{"gene":"SEC23IP","run_date":"2026-06-10T07:46:30","timeline":{"discoveries":[{"year":1999,"finding":"p125 (SEC23IP) was identified as a novel mammalian Sec23p-interacting protein, distinct from Sec24p. The N-terminal proline-rich region of p125 mediates binding to Sec23p, demonstrated by GST-fusion pulldown and yeast two-hybrid assay. The central and C-terminal regions share homology with phosphatidic acid-preferring phospholipase A1. Overexpression of p125 caused disorganization of the ER-Golgi intermediate compartment and Golgi apparatus, implicating it in the early secretory pathway.","method":"GST-fusion protein pulldown, yeast two-hybrid, transient overexpression in mammalian cells with organelle morphology assessment","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (GST pulldown, yeast two-hybrid, cell overexpression phenotype) in a single study establishing binding domain and functional consequence","pmids":["10400679"],"is_preprint":false},{"year":2000,"finding":"The proline-rich region (residues 135–259) of p125 is responsible for binding to Sec23p. For correct intracellular localization of p125 to ER-Golgi intermediate regions, a larger region (residues 135–1000) comprising both the proline-rich and phospholipase A1 homology regions is required. Expressed p125 principally colocalizes with p115 and GM130, both involved in vesicle tethering to Golgi membranes.","method":"Expression of deletion mutant series in cultured cells, co-localization by immunofluorescence","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — deletion mapping with multiple constructs in single lab, functional domain assignment with localization readout","pmids":["11112430"],"is_preprint":false},{"year":2004,"finding":"p125 localizes principally to ER exit sites (ERES), as demonstrated by immunofluorescence and electron microscopy. The p125-specific N-terminal region is critical for ERES localization. RNAi-mediated depletion of p125 disrupted the organization of ERES and substantially disturbed the cis-Golgi compartment structure, while protein export from the ER occurred without significant delay.","method":"Immunofluorescence, electron microscopy, chimeric protein analysis, RNA interference knockdown with organelle morphology readout","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (EM, IF, RNAi, domain-swap chimeras) establishing subcellular localization and functional role in ERES organization","pmids":["15623529"],"is_preprint":false},{"year":2002,"finding":"A paralog of p125, KIAA0725p, lacks the N-terminal proline-rich Sec23p-interacting region and does not bind Sec23p in vitro. KIAA0725p possesses phospholipase A1 activity preferentially for phosphatidic acid, indicating the lipase domain of the p125 family is enzymatically active, though p125 itself was not directly shown to have phospholipase activity in this study.","method":"In vitro binding analysis, overexpression with organelle morphology assessment, enzymatic activity assay on paralog","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — direct in vitro binding and enzymatic assays on paralog inform the functional domain architecture of p125 family; p125 itself not directly assayed for lipase activity","pmids":["11788596"],"is_preprint":false},{"year":2010,"finding":"p125A (SEC23IP) also interacts with the C-terminal region of Sec31A, in addition to its known interaction with Sec23A. The Sec31A-interacting domain maps to residues 260–600 of p125A, a distinct domain from that required for Sec23A interaction. Gel filtration and immunodepletion studies demonstrate that the majority of cytosolic p125A exists as a ternary complex with Sec13/Sec31A, suggesting p125A, Sec13, and Sec31A form preassembled heterohexamers in the cytosol. Silencing of p125A disrupted Golgi morphology and impaired protein export from the ER.","method":"Co-immunoprecipitation, gel filtration, immunodepletion, siRNA knockdown with Golgi morphology and ER-export assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal biochemical approaches (gel filtration, immunodepletion, Co-IP) plus functional KD phenotype in a rigorous single study","pmids":["20679433"],"is_preprint":false},{"year":2011,"finding":"p125/Sec23ip knockout male mice are subfertile; sperm from knockout mice have round heads and lack the acrosome. p125 is expressed at stages I–XII of spermatogenesis, similar to acrosome biogenesis proteins, establishing a required role for p125 in acrosome biogenesis during spermiogenesis.","method":"Gene knockout mouse model, sperm morphology analysis, immunostaining for expression staging","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 2 / Strong — defined genetic loss-of-function with specific and reproducible cellular phenotype (acrosome absence) in vivo","pmids":["21640725"],"is_preprint":false},{"year":2020,"finding":"Sec23ip was identified as part of the 14-3-3γ protein network in MA-10 Leydig cells. siRNA-mediated silencing of Sec23ip decreased steroidogenesis, and in Sec23ip-silenced cells, cholesterol mobilization from the cytoplasmic membrane to mitochondria was impaired, indicating Sec23ip facilitates cholesterol trafficking for acute steroidogenesis.","method":"LC-MS proteomics (14-3-3γ interactome), siRNA knockdown, steroidogenesis assay, cholesterol trafficking assay","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — MS-based interaction identification plus functional siRNA KD with specific biochemical readout (cholesterol trafficking, steroid output), single lab","pmids":["31875919"],"is_preprint":false},{"year":2024,"finding":"Sec23IP at ERES acts as a VPS13B/COH1 adaptor, recruiting VPS13B to ERES-Golgi interfaces via direct interaction with the VPS13 adaptor binding domain (VAB) of VPS13B. Disease-associated missense mutations in VPS13B-VAB impair binding to Sec23IP. Knockout of VPS13B or Sec23IP blocks formation of tubular ERGIC cargo carriers and delays ER export of procollagen, linking the Sec23IP-VPS13B interaction to collagen secretion and joint laxity in Cohen syndrome.","method":"Co-immunoprecipitation, co-localization imaging, knockout cell lines, procollagen trafficking assay, mutant binding analysis","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct interaction demonstrated by Co-IP, disease mutations tested, KO phenotype with specific cargo readout (procollagen), multiple orthogonal approaches in single rigorous study","pmids":["39352497"],"is_preprint":false},{"year":2025,"finding":"p125A (SEC23IP) bridges the COPII outer coat assembly to PI4P-rich ERGIC/cis-Golgi acceptor membranes by simultaneously binding phosphatidylinositol 4-phosphate (PI4P), Sec31, and Sec23. In cell-free reconstitutions, apposition of donor and acceptor membranes promoted Sec13/31 outer layer assembly, and p125A stabilized this donor-acceptor contact. Loss of p125A selectively destabilized COPII outer layer assembly and inhibited fibrillar collagen traffic from the ER, while a p125A chimera with a Golgi-targeted PI4P-binding domain could rescue outer layer assembly. The C-terminal helical domain of Sec31A is essential for its interaction with p125A at ERES.","method":"Cell-free reconstitution, domain-swap chimeras, p125A knockout cells, transcriptome and secretome analysis, fluorescence imaging of COPII dynamics","journal":"bioRxiv","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cell-free reconstitution with domain mutagenesis and multiple functional readouts (COPII assembly, collagen secretion) in single preprint study; not yet peer-reviewed","pmids":["40463098"],"is_preprint":true}],"current_model":"SEC23IP (p125A) is a mammalian-specific ER exit site (ERES) protein that physically bridges the COPII inner (Sec23/24) and outer (Sec13/31) coat subcomplexes while also binding PI4P on ERGIC/cis-Golgi acceptor membranes, thereby stabilizing donor-acceptor membrane contacts to facilitate COPII outer coat assembly and tunnel-based ER-to-Golgi traffic of large cargoes such as fibrillar collagens; it additionally recruits VPS13B/COH1 to the ERES-Golgi interface, acts as a 14-3-3γ network component required for cholesterol trafficking and steroidogenesis in Leydig cells, and is essential in vivo for acrosome biogenesis during spermiogenesis."},"narrative":{"mechanistic_narrative":"SEC23IP (p125A) is a mammalian ER exit site (ERES) protein that organizes the early secretory pathway and facilitates COPII-mediated ER-to-Golgi traffic [PMID:10400679, PMID:15623529]. It was identified through its N-terminal proline-rich region, which binds the COPII inner coat subunit Sec23, with its central and C-terminal regions sharing homology with phosphatidic acid-preferring phospholipase A1 [PMID:10400679]. SEC23IP localizes principally to ERES via its specific N-terminal region, and its depletion disrupts ERES organization and cis-Golgi structure [PMID:15623529]. Mechanistically, SEC23IP bridges the COPII inner and outer coats: a distinct domain (residues 260–600) binds the C-terminal helical region of Sec31A, and most cytosolic SEC23IP exists in a preassembled ternary complex with Sec13/Sec31A [PMID:20679433]. By simultaneously binding Sec23, Sec31, and PI4P on ERGIC/cis-Golgi acceptor membranes, it stabilizes donor-acceptor membrane apposition to promote COPII outer coat assembly and traffic of large cargoes such as fibrillar collagens [PMID:40463098]. SEC23IP additionally functions as an adaptor that recruits VPS13B/COH1 to the ERES-Golgi interface, an interaction disrupted by Cohen syndrome-associated VPS13B mutations and required for tubular ERGIC carrier formation and procollagen export [PMID:39352497]. In vivo, Sec23ip is essential for acrosome biogenesis during spermiogenesis [PMID:21640725], and it acts within the 14-3-3γ network to support cholesterol trafficking and steroidogenesis in Leydig cells [PMID:31875919].","teleology":[{"year":1999,"claim":"Established SEC23IP as a Sec23-interacting protein of the early secretory pathway, defining the binding domain and a candidate enzymatic domain that placed it at the ER-Golgi interface.","evidence":"GST-fusion pulldown, yeast two-hybrid, and overexpression organelle morphology in mammalian cells","pmids":["10400679"],"confidence":"High","gaps":["Did not localize endogenous protein or test loss-of-function","Phospholipase A1 homology not demonstrated to be catalytically active in p125 itself","Mechanism linking overexpression to ERGIC/Golgi disorganization unresolved"]},{"year":2000,"claim":"Mapped the Sec23-binding determinant to residues 135–259 and showed correct ERES/Golgi localization requires a larger region, while co-localization with p115 and GM130 connected SEC23IP to vesicle tethering machinery.","evidence":"Deletion mutant series and immunofluorescence co-localization in cultured cells","pmids":["11112430"],"confidence":"Medium","gaps":["Co-localization does not establish direct interaction with tethering factors","Functional consequence of the localization determinant not tested by loss-of-function"]},{"year":2002,"claim":"Showed the phospholipase A1 homology domain of the p125 family is enzymatically active toward phosphatidic acid, using the paralog KIAA0725p which lacks the Sec23-binding region.","evidence":"In vitro binding and enzymatic activity assays on the paralog, overexpression morphology","pmids":["11788596"],"confidence":"Medium","gaps":["p125/SEC23IP itself was not directly assayed for lipase activity","Physiological substrate and relevance of the lipase domain in vivo unknown"]},{"year":2004,"claim":"Localized SEC23IP specifically to ERES and demonstrated its requirement for ERES and cis-Golgi organization, distinguishing its structural role from bulk ER export.","evidence":"Immunofluorescence, electron microscopy, domain-swap chimeras, and RNAi with organelle morphology readouts","pmids":["15623529"],"confidence":"High","gaps":["Did not identify the molecular partners mediating ERES organization","Why ER export was unaffected despite ERES disruption was not resolved"]},{"year":2010,"claim":"Revealed SEC23IP as a bridge between COPII inner and outer coats by mapping a separate Sec31A-binding domain and showing it forms a preassembled cytosolic ternary complex with Sec13/Sec31A.","evidence":"Co-immunoprecipitation, gel filtration, immunodepletion, and siRNA with ER-export and Golgi morphology assays","pmids":["20679433"],"confidence":"High","gaps":["Stoichiometry and structure of the ternary complex not resolved","How the preassembled complex engages nascent COPII buds at ERES unclear"]},{"year":2011,"claim":"Defined a non-redundant in vivo role for Sec23ip in acrosome biogenesis, linking its secretory-pathway function to male fertility.","evidence":"Sec23ip knockout mouse with sperm morphology analysis and expression staging","pmids":["21640725"],"confidence":"High","gaps":["Molecular basis of the acrosome defect (which cargo/trafficking step) not identified","Whether the phenotype reflects ERES/COPII function specifically was not tested"]},{"year":2020,"claim":"Connected Sec23ip to lipid trafficking by placing it in the 14-3-3γ network and showing its loss impairs cholesterol mobilization and steroidogenesis in Leydig cells.","evidence":"LC-MS interactome, siRNA knockdown, steroidogenesis and cholesterol-trafficking assays in MA-10 cells","pmids":["31875919"],"confidence":"Medium","gaps":["Direct physical interaction with 14-3-3γ not validated reciprocally","Mechanism linking ERES function to cytoplasm-to-mitochondria cholesterol transport unclear"]},{"year":2024,"claim":"Identified SEC23IP as the ERES adaptor that recruits VPS13B/COH1 via its VAB domain, mechanistically linking the interaction to tubular ERGIC carrier formation, procollagen export, and Cohen syndrome.","evidence":"Co-IP, co-localization, knockout cell lines, procollagen trafficking, and disease-mutant binding assays","pmids":["39352497"],"confidence":"High","gaps":["Whether VPS13B-mediated lipid transfer is the functional output at ERES not directly shown","Relationship between SEC23IP-VPS13B recruitment and COPII coat assembly not integrated"]},{"year":2025,"claim":"Reconstituted SEC23IP's coordinating mechanism, showing it simultaneously binds PI4P, Sec31, and Sec23 to stabilize donor-acceptor membrane contacts and drive COPII outer coat assembly for large cargo such as fibrillar collagen.","evidence":"Cell-free reconstitution, domain-swap chimeras, knockout cells, and secretome/transcriptome analysis (preprint)","pmids":["40463098"],"confidence":"High","gaps":["Not yet peer-reviewed","Structural basis for simultaneous tripartite binding not resolved","How tunnel/carrier geometry accommodates large cargo not established"]},{"year":null,"claim":"It remains unresolved whether SEC23IP's phospholipase A1 homology domain is catalytically active in vivo and how this enzymatic potential integrates with its structural coat-bridging and PI4P-sensing roles.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No direct demonstration of SEC23IP lipase activity","No structure of SEC23IP in complex with COPII coat or membrane","Integration of lipid-modifying, adaptor, and coat-bridging functions unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4,7,8]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[8]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[8]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,2,8]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[1,2]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,2,4,8]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[7,8]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[7,8]}],"complexes":["COPII coat","p125A-Sec13-Sec31A ternary complex"],"partners":["SEC23A","SEC31A","SEC13","VPS13B","YWHAG"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y6Y8","full_name":"SEC23-interacting protein","aliases":["p125"],"length_aa":1000,"mass_kda":111.1,"function":"Plays a role in the organization of endoplasmic reticulum exit sites. Specifically binds to phosphatidylinositol 3-phosphate (PI(3)P), phosphatidylinositol 4-phosphate (PI(4)P) and phosphatidylinositol 5-phosphate (PI(5)P)","subcellular_location":"Cytoplasmic vesicle, COPII-coated vesicle membrane; Endoplasmic reticulum","url":"https://www.uniprot.org/uniprotkb/Q9Y6Y8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SEC23IP","classification":"Not Classified","n_dependent_lines":65,"n_total_lines":1208,"dependency_fraction":0.05380794701986755},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PDCD6","stoichiometry":10.0},{"gene":"SEC13","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SEC23IP","total_profiled":1310},"omim":[{"mim_id":"617852","title":"SEC23-INTERACTING PROTEIN; SEC23IP","url":"https://www.omim.org/entry/617852"},{"mim_id":"614603","title":"DDHD DOMAIN-CONTAINING PROTEIN 1; DDHD1","url":"https://www.omim.org/entry/614603"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Vesicles","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SEC23IP"},"hgnc":{"alias_symbol":["p125","iPLA1beta","iPLA1β","p125A"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y6Y8","domains":[{"cath_id":"-","chopping":"273-406_420-427","consensus_level":"high","plddt":87.9116,"start":273,"end":427},{"cath_id":"-","chopping":"456-466_490-597_777-859_938-975","consensus_level":"high","plddt":83.925,"start":456,"end":975},{"cath_id":"1.10.150.50","chopping":"651-712","consensus_level":"high","plddt":87.9566,"start":651,"end":712}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y6Y8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y6Y8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y6Y8-F1-predicted_aligned_error_v6.png","plddt_mean":64.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SEC23IP","jax_strain_url":"https://www.jax.org/strain/search?query=SEC23IP"},"sequence":{"accession":"Q9Y6Y8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y6Y8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y6Y8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y6Y8"}},"corpus_meta":[{"pmid":"8314789","id":"PMC_8314789","title":"Bombesin stimulation of p125 focal adhesion kinase tyrosine phosphorylation. 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Dissociation from tyrosine phosphorylation of p125 focal adhesion kinase.","date":"1996","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8910389","citation_count":109,"is_preprint":false},{"pmid":"8631827","id":"PMC_8631827","title":"Requirement for phosphatidylinositol 3'-kinase activity in platelet-derived growth factor-stimulated tyrosine phosphorylation of p125 focal adhesion kinase and paxillin.","date":"1996","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8631827","citation_count":93,"is_preprint":false},{"pmid":"10400679","id":"PMC_10400679","title":"p125 is a novel mammalian Sec23p-interacting protein with structural similarity to phospholipid-modifying proteins.","date":"1999","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10400679","citation_count":90,"is_preprint":false},{"pmid":"10373543","id":"PMC_10373543","title":"The naturally occurring mutants of DDB are impaired in stimulating nuclear import of the p125 subunit and E2F1-activated transcription.","date":"1999","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/10373543","citation_count":88,"is_preprint":false},{"pmid":"11788596","id":"PMC_11788596","title":"A novel phospholipase A1 with sequence homology to a mammalian Sec23p-interacting protein, p125.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11788596","citation_count":86,"is_preprint":false},{"pmid":"9756930","id":"PMC_9756930","title":"Activation of human endothelial cells via S-endo-1 antigen (CD146) stimulates the tyrosine phosphorylation of focal adhesion kinase p125(FAK).","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9756930","citation_count":86,"is_preprint":false},{"pmid":"11069767","id":"PMC_11069767","title":"p125 focal adhesion kinase promotes malignant astrocytoma cell proliferation in vivo.","date":"2000","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/11069767","citation_count":84,"is_preprint":false},{"pmid":"21918226","id":"PMC_21918226","title":"Coronavirus infection induces DNA replication stress partly through interaction of its nonstructural protein 13 with the p125 subunit of DNA polymerase δ.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21918226","citation_count":82,"is_preprint":false},{"pmid":"15623529","id":"PMC_15623529","title":"p125 is localized in endoplasmic reticulum exit sites and involved in their organization.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15623529","citation_count":80,"is_preprint":false},{"pmid":"10480866","id":"PMC_10480866","title":"Direct interaction of proliferating cell nuclear antigen with the p125 catalytic subunit of mammalian DNA polymerase delta.","date":"1999","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10480866","citation_count":75,"is_preprint":false},{"pmid":"9553131","id":"PMC_9553131","title":"Growth hormone stimulates the tyrosine phosphorylation and association of p125 focal adhesion kinase (FAK) with JAK2. 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A novel proximal signal in insulin secretion.","date":"1996","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8798659","citation_count":23,"is_preprint":false},{"pmid":"21640725","id":"PMC_21640725","title":"p125/Sec23-interacting protein (Sec23ip) is required for spermiogenesis.","date":"2011","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/21640725","citation_count":22,"is_preprint":false},{"pmid":"9545286","id":"PMC_9545286","title":"Characterization of the p125 subunit of human DNA polymerase delta and its deletion mutants. Interaction with cyclin-dependent kinase-cyclins.","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9545286","citation_count":22,"is_preprint":false},{"pmid":"9632700","id":"PMC_9632700","title":"Pervanadate stimulates amylase release and protein tyrosine phosphorylation of paxillin and p125(FAK) in differentiated AR4-2J pancreatic acinar cells.","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9632700","citation_count":21,"is_preprint":false},{"pmid":"27022290","id":"PMC_27022290","title":"p53 inhibits the expression of p125 and the methylation of POLD1 gene promoter by downregulating the Sp1-induced DNMT1 activities in breast cancer.","date":"2016","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/27022290","citation_count":20,"is_preprint":false},{"pmid":"21372597","id":"PMC_21372597","title":"Significance of DNA polymerase delta catalytic subunit p125 induced by mutant p53 in the invasive potential of human hepatocellular carcinoma.","date":"2011","source":"Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/21372597","citation_count":19,"is_preprint":false},{"pmid":"7681835","id":"PMC_7681835","title":"Identification of p125, a component of a group of 120-kDa proteins that are phosphorylated on tyrosine residues in response to bradykinin and bombesin stimulation, in anti-ras-GTPase-activating protein immunoprecipitates of Swiss 3T3 cells.","date":"1993","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7681835","citation_count":19,"is_preprint":false},{"pmid":"34831127","id":"PMC_34831127","title":"Inhibition of Vasculogenic Mimicry and Angiogenesis by an Anti-EGFR IgG1-Human Endostatin-P125A Fusion Protein Reduces Triple Negative Breast Cancer Metastases.","date":"2021","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/34831127","citation_count":18,"is_preprint":false},{"pmid":"8589330","id":"PMC_8589330","title":"Endothelin-1 stimulates tyrosine phosphorylation of p125 focal adhesion kinase in mesangial cells.","date":"1995","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/8589330","citation_count":18,"is_preprint":false},{"pmid":"9867854","id":"PMC_9867854","title":"Low density lipoprotein phosphorylates the focal adhesion-associated kinase p125(FAK) in human platelets independent of integrin alphaIIb beta3.","date":"1999","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9867854","citation_count":17,"is_preprint":false},{"pmid":"9252385","id":"PMC_9252385","title":"Decrease in the amount of focal adhesion kinase (p125(FAK)) in interleukin-1beta-stimulated human umbilical vein endothelial cells by binding of human monocytic cell lines.","date":"1997","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9252385","citation_count":15,"is_preprint":false},{"pmid":"39352497","id":"PMC_39352497","title":"Sec23IP recruits VPS13B/COH1 to ER exit site-Golgi interface for tubular ERGIC formation.","date":"2024","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/39352497","citation_count":14,"is_preprint":false},{"pmid":"10737896","id":"PMC_10737896","title":"Tyrosine phosphorylation of p125(Fak), p130(Cas), and paxillin does not require extracellular signal-regulated kinase activation in Swiss 3T3 cells stimulated by bombesin or platelet-derived growth factor.","date":"2000","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/10737896","citation_count":13,"is_preprint":false},{"pmid":"10924330","id":"PMC_10924330","title":"Nitric oxide stimulates tyrosine phosphorylation of p125(FAK) and paxillin in rat pancreatic acini.","date":"2000","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/10924330","citation_count":13,"is_preprint":false},{"pmid":"20844568","id":"PMC_20844568","title":"AAV-P125A-endostatin and paclitaxel treatment increases endoreduplication in endothelial cells and inhibits metastasis of breast cancer.","date":"2010","source":"Gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/20844568","citation_count":12,"is_preprint":false},{"pmid":"10095157","id":"PMC_10095157","title":"Regulation of the actin cytoskeleton by p125 focal adhesion kinase in rat pancreatic acinar cells.","date":"1999","source":"Digestion","url":"https://pubmed.ncbi.nlm.nih.gov/10095157","citation_count":12,"is_preprint":false},{"pmid":"10594689","id":"PMC_10594689","title":"Adhesion to fibronectin promotes the activation of the p125(FAK)/Zap-70complex in human T cells.","date":"1999","source":"Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/10594689","citation_count":12,"is_preprint":false},{"pmid":"10486260","id":"PMC_10486260","title":"Growth hormone stimulates tyrosine phosphorylation of focal adhesion kinase (p125(FAK)) and actin stress fiber formation in human osteoblast-like cells, Saos2.","date":"1999","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/10486260","citation_count":12,"is_preprint":false},{"pmid":"21225621","id":"PMC_21225621","title":"Inhibition of ovarian cancer by RGD-P125A-endostatin-Fc fusion proteins.","date":"2011","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/21225621","citation_count":11,"is_preprint":false},{"pmid":"10704824","id":"PMC_10704824","title":"A role for phosphoinositides in tyrosine phosphorylation of p125 focal adhesion kinase in rat pancreatic acini.","date":"2000","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/10704824","citation_count":10,"is_preprint":false},{"pmid":"1663821","id":"PMC_1663821","title":"Bovine viral diarrhea virus proteins: relatedness of p175 with p80 and p125 and evidence of glycoprotein processing.","date":"1991","source":"Canadian journal of microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/1663821","citation_count":9,"is_preprint":false},{"pmid":"35776191","id":"PMC_35776191","title":"RNA-sequencing of myxoinflammatory fibroblastic sarcomas reveals a novel SND1::BRAF fusion and 3 different molecular aberrations with the potential to upregulate the TEAD1 gene including SEC23IP::VGLL3 and TEAD1::MRTFB gene fusions.","date":"2022","source":"Virchows Archiv : an international journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/35776191","citation_count":8,"is_preprint":false},{"pmid":"11114723","id":"PMC_11114723","title":"Interaction of the retinoblastoma protein (pRb) with the catalytic subunit of DNA polymerase delta (p125).","date":"2000","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/11114723","citation_count":8,"is_preprint":false},{"pmid":"10928051","id":"PMC_10928051","title":"Expression of focal adhesion kinase (p125 FAK) and proline-rich tyrosine kinase 2 (PYK2/CAKb) in cerebral metastases, correlation with VEGF-R-, ecNOS III-labelling and morphometric data.","date":"2000","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/10928051","citation_count":8,"is_preprint":false},{"pmid":"10415383","id":"PMC_10415383","title":"Platelet-activating factor stimulation of p125(FAK) and p130(Cas) tyrosine phosphorylation in brain.","date":"1999","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/10415383","citation_count":8,"is_preprint":false},{"pmid":"31875919","id":"PMC_31875919","title":"Identification of Sec23ip, Part of 14-3-3γ Protein Network, as a Regulator of Acute Steroidogenesis in MA-10 Leydig Cells.","date":"2020","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/31875919","citation_count":7,"is_preprint":false},{"pmid":"2515195","id":"PMC_2515195","title":"An immunocytochemical study of the proliferating cell nuclear matrix antigen p125/6.5 during rat spermatogenesis.","date":"1989","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/2515195","citation_count":5,"is_preprint":false},{"pmid":"38315147","id":"PMC_38315147","title":"Antibody-Drug Conjugate αEGFR-E-P125A Reduces Triple-negative Breast Cancer Vasculogenic Mimicry, Motility, and Metastasis through Inhibition of EGFR, Integrin, and FAK/STAT3 Signaling.","date":"2024","source":"Cancer research communications","url":"https://pubmed.ncbi.nlm.nih.gov/38315147","citation_count":4,"is_preprint":false},{"pmid":"8925892","id":"PMC_8925892","title":"Tyrosine phosphorylation and subcellular redistribution of p125 ras guanosine triphosphatase-activating protein in human neutrophils stimulated with FMLP.","date":"1996","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/8925892","citation_count":4,"is_preprint":false},{"pmid":"40463098","id":"PMC_40463098","title":"p125A (Sec23ip) couples COPII coat assembly with donor-acceptor membrane organization to facilitate tunnel-based traffic.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/40463098","citation_count":3,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":31386,"output_tokens":2673,"usd":0.067127,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9935,"output_tokens":3497,"usd":0.06855,"stage2_stop_reason":"end_turn"},"total_usd":0.135677,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"p125 (SEC23IP) was identified as a novel mammalian Sec23p-interacting protein, distinct from Sec24p. The N-terminal proline-rich region of p125 mediates binding to Sec23p, demonstrated by GST-fusion pulldown and yeast two-hybrid assay. The central and C-terminal regions share homology with phosphatidic acid-preferring phospholipase A1. Overexpression of p125 caused disorganization of the ER-Golgi intermediate compartment and Golgi apparatus, implicating it in the early secretory pathway.\",\n      \"method\": \"GST-fusion protein pulldown, yeast two-hybrid, transient overexpression in mammalian cells with organelle morphology assessment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (GST pulldown, yeast two-hybrid, cell overexpression phenotype) in a single study establishing binding domain and functional consequence\",\n      \"pmids\": [\"10400679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The proline-rich region (residues 135–259) of p125 is responsible for binding to Sec23p. For correct intracellular localization of p125 to ER-Golgi intermediate regions, a larger region (residues 135–1000) comprising both the proline-rich and phospholipase A1 homology regions is required. Expressed p125 principally colocalizes with p115 and GM130, both involved in vesicle tethering to Golgi membranes.\",\n      \"method\": \"Expression of deletion mutant series in cultured cells, co-localization by immunofluorescence\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — deletion mapping with multiple constructs in single lab, functional domain assignment with localization readout\",\n      \"pmids\": [\"11112430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"p125 localizes principally to ER exit sites (ERES), as demonstrated by immunofluorescence and electron microscopy. The p125-specific N-terminal region is critical for ERES localization. RNAi-mediated depletion of p125 disrupted the organization of ERES and substantially disturbed the cis-Golgi compartment structure, while protein export from the ER occurred without significant delay.\",\n      \"method\": \"Immunofluorescence, electron microscopy, chimeric protein analysis, RNA interference knockdown with organelle morphology readout\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (EM, IF, RNAi, domain-swap chimeras) establishing subcellular localization and functional role in ERES organization\",\n      \"pmids\": [\"15623529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"A paralog of p125, KIAA0725p, lacks the N-terminal proline-rich Sec23p-interacting region and does not bind Sec23p in vitro. KIAA0725p possesses phospholipase A1 activity preferentially for phosphatidic acid, indicating the lipase domain of the p125 family is enzymatically active, though p125 itself was not directly shown to have phospholipase activity in this study.\",\n      \"method\": \"In vitro binding analysis, overexpression with organelle morphology assessment, enzymatic activity assay on paralog\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — direct in vitro binding and enzymatic assays on paralog inform the functional domain architecture of p125 family; p125 itself not directly assayed for lipase activity\",\n      \"pmids\": [\"11788596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"p125A (SEC23IP) also interacts with the C-terminal region of Sec31A, in addition to its known interaction with Sec23A. The Sec31A-interacting domain maps to residues 260–600 of p125A, a distinct domain from that required for Sec23A interaction. Gel filtration and immunodepletion studies demonstrate that the majority of cytosolic p125A exists as a ternary complex with Sec13/Sec31A, suggesting p125A, Sec13, and Sec31A form preassembled heterohexamers in the cytosol. Silencing of p125A disrupted Golgi morphology and impaired protein export from the ER.\",\n      \"method\": \"Co-immunoprecipitation, gel filtration, immunodepletion, siRNA knockdown with Golgi morphology and ER-export assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal biochemical approaches (gel filtration, immunodepletion, Co-IP) plus functional KD phenotype in a rigorous single study\",\n      \"pmids\": [\"20679433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"p125/Sec23ip knockout male mice are subfertile; sperm from knockout mice have round heads and lack the acrosome. p125 is expressed at stages I–XII of spermatogenesis, similar to acrosome biogenesis proteins, establishing a required role for p125 in acrosome biogenesis during spermiogenesis.\",\n      \"method\": \"Gene knockout mouse model, sperm morphology analysis, immunostaining for expression staging\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — defined genetic loss-of-function with specific and reproducible cellular phenotype (acrosome absence) in vivo\",\n      \"pmids\": [\"21640725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Sec23ip was identified as part of the 14-3-3γ protein network in MA-10 Leydig cells. siRNA-mediated silencing of Sec23ip decreased steroidogenesis, and in Sec23ip-silenced cells, cholesterol mobilization from the cytoplasmic membrane to mitochondria was impaired, indicating Sec23ip facilitates cholesterol trafficking for acute steroidogenesis.\",\n      \"method\": \"LC-MS proteomics (14-3-3γ interactome), siRNA knockdown, steroidogenesis assay, cholesterol trafficking assay\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — MS-based interaction identification plus functional siRNA KD with specific biochemical readout (cholesterol trafficking, steroid output), single lab\",\n      \"pmids\": [\"31875919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Sec23IP at ERES acts as a VPS13B/COH1 adaptor, recruiting VPS13B to ERES-Golgi interfaces via direct interaction with the VPS13 adaptor binding domain (VAB) of VPS13B. Disease-associated missense mutations in VPS13B-VAB impair binding to Sec23IP. Knockout of VPS13B or Sec23IP blocks formation of tubular ERGIC cargo carriers and delays ER export of procollagen, linking the Sec23IP-VPS13B interaction to collagen secretion and joint laxity in Cohen syndrome.\",\n      \"method\": \"Co-immunoprecipitation, co-localization imaging, knockout cell lines, procollagen trafficking assay, mutant binding analysis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct interaction demonstrated by Co-IP, disease mutations tested, KO phenotype with specific cargo readout (procollagen), multiple orthogonal approaches in single rigorous study\",\n      \"pmids\": [\"39352497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"p125A (SEC23IP) bridges the COPII outer coat assembly to PI4P-rich ERGIC/cis-Golgi acceptor membranes by simultaneously binding phosphatidylinositol 4-phosphate (PI4P), Sec31, and Sec23. In cell-free reconstitutions, apposition of donor and acceptor membranes promoted Sec13/31 outer layer assembly, and p125A stabilized this donor-acceptor contact. Loss of p125A selectively destabilized COPII outer layer assembly and inhibited fibrillar collagen traffic from the ER, while a p125A chimera with a Golgi-targeted PI4P-binding domain could rescue outer layer assembly. The C-terminal helical domain of Sec31A is essential for its interaction with p125A at ERES.\",\n      \"method\": \"Cell-free reconstitution, domain-swap chimeras, p125A knockout cells, transcriptome and secretome analysis, fluorescence imaging of COPII dynamics\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cell-free reconstitution with domain mutagenesis and multiple functional readouts (COPII assembly, collagen secretion) in single preprint study; not yet peer-reviewed\",\n      \"pmids\": [\"40463098\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"SEC23IP (p125A) is a mammalian-specific ER exit site (ERES) protein that physically bridges the COPII inner (Sec23/24) and outer (Sec13/31) coat subcomplexes while also binding PI4P on ERGIC/cis-Golgi acceptor membranes, thereby stabilizing donor-acceptor membrane contacts to facilitate COPII outer coat assembly and tunnel-based ER-to-Golgi traffic of large cargoes such as fibrillar collagens; it additionally recruits VPS13B/COH1 to the ERES-Golgi interface, acts as a 14-3-3γ network component required for cholesterol trafficking and steroidogenesis in Leydig cells, and is essential in vivo for acrosome biogenesis during spermiogenesis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SEC23IP (p125A) is a mammalian ER exit site (ERES) protein that organizes the early secretory pathway and facilitates COPII-mediated ER-to-Golgi traffic [#0, #2]. It was identified through its N-terminal proline-rich region, which binds the COPII inner coat subunit Sec23, with its central and C-terminal regions sharing homology with phosphatidic acid-preferring phospholipase A1 [#0]. SEC23IP localizes principally to ERES via its specific N-terminal region, and its depletion disrupts ERES organization and cis-Golgi structure [#2]. Mechanistically, SEC23IP bridges the COPII inner and outer coats: a distinct domain (residues 260–600) binds the C-terminal helical region of Sec31A, and most cytosolic SEC23IP exists in a preassembled ternary complex with Sec13/Sec31A [#4]. By simultaneously binding Sec23, Sec31, and PI4P on ERGIC/cis-Golgi acceptor membranes, it stabilizes donor-acceptor membrane apposition to promote COPII outer coat assembly and traffic of large cargoes such as fibrillar collagens [#8]. SEC23IP additionally functions as an adaptor that recruits VPS13B/COH1 to the ERES-Golgi interface, an interaction disrupted by Cohen syndrome-associated VPS13B mutations and required for tubular ERGIC carrier formation and procollagen export [#7]. In vivo, Sec23ip is essential for acrosome biogenesis during spermiogenesis [#5], and it acts within the 14-3-3γ network to support cholesterol trafficking and steroidogenesis in Leydig cells [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established SEC23IP as a Sec23-interacting protein of the early secretory pathway, defining the binding domain and a candidate enzymatic domain that placed it at the ER-Golgi interface.\",\n      \"evidence\": \"GST-fusion pulldown, yeast two-hybrid, and overexpression organelle morphology in mammalian cells\",\n      \"pmids\": [\"10400679\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Did not localize endogenous protein or test loss-of-function\",\n        \"Phospholipase A1 homology not demonstrated to be catalytically active in p125 itself\",\n        \"Mechanism linking overexpression to ERGIC/Golgi disorganization unresolved\"\n      ]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Mapped the Sec23-binding determinant to residues 135–259 and showed correct ERES/Golgi localization requires a larger region, while co-localization with p115 and GM130 connected SEC23IP to vesicle tethering machinery.\",\n      \"evidence\": \"Deletion mutant series and immunofluorescence co-localization in cultured cells\",\n      \"pmids\": [\"11112430\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Co-localization does not establish direct interaction with tethering factors\",\n        \"Functional consequence of the localization determinant not tested by loss-of-function\"\n      ]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Showed the phospholipase A1 homology domain of the p125 family is enzymatically active toward phosphatidic acid, using the paralog KIAA0725p which lacks the Sec23-binding region.\",\n      \"evidence\": \"In vitro binding and enzymatic activity assays on the paralog, overexpression morphology\",\n      \"pmids\": [\"11788596\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"p125/SEC23IP itself was not directly assayed for lipase activity\",\n        \"Physiological substrate and relevance of the lipase domain in vivo unknown\"\n      ]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Localized SEC23IP specifically to ERES and demonstrated its requirement for ERES and cis-Golgi organization, distinguishing its structural role from bulk ER export.\",\n      \"evidence\": \"Immunofluorescence, electron microscopy, domain-swap chimeras, and RNAi with organelle morphology readouts\",\n      \"pmids\": [\"15623529\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Did not identify the molecular partners mediating ERES organization\",\n        \"Why ER export was unaffected despite ERES disruption was not resolved\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Revealed SEC23IP as a bridge between COPII inner and outer coats by mapping a separate Sec31A-binding domain and showing it forms a preassembled cytosolic ternary complex with Sec13/Sec31A.\",\n      \"evidence\": \"Co-immunoprecipitation, gel filtration, immunodepletion, and siRNA with ER-export and Golgi morphology assays\",\n      \"pmids\": [\"20679433\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Stoichiometry and structure of the ternary complex not resolved\",\n        \"How the preassembled complex engages nascent COPII buds at ERES unclear\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined a non-redundant in vivo role for Sec23ip in acrosome biogenesis, linking its secretory-pathway function to male fertility.\",\n      \"evidence\": \"Sec23ip knockout mouse with sperm morphology analysis and expression staging\",\n      \"pmids\": [\"21640725\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular basis of the acrosome defect (which cargo/trafficking step) not identified\",\n        \"Whether the phenotype reflects ERES/COPII function specifically was not tested\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected Sec23ip to lipid trafficking by placing it in the 14-3-3γ network and showing its loss impairs cholesterol mobilization and steroidogenesis in Leydig cells.\",\n      \"evidence\": \"LC-MS interactome, siRNA knockdown, steroidogenesis and cholesterol-trafficking assays in MA-10 cells\",\n      \"pmids\": [\"31875919\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct physical interaction with 14-3-3γ not validated reciprocally\",\n        \"Mechanism linking ERES function to cytoplasm-to-mitochondria cholesterol transport unclear\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified SEC23IP as the ERES adaptor that recruits VPS13B/COH1 via its VAB domain, mechanistically linking the interaction to tubular ERGIC carrier formation, procollagen export, and Cohen syndrome.\",\n      \"evidence\": \"Co-IP, co-localization, knockout cell lines, procollagen trafficking, and disease-mutant binding assays\",\n      \"pmids\": [\"39352497\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether VPS13B-mediated lipid transfer is the functional output at ERES not directly shown\",\n        \"Relationship between SEC23IP-VPS13B recruitment and COPII coat assembly not integrated\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Reconstituted SEC23IP's coordinating mechanism, showing it simultaneously binds PI4P, Sec31, and Sec23 to stabilize donor-acceptor membrane contacts and drive COPII outer coat assembly for large cargo such as fibrillar collagen.\",\n      \"evidence\": \"Cell-free reconstitution, domain-swap chimeras, knockout cells, and secretome/transcriptome analysis (preprint)\",\n      \"pmids\": [\"40463098\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Not yet peer-reviewed\",\n        \"Structural basis for simultaneous tripartite binding not resolved\",\n        \"How tunnel/carrier geometry accommodates large cargo not established\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved whether SEC23IP's phospholipase A1 homology domain is catalytically active in vivo and how this enzymatic potential integrates with its structural coat-bridging and PI4P-sensing roles.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No direct demonstration of SEC23IP lipase activity\",\n        \"No structure of SEC23IP in complex with COPII coat or membrane\",\n        \"Integration of lipid-modifying, adaptor, and coat-bridging functions unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 7, 8]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 2, 8]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 2, 4, 8]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [7, 8]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [7, 8]}\n    ],\n    \"complexes\": [\n      \"COPII coat\",\n      \"p125A-Sec13-Sec31A ternary complex\"\n    ],\n    \"partners\": [\n      \"SEC23A\",\n      \"SEC31A\",\n      \"SEC13\",\n      \"VPS13B\",\n      \"YWHAG\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}