gene upregulation, and tissue abnormalities, without disruption of ESCRT-I complex assembly or endosomal function. The UEVL mutation causes accumulation of active TBK1 on phagophores, leading to increased p62 phosphorylation and inclusion formation.","method":"Knock-in mouse model with UEVL domain deletion, autophagic flux assays, LC3 proximity proteomics, p62/ubiquitin immunostaining, histopathology","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vivo domain-deletion knock-in mouse model with multiple orthogonal functional readouts and proximity proteomics; confirms domain-function separation established in PMID:31519728","pmids":["39607828"],"is_preprint":false},{"year":2012,"finding":"A homozygous missense mutation (p.K382N) in VPS37A causes autosomal recessive complex hereditary spastic paraparesis in humans. Knockdown of Vps37a in zebrafish by morpholino oligonucleotides significantly reduces mobility, supporting a causal role for VPS37A loss-of-function in upper motor neuron disease.","method":"Whole genome linkage analysis, candidate gene sequencing, zebrafish morpholino knockdown with locomotion phenotype","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human genetics combined with zebrafish in vivo knockdown demonstrating locomotor phenotype; mechanistic detail limited to ESCRT pathway membership","pmids":["22717650"],"is_preprint":false},{"year":2017,"finding":"Knockdown of HCRP1 in HCC cells induces epithelial-mesenchymal transition (EMT) through the TGF-β signaling pathway, with decreased E-cadherin and β-catenin and increased N-cadherin and vimentin.","method":"siRNA knockdown, western blot for EMT markers, migration/invasion assays, TGF-β pathway analysis","journal":"International journal of oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single knockdown approach, no direct mechanistic interaction demonstrated between HCRP1 and TGF-β pathway components","pmids":["28350062"],"is_preprint":false},{"year":2020,"finding":"HCRP-1 depletion in prostate cancer cells induces Src and FAK phosphorylation, promoting cell migration, invasion, and angiogenesis; these effects can be reversed by Src inhibitor PP2 or FAK inhibitor. Co-immunoprecipitation was used to assess interactions.","method":"Co-immunoprecipitation, siRNA knockdown, western blot for pSrc/pFAK, transwell and tube formation assays, xenograft model","journal":"International journal of biological sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab; the source paper (PMID:31929761) was subsequently retracted (PMID:34803514); findings must be treated as unreliable","pmids":["31929761","34803514"],"is_preprint":false},{"year":2025,"finding":"VPS37A overexpression in colorectal cancer cells redirects TNFR1 to lysosomal degradation via the autophagy-lysosomal pathway, thereby suppressing NF-κB nuclear translocation and transcriptional activity under metabolic stress, and triggering cell death via apoptosis, necroptosis, and ferroptosis.","method":"VPS37A overexpression constructs, NF-κB luciferase reporter assay, lysosomal inhibition experiments, RNA sequencing, xenograft model","journal":"Oncology research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assays and lysosomal inhibition rescue provide mechanistic support; single lab but multiple orthogonal methods","pmids":["40746890"],"is_preprint":false},{"year":2024,"finding":"In MLKL-knockout colorectal cancer cells, autophagy becomes critically dependent on VPS37A. Activation of p38 MAPK by homoharringtonine prevents VPS37A from supporting autophagy in MLKL-deficient cells, triggering parthanatos cell death.","method":"MLKL gene knockout, VPS37A knockdown in MLKL-KO background, p38 MAPK inhibition/activation, autophagic flux assays, in vivo tumorigenicity assay","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single lab, mechanistic link between p38MAPK and VPS37A autophagy function is indirect/inferred","pmids":[],"is_preprint":true}],"current_model":"VPS37A (HCRP1) is a subunit of the mammalian ESCRT-I complex that interacts with Tsg101 via its mod(r) domain and with hVps28; it is required for lysosomal sorting and degradation of ubiquitinated membrane receptors such as EGFR at endosomes, controls glucagon receptor localization at endosomes to regulate hepatic gluconeogenesis, and—through a separable N-terminal UEV-like domain—recruits ESCRT-III (CHMP2A) and VPS4 machinery to phagophores for autophagosome closure, a function whose impairment causes neuronal dysfunction and motor disease in vivo."},"narrative":{"mechanistic_narrative":"VPS37A (HCRP1) is a subunit of the mammalian ESCRT-I complex that functions in membrane-remodeling reactions underlying both endosomal cargo sorting and autophagosome biogenesis [PMID:15240819, PMID:31519728]. Within ESCRT-I it interacts with Tsg101 through its mod(r) domain and with hVps28, cofractionating and colocalizing with these partners on LAMP1-positive endosomes; in this context it is required for lysosomal sorting and degradation of ubiquitinated membrane receptors such as the EGF receptor [PMID:15240819]. A genetically and structurally separable N-terminal ubiquitin-E2-variant-like (UEVL) domain mediates a distinct function in autophagy: it recruits VPS37A to the phagophore and is required to bring the ESCRT-I subunit VPS28 and the ESCRT-III subunit CHMP2A to the closing autophagosome, while being dispensable for ESCRT-I assembly and EGFR degradation [PMID:31519728]. This autophagosome-closure activity is physiologically essential in vivo: mice carrying a UEVL-domain deletion show impaired autophagic flux, p62/SQSTM1 and ubiquitin accumulation, aberrant accumulation of active TBK1 on phagophores, and neuronal dysfunction [PMID:39607828]. By controlling receptor trafficking, VPS37A also governs glucagon receptor localization in hepatocytes, restraining endosomal cAMP/PKA/p-CREB signaling and gluconeogenesis [PMID:36243006]. A homozygous VPS37A missense mutation causes autosomal recessive complex hereditary spastic paraparesis, with zebrafish knockdown reproducing the locomotor defect [PMID:22717650].","teleology":[{"year":2004,"claim":"Established that VPS37A is a bona fide subunit of human ESCRT-I and connects the complex to endosomal receptor degradation, defining its core molecular identity.","evidence":"Reciprocal Co-IP, size exclusion chromatography, colocalization, and siRNA knockdown with EGFR degradation assay","pmids":["15240819"],"confidence":"High","gaps":["Did not resolve the structural basis of complex assembly","Did not address roles outside the MVB/endosomal pathway"]},{"year":2004,"claim":"Mapped the Tsg101-binding determinant to the mod(r) domain, defining the interface that anchors VPS37A within ESCRT-I.","evidence":"Co-IP with domain-mapping constructs","pmids":["15240819"],"confidence":"Medium","gaps":["No structural model of the mod(r)–Tsg101 interface","Functional consequence of disrupting only this interface not isolated"]},{"year":2012,"claim":"Linked VPS37A loss-of-function to human upper motor neuron disease, establishing physiological importance beyond cell culture.","evidence":"Whole-genome linkage, candidate gene sequencing, and zebrafish morpholino knockdown with locomotion phenotype","pmids":["22717650"],"confidence":"Medium","gaps":["Mechanism connecting VPS37A loss to neuronal degeneration not defined at the time","Effect of the K382N mutation on specific VPS37A functions untested"]},{"year":2019,"claim":"Discovered a second, separable function: VPS37A is required for phagophore closure and uses its N-terminal UEVL domain to recruit downstream ESCRT machinery to the autophagosome, distinguishing autophagy from endosomal roles.","evidence":"Genome-wide CRISPR screen, live-cell imaging, domain-deletion complementation, and epistasis with CHMP2A/VPS4","pmids":["31519728"],"confidence":"High","gaps":["Molecular signal recruiting VPS37A to the phagophore not identified","How the UEVL domain engages VPS28/CHMP2A structurally is unknown"]},{"year":2022,"claim":"Showed that VPS37A-controlled receptor trafficking has organ-level metabolic consequences by restraining endosomal glucagon receptor signaling.","evidence":"Hepatocyte-specific in vivo knockdown, agonist trafficking assay, cAMP/PKA/p-CREB readouts, and plasma-membrane rescue","pmids":["36243006"],"confidence":"High","gaps":["Whether Gcgr regulation requires ESCRT-I assembly or autophagy not dissected","Direct interaction between VPS37A and Gcgr not demonstrated"]},{"year":2024,"claim":"Demonstrated in vivo that the UEVL domain is specifically required for autophagosome closure and that its loss drives TBK1/p62 pathology and neuronal dysfunction, confirming the domain-function separation.","evidence":"UEVL-deletion knock-in mouse, autophagic flux assays, LC3 proximity proteomics, and histopathology","pmids":["39607828"],"confidence":"High","gaps":["Mechanism by which TBK1 accumulates on UEVL-mutant phagophores unresolved","Cell-type basis of the neuronal phenotype not defined"]},{"year":2025,"claim":"Indicated that VPS37A overexpression can redirect TNFR1 to lysosomal degradation and suppress NF-κB signaling under metabolic stress in colorectal cancer cells.","evidence":"Overexpression constructs, NF-κB reporter assay, lysosomal inhibition rescue, RNA-seq, and xenografts","pmids":["40746890"],"confidence":"Medium","gaps":["Direct VPS37A–TNFR1 interaction not shown","Relative contribution of ESCRT vs autophagy routes unresolved"]},{"year":null,"claim":"How VPS37A is selectively targeted to the phagophore versus the endosome, and how its two domains are coordinated to partition between sorting and autophagy, remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No identified recruitment signal directing VPS37A to phagophore membranes","No structural model of the UEVL domain engaging VPS28/CHMP2A","Cancer-context roles (EMT, TNFR1, MLKL-dependent autophagy) rest on low-confidence or retracted data"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,2]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[2,5]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,4]}],"complexes":["ESCRT-I"],"partners":["TSG101","VPS28","HGS","CHMP2A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8NEZ2","full_name":"Vacuolar protein sorting-associated protein 37A","aliases":["ESCRT-I complex subunit VPS37A","Hepatocellular carcinoma-related protein 1"],"length_aa":397,"mass_kda":44.3,"function":"Component of the ESCRT-I complex, a regulator of vesicular trafficking process. Required for the sorting of endocytic ubiquitinated cargos into multivesicular bodies. May be involved in cell growth and differentiation","subcellular_location":"Late endosome membrane; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q8NEZ2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/VPS37A","classification":"Not Classified","n_dependent_lines":555,"n_total_lines":1208,"dependency_fraction":0.4594370860927152},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"TSG101","stoichiometry":10.0},{"gene":"COPA","stoichiometry":0.2},{"gene":"VPS28","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/VPS37A","total_profiled":1310},"omim":[{"mim_id":"621454","title":"MULTIVESICULAR BODY SUBUNIT 12B; MVB12B","url":"https://www.omim.org/entry/621454"},{"mim_id":"621453","title":"MULTIVESICULAR BODY SUBUNIT 12A; MVB12A","url":"https://www.omim.org/entry/621453"},{"mim_id":"614898","title":"SPASTIC PARAPLEGIA 53, AUTOSOMAL RECESSIVE; SPG53","url":"https://www.omim.org/entry/614898"},{"mim_id":"609927","title":"VPS37A SUBUNIT OF ESCRIT-I; VPS37A","url":"https://www.omim.org/entry/609927"},{"mim_id":"609787","title":"UBIQUITIN-ASSOCIATED PROTEIN 1; UBAP1","url":"https://www.omim.org/entry/609787"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Centrosome","reliability":"Approved"},{"location":"Acrosome","reliability":"Approved"},{"location":"Flagellar centriole","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"},{"location":"Equatorial segment","reliability":"Additional"},{"location":"Perinuclear theca","reliability":"Additional"},{"location":"Mid piece","reliability":"Additional"},{"location":"Principal piece","reliability":"Additional"},{"location":"End piece","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/VPS37A"},"hgnc":{"alias_symbol":["FLJ32642","HCRP1","SPG53"],"prev_symbol":["PQBP2"]},"alphafold":{"accession":"Q8NEZ2","domains":[{"cath_id":"3.10.110.10","chopping":"25-131","consensus_level":"high","plddt":93.275,"start":25,"end":131},{"cath_id":"1.20.5","chopping":"248-314","consensus_level":"high","plddt":94.1566,"start":248,"end":314},{"cath_id":"1.20.58","chopping":"327-395","consensus_level":"high","plddt":92.3267,"start":327,"end":395}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NEZ2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NEZ2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NEZ2-F1-predicted_aligned_error_v6.png","plddt_mean":76.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=VPS37A","jax_strain_url":"https://www.jax.org/strain/search?query=VPS37A"},"sequence":{"accession":"Q8NEZ2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8NEZ2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8NEZ2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NEZ2"}},"corpus_meta":[{"pmid":"15240819","id":"PMC_15240819","title":"The growth-regulatory protein HCRP1/hVps37A is a subunit of mammalian ESCRT-I and mediates receptor down-regulation.","date":"2004","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/15240819","citation_count":138,"is_preprint":false},{"pmid":"31519728","id":"PMC_31519728","title":"VPS37A directs ESCRT recruitment for phagophore closure.","date":"2019","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/31519728","citation_count":99,"is_preprint":false},{"pmid":"14623289","id":"PMC_14623289","title":"HCRP1, a novel gene that is downregulated in hepatocellular carcinoma, encodes a growth-inhibitory protein.","date":"2003","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/14623289","citation_count":65,"is_preprint":false},{"pmid":"22717650","id":"PMC_22717650","title":"A founder mutation in Vps37A causes autosomal recessive complex hereditary spastic paraparesis.","date":"2012","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22717650","citation_count":60,"is_preprint":false},{"pmid":"36243006","id":"PMC_36243006","title":"Vps37a regulates hepatic glucose production by controlling glucagon receptor localization to endosomes.","date":"2022","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/36243006","citation_count":20,"is_preprint":false},{"pmid":"28122307","id":"PMC_28122307","title":"HCRP1 downregulation promotes hepatocellular carcinoma cell migration and invasion through the induction of EGFR activation and epithelial-mesenchymal transition.","date":"2017","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/28122307","citation_count":18,"is_preprint":false},{"pmid":"27311861","id":"PMC_27311861","title":"Decreased HCRP1 promotes breast cancer metastasis by enhancing EGFR phosphorylation.","date":"2016","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/27311861","citation_count":15,"is_preprint":false},{"pmid":"27739029","id":"PMC_27739029","title":"HCRP1 is downregulated in non-small cell lung cancer and regulates proliferation, invasion, and drug resistance.","date":"2016","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/27739029","citation_count":13,"is_preprint":false},{"pmid":"31152734","id":"PMC_31152734","title":"HCRP1 inhibits cell proliferation and invasion and promotes chemosensitivity in esophageal squamous cell carcinoma.","date":"2019","source":"Chemico-biological interactions","url":"https://pubmed.ncbi.nlm.nih.gov/31152734","citation_count":12,"is_preprint":false},{"pmid":"28350062","id":"PMC_28350062","title":"HCRP1 inhibits TGF-β induced epithelial-mesenchymal transition in hepatocellular carcinoma.","date":"2017","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/28350062","citation_count":12,"is_preprint":false},{"pmid":"28458158","id":"PMC_28458158","title":"HCRP1 regulates proliferation, invasion, and drug resistance via EGFR signaling in prostate cancer.","date":"2017","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/28458158","citation_count":9,"is_preprint":false},{"pmid":"31929761","id":"PMC_31929761","title":"HCRP-1 regulates cell migration, invasion and angiogenesis via Src/ FAK signaling in human prostate cancer.","date":"2020","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31929761","citation_count":7,"is_preprint":false},{"pmid":"28826094","id":"PMC_28826094","title":"Up-regulation of HCRP1 inhibits proliferation and invasion in glioma cells via suppressing the ERK and AKT signaling pathways.","date":"2017","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/28826094","citation_count":5,"is_preprint":false},{"pmid":"39607828","id":"PMC_39607828","title":"Unveiling the physiological impact of ESCRT-dependent autophagosome closure by targeting the VPS37A ubiquitin E2 variant-like domain.","date":"2024","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/39607828","citation_count":4,"is_preprint":false},{"pmid":"36276496","id":"PMC_36276496","title":"HCRP-1 alleviates the malignant phenotype and angiogenesis of oral squamous cell carcinoma cells via the downregulation of the EGFR/STAT3 signaling pathway.","date":"2022","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/36276496","citation_count":3,"is_preprint":false},{"pmid":"31949663","id":"PMC_31949663","title":"HCRP1, ID4 and Glypican-3: an optimal panel of biomarkers for diagnosis of hepatocellular carcinoma.","date":"2018","source":"International journal of clinical and experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/31949663","citation_count":2,"is_preprint":false},{"pmid":"40746890","id":"PMC_40746890","title":"VPS37A Activates the Autophagy-Lysosomal Pathway for TNFR1 Degradation and Induces NF-κB-Regulated Cell Death under Metabolic Stress in Colorectal Cancer.","date":"2025","source":"Oncology research","url":"https://pubmed.ncbi.nlm.nih.gov/40746890","citation_count":1,"is_preprint":false},{"pmid":"34803514","id":"PMC_34803514","title":"Retraction: HCRP-1 regulates cell migration, invasion and angiogenesis via Src/ FAK signaling in human prostate cancer.","date":"2021","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34803514","citation_count":1,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.09.05.611491","title":"Inactivation of necroptosis-promoting protein MLKL creates a therapeutic vulnerability in colorectal cancer cells","date":"2024-09-06","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.05.611491","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11380,"output_tokens":3006,"usd":0.039615,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10356,"output_tokens":2768,"usd":0.06049,"stage2_stop_reason":"end_turn"},"total_usd":0.100105,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"HCRP1/hVps37A is a subunit of mammalian ESCRT-I, interacting with Tsg101 (via its mod(r) domain), hVps28, and their upstream regulator Hrs. It cofractionates with Tsg101 and hVps28 by size exclusion chromatography and colocalizes with hVps28 on LAMP1-positive endosomes. siRNA depletion of HCRP1 strongly retards EGF receptor degradation, while depletion of Tsg101 reduces cellular levels of hVps28 and HCRP1 (but not vice versa).\",\n      \"method\": \"Co-immunoprecipitation, size exclusion chromatography, colocalization by immunofluorescence, siRNA knockdown with EGFR degradation assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, biochemical fractionation, colocalization, and functional siRNA knockdown with defined receptor-sorting phenotype; foundational paper independently replicated by subsequent studies\",\n      \"pmids\": [\"15240819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The mod(r) domain of hVps37A (HCRP1) is required for its interaction with Tsg101 and is shared with paralogs hVps37B and hVps37C.\",\n      \"method\": \"Co-immunoprecipitation with domain-mapping constructs\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mapping by Co-IP in single lab with clear functional context\",\n      \"pmids\": [\"15240819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"VPS37A is a critical component for phagophore closure (autophagosome completion). It localizes to the phagophore via its N-terminal ubiquitin E2 variant (UEV)-like domain, which is required for autophagosome completion but dispensable for ESCRT-I complex formation and EGFR degradation in the MVB pathway. Loss of VPS37A abrogates phagophore recruitment of the ESCRT-I subunit VPS28 and the ESCRT-III subunit CHMP2A. Inhibition of membrane closure (by CHMP2A depletion or VPS4 inhibition) causes VPS37A accumulation on the phagophore.\",\n      \"method\": \"Genome-wide CRISPR screen (FACS-based HaloTag-LC3 autophagosome completion assay), live-cell imaging/localization, domain-deletion mutants, siRNA knockdown with defined phagophore-closure phenotype\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide unbiased CRISPR screen followed by mechanistic validation with domain mutants, localization studies, and epistasis experiments in single rigorous study\",\n      \"pmids\": [\"31519728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The N-terminal UEV-like domain of VPS37A is dispensable for ESCRT-I complex formation and for EGFR degradation in the MVB pathway, but is specifically required for phagophore closure, establishing a functional separation between VPS37A's roles in endosomal sorting and autophagosome closure.\",\n      \"method\": \"Domain-deletion mutants complementing VPS37A-KO cells, EGFR degradation assay, autophagosome completion assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — domain mutagenesis with two distinct functional readouts in same study\",\n      \"pmids\": [\"31519728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Vps37a controls glucagon receptor (Gcgr) localization by preventing its accumulation in endosomes. Hepatocyte-specific knockdown of Vps37a causes endosomal accumulation of Gcgr, resulting in overactivation of the cAMP/PKA/p-CREB signaling pathway and increased gluconeogenesis, without affecting β-oxidation. Shifting the receptor back to the plasma membrane rescues differential signaling, indicating that Vps37a uncouples glucose production from lipid usage downstream of Gcgr by controlling receptor spatiotemporal localization.\",\n      \"method\": \"Hepatocyte-specific siRNA knockdown in vivo, Cy5-glucagon agonist trafficking assay, cAMP/PKA/p-CREB signaling readouts, plasma-membrane targeting rescue experiment\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo hepatocyte-specific KD with receptor-localization tracking, signaling pathway readouts, and mechanistic rescue; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"36243006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The UEV-like (UEVL) β-strand region (residues 43–139) of VPS37A is required for autophagosome closure in vivo. Mice homozygous for a VPS37A UEVL mutation (Δ43-139) show impaired bulk autophagic flux, p62/SQSTM1 and ubiquitinated protein accumulation, neuronal dysfunction, growth retardation, antioxidant gene upregulation, and tissue abnormalities, without disruption of ESCRT-I complex assembly or endosomal function. The UEVL mutation causes accumulation of active TBK1 on phagophores, leading to increased p62 phosphorylation and inclusion formation.\",\n      \"method\": \"Knock-in mouse model with UEVL domain deletion, autophagic flux assays, LC3 proximity proteomics, p62/ubiquitin immunostaining, histopathology\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vivo domain-deletion knock-in mouse model with multiple orthogonal functional readouts and proximity proteomics; confirms domain-function separation established in PMID:31519728\",\n      \"pmids\": [\"39607828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"A homozygous missense mutation (p.K382N) in VPS37A causes autosomal recessive complex hereditary spastic paraparesis in humans. Knockdown of Vps37a in zebrafish by morpholino oligonucleotides significantly reduces mobility, supporting a causal role for VPS37A loss-of-function in upper motor neuron disease.\",\n      \"method\": \"Whole genome linkage analysis, candidate gene sequencing, zebrafish morpholino knockdown with locomotion phenotype\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human genetics combined with zebrafish in vivo knockdown demonstrating locomotor phenotype; mechanistic detail limited to ESCRT pathway membership\",\n      \"pmids\": [\"22717650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Knockdown of HCRP1 in HCC cells induces epithelial-mesenchymal transition (EMT) through the TGF-β signaling pathway, with decreased E-cadherin and β-catenin and increased N-cadherin and vimentin.\",\n      \"method\": \"siRNA knockdown, western blot for EMT markers, migration/invasion assays, TGF-β pathway analysis\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single knockdown approach, no direct mechanistic interaction demonstrated between HCRP1 and TGF-β pathway components\",\n      \"pmids\": [\"28350062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HCRP-1 depletion in prostate cancer cells induces Src and FAK phosphorylation, promoting cell migration, invasion, and angiogenesis; these effects can be reversed by Src inhibitor PP2 or FAK inhibitor. Co-immunoprecipitation was used to assess interactions.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, western blot for pSrc/pFAK, transwell and tube formation assays, xenograft model\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab; the source paper (PMID:31929761) was subsequently retracted (PMID:34803514); findings must be treated as unreliable\",\n      \"pmids\": [\"31929761\", \"34803514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"VPS37A overexpression in colorectal cancer cells redirects TNFR1 to lysosomal degradation via the autophagy-lysosomal pathway, thereby suppressing NF-κB nuclear translocation and transcriptional activity under metabolic stress, and triggering cell death via apoptosis, necroptosis, and ferroptosis.\",\n      \"method\": \"VPS37A overexpression constructs, NF-κB luciferase reporter assay, lysosomal inhibition experiments, RNA sequencing, xenograft model\",\n      \"journal\": \"Oncology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assays and lysosomal inhibition rescue provide mechanistic support; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"40746890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In MLKL-knockout colorectal cancer cells, autophagy becomes critically dependent on VPS37A. Activation of p38 MAPK by homoharringtonine prevents VPS37A from supporting autophagy in MLKL-deficient cells, triggering parthanatos cell death.\",\n      \"method\": \"MLKL gene knockout, VPS37A knockdown in MLKL-KO background, p38 MAPK inhibition/activation, autophagic flux assays, in vivo tumorigenicity assay\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single lab, mechanistic link between p38MAPK and VPS37A autophagy function is indirect/inferred\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"VPS37A (HCRP1) is a subunit of the mammalian ESCRT-I complex that interacts with Tsg101 via its mod(r) domain and with hVps28; it is required for lysosomal sorting and degradation of ubiquitinated membrane receptors such as EGFR at endosomes, controls glucagon receptor localization at endosomes to regulate hepatic gluconeogenesis, and—through a separable N-terminal UEV-like domain—recruits ESCRT-III (CHMP2A) and VPS4 machinery to phagophores for autophagosome closure, a function whose impairment causes neuronal dysfunction and motor disease in vivo.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"VPS37A (HCRP1) is a subunit of the mammalian ESCRT-I complex that functions in membrane-remodeling reactions underlying both endosomal cargo sorting and autophagosome biogenesis [#0, #2]. Within ESCRT-I it interacts with Tsg101 through its mod(r) domain and with hVps28, cofractionating and colocalizing with these partners on LAMP1-positive endosomes; in this context it is required for lysosomal sorting and degradation of ubiquitinated membrane receptors such as the EGF receptor [#0, #1]. A genetically and structurally separable N-terminal ubiquitin-E2-variant-like (UEVL) domain mediates a distinct function in autophagy: it recruits VPS37A to the phagophore and is required to bring the ESCRT-I subunit VPS28 and the ESCRT-III subunit CHMP2A to the closing autophagosome, while being dispensable for ESCRT-I assembly and EGFR degradation [#2, #3]. This autophagosome-closure activity is physiologically essential in vivo: mice carrying a UEVL-domain deletion show impaired autophagic flux, p62/SQSTM1 and ubiquitin accumulation, aberrant accumulation of active TBK1 on phagophores, and neuronal dysfunction [#5]. By controlling receptor trafficking, VPS37A also governs glucagon receptor localization in hepatocytes, restraining endosomal cAMP/PKA/p-CREB signaling and gluconeogenesis [#4]. A homozygous VPS37A missense mutation causes autosomal recessive complex hereditary spastic paraparesis, with zebrafish knockdown reproducing the locomotor defect [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established that VPS37A is a bona fide subunit of human ESCRT-I and connects the complex to endosomal receptor degradation, defining its core molecular identity.\",\n      \"evidence\": \"Reciprocal Co-IP, size exclusion chromatography, colocalization, and siRNA knockdown with EGFR degradation assay\",\n      \"pmids\": [\"15240819\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Did not resolve the structural basis of complex assembly\",\n        \"Did not address roles outside the MVB/endosomal pathway\"\n      ]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Mapped the Tsg101-binding determinant to the mod(r) domain, defining the interface that anchors VPS37A within ESCRT-I.\",\n      \"evidence\": \"Co-IP with domain-mapping constructs\",\n      \"pmids\": [\"15240819\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structural model of the mod(r)\\u2013Tsg101 interface\",\n        \"Functional consequence of disrupting only this interface not isolated\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Linked VPS37A loss-of-function to human upper motor neuron disease, establishing physiological importance beyond cell culture.\",\n      \"evidence\": \"Whole-genome linkage, candidate gene sequencing, and zebrafish morpholino knockdown with locomotion phenotype\",\n      \"pmids\": [\"22717650\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism connecting VPS37A loss to neuronal degeneration not defined at the time\",\n        \"Effect of the K382N mutation on specific VPS37A functions untested\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Discovered a second, separable function: VPS37A is required for phagophore closure and uses its N-terminal UEVL domain to recruit downstream ESCRT machinery to the autophagosome, distinguishing autophagy from endosomal roles.\",\n      \"evidence\": \"Genome-wide CRISPR screen, live-cell imaging, domain-deletion complementation, and epistasis with CHMP2A/VPS4\",\n      \"pmids\": [\"31519728\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular signal recruiting VPS37A to the phagophore not identified\",\n        \"How the UEVL domain engages VPS28/CHMP2A structurally is unknown\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed that VPS37A-controlled receptor trafficking has organ-level metabolic consequences by restraining endosomal glucagon receptor signaling.\",\n      \"evidence\": \"Hepatocyte-specific in vivo knockdown, agonist trafficking assay, cAMP/PKA/p-CREB readouts, and plasma-membrane rescue\",\n      \"pmids\": [\"36243006\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether Gcgr regulation requires ESCRT-I assembly or autophagy not dissected\",\n        \"Direct interaction between VPS37A and Gcgr not demonstrated\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated in vivo that the UEVL domain is specifically required for autophagosome closure and that its loss drives TBK1/p62 pathology and neuronal dysfunction, confirming the domain-function separation.\",\n      \"evidence\": \"UEVL-deletion knock-in mouse, autophagic flux assays, LC3 proximity proteomics, and histopathology\",\n      \"pmids\": [\"39607828\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which TBK1 accumulates on UEVL-mutant phagophores unresolved\",\n        \"Cell-type basis of the neuronal phenotype not defined\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Indicated that VPS37A overexpression can redirect TNFR1 to lysosomal degradation and suppress NF-\\u03baB signaling under metabolic stress in colorectal cancer cells.\",\n      \"evidence\": \"Overexpression constructs, NF-\\u03baB reporter assay, lysosomal inhibition rescue, RNA-seq, and xenografts\",\n      \"pmids\": [\"40746890\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct VPS37A\\u2013TNFR1 interaction not shown\",\n        \"Relative contribution of ESCRT vs autophagy routes unresolved\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How VPS37A is selectively targeted to the phagophore versus the endosome, and how its two domains are coordinated to partition between sorting and autophagy, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No identified recruitment signal directing VPS37A to phagophore membranes\",\n        \"No structural model of the UEVL domain engaging VPS28/CHMP2A\",\n        \"Cancer-context roles (EMT, TNFR1, MLKL-dependent autophagy) rest on low-confidence or retracted data\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [2, 5]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"complexes\": [\"ESCRT-I\"],\n    \"partners\": [\"TSG101\", \"VPS28\", \"HGS\", \"CHMP2A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}