{"gene":"SNX2","run_date":"2026-06-10T07:46:37","timeline":{"discoveries":[{"year":2006,"finding":"The mammalian retromer complex assembles as two autonomously assembling subcomplexes: a Vps26-Vps29-Vps35 obligate heterotrimer and a SNX1/SNX2 alternative heterodimer or homodimer. Association of Vps26-Vps29-Vps35 with endosomes requires the presence of either SNX1 or SNX2, whereas SNX1/2 can be recruited to endosomes independently of Vps26-Vps29-Vps35. Either SNX1 or SNX2 is essential for retrieval of the cation-independent mannose 6-phosphate receptor (CI-MPR) to the TGN.","method":"Biochemical fractionation, co-immunoprecipitation, siRNA knockdown, and trafficking assays in HeLa cells","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, siRNA knockdown with defined cargo trafficking readout, multiple orthogonal methods in a rigorous single study","pmids":["17101778"],"is_preprint":false},{"year":2007,"finding":"SNX1 and SNX2 are each required for efficient retrograde transport of Shiga toxin from early endosomes to the trans-Golgi network; combined depletion of both SNX1 and SNX2 by siRNA inhibits Shiga toxin transport to the Golgi by ~80%, and individual depletion of either causes ≥40% inhibition, indicating partial redundancy.","method":"siRNA knockdown of SNX1 and/or SNX2 in Vero cells followed by Shiga toxin trafficking assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with defined cargo trafficking readout, single lab, single method","pmids":["17498660"],"is_preprint":false},{"year":2001,"finding":"SNX2 was identified as a protein interaction partner of FBP17 (formin-binding protein 17) by yeast two-hybrid screening of a human kidney library, providing a link between the EGF receptor pathway and FBP17.","method":"Yeast two-hybrid screen","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single yeast two-hybrid result, no in-cell or in vitro validation reported","pmids":["11438682"],"is_preprint":false},{"year":2013,"finding":"SNX2-ABL1 fusion protein (lacking SH3 and SH2 domains) confers IL-3-independent proliferation on Ba/F3 cells, demonstrating constitutive ABL1 kinase activity. SNX2-ABL1-expressing cells showed markedly reduced sensitivity to imatinib and dasatinib compared to BCR-ABL1-expressing cells.","method":"Retroviral expression of SNX2-ABL1 in murine Ba/F3 cells, IL-3 independence assay, TKI sensitivity assays","journal":"Leukemia research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional reconstitution in Ba/F3 cells with IL-3 independence and pharmacological readouts, single lab","pmids":["24367893"],"is_preprint":false},{"year":2022,"finding":"During nutritional stress (starvation), SNX2 regulates endosome-ER contact sites through interaction with VAPB, an ER protein. SNX1 and SNX2 cooperation induces tubulation of early endosomes toward VAPB-positive ER subdomains involved in autophagosome biogenesis.","method":"Live-cell imaging, siRNA knockdown, co-localization assays in mammalian cells under starvation conditions","journal":"Life science alliance","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — localization and knockdown data with functional autophagy readout, single lab, limited biochemical validation described in abstract","pmids":["36585258"],"is_preprint":false},{"year":2024,"finding":"SNX2, as part of the ESCPE-1 complex (SNX2/SNX6), deforms membranes enriched with Folch I lipids and CI-MPR cargo motifs in a fully reconstituted biochemical system. Notably, ESCPE-1 does not recruit Retromer to membranes on its own; rather, VARP is required to reconstitute the proposed endosomal supercomplex containing SNX27, ESCPE-1, and Retromer on PI(3)P-enriched membranes.","method":"In vitro membrane reconstitution with purified mammalian proteins, liposome tubulation assay, AlphaFold2 Multimer modeling","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — biochemical reconstitution with purified proteins, but preprint with no peer review and single study","pmids":["bio_10.1101_2024.07.11.603126"],"is_preprint":true}],"current_model":"SNX2 is a phosphoinositide (PI3P)-binding SNX-BAR protein that functions as part of the retromer complex on endosomal membranes: it forms alternative heterodimers or homodimers with SNX1, recruits the Vps26-Vps29-Vps35 subcomplex to endosomes, and is essential (redundantly with SNX1) for retrograde trafficking of CI-MPR and Shiga toxin from endosomes to the TGN; additionally, SNX2 participates in endosome-ER contact site formation via VAPB interaction during starvation to support autophagosome biogenesis, and as part of the ESCPE-1 (SNX2/SNX6) complex it can deform membranes containing physiological cargo motifs in a reconstituted system."},"narrative":{"mechanistic_narrative":"SNX2 is a sorting nexin that organizes endosomal retrograde trafficking as a membrane-recruitment module of the mammalian retromer pathway [PMID:17101778]. It assembles into an alternative SNX1/SNX2 heterodimer (or homodimer) whose presence on endosomes is required to recruit the Vps26-Vps29-Vps35 heterotrimer, while SNX1/2 themselves localize to endosomes independently of that subcomplex; either SNX1 or SNX2 suffices to retrieve the cation-independent mannose 6-phosphate receptor to the trans-Golgi network [PMID:17101778]. SNX1 and SNX2 act with partial redundancy in retrograde transport, as combined depletion blocks Shiga toxin delivery to the Golgi by ~80% whereas single depletion gives ≥40% inhibition [PMID:17498660]. Beyond retrieval, SNX2 cooperates with SNX1 to tubulate early endosomes toward VAPB-positive ER subdomains, building endosome-ER contact sites that support autophagosome biogenesis during starvation [PMID:36585258]. As part of the ESCPE-1 (SNX2/SNX6) complex, SNX2 deforms cargo-motif- and lipid-enriched membranes in a reconstituted system, with VARP required to assemble a larger endosomal supercomplex linking SNX27, ESCPE-1, and Retromer [PMID:bio_10.1101_2024.07.11.603126].","teleology":[{"year":2001,"claim":"Before its endosomal role was defined, an unbiased interaction screen placed SNX2 in a protein network, linking it to FBP17 and the EGF receptor pathway.","evidence":"Yeast two-hybrid screen of a human kidney library","pmids":["11438682"],"confidence":"Low","gaps":["Single yeast two-hybrid hit with no in-cell or in vitro validation","Functional consequence of the FBP17 interaction not established","No link drawn to retromer function"]},{"year":2006,"claim":"Established the architectural logic of mammalian retromer by showing SNX1/SNX2 form an autonomous membrane-recruitment dimer required to bring the Vps26-Vps29-Vps35 trimer to endosomes for CI-MPR retrieval.","evidence":"Biochemical fractionation, reciprocal Co-IP, siRNA knockdown and CI-MPR trafficking assays in HeLa cells","pmids":["17101778"],"confidence":"High","gaps":["Did not resolve whether SNX1 and SNX2 have distinct cargo preferences","Lipid/PI3P-binding determinants of recruitment not dissected here","Structural basis of SNX1/2 dimer-trimer coupling not shown"]},{"year":2007,"claim":"Extended SNX2 function to a defined physiological/toxin cargo and quantified its redundancy with SNX1 in retrograde transport.","evidence":"Single and combined siRNA knockdown of SNX1/SNX2 with Shiga toxin trafficking assay in Vero cells","pmids":["17498660"],"confidence":"Medium","gaps":["Single lab, single method","Does not distinguish direct cargo engagement from general retromer disruption","Residual ~20% transport after double knockdown unexplained"]},{"year":2013,"claim":"Showed that an SNX2-ABL1 gene fusion creates a constitutively active kinase, framing SNX2 as a fusion partner in a leukemogenic oncoprotein with altered TKI sensitivity.","evidence":"Retroviral expression of SNX2-ABL1 in Ba/F3 cells, IL-3 independence and imatinib/dasatinib sensitivity assays","pmids":["24367893"],"confidence":"Medium","gaps":["Contribution of the SNX2 portion to localization or signaling not dissected","Single lab, model cell line only","No patient-level functional validation described"]},{"year":2022,"claim":"Revealed a non-canonical SNX2 role beyond retrograde sorting: nucleating endosome-ER contact sites that support autophagy under nutrient stress.","evidence":"Live-cell imaging, siRNA knockdown and co-localization in starved mammalian cells; VAPB interaction","pmids":["36585258"],"confidence":"Medium","gaps":["Limited biochemical validation of the SNX2-VAPB interaction","Direct vs indirect binding to VAPB not resolved","Mechanistic link between tubulation and autophagosome formation incomplete"]},{"year":2024,"claim":"Reconstituted SNX2 (in ESCPE-1) membrane-deforming activity with purified proteins and showed VARP, not ESCPE-1 alone, couples ESCPE-1 to Retromer in a proposed endosomal supercomplex.","evidence":"In vitro liposome tubulation with purified mammalian proteins and AlphaFold2-Multimer modeling (preprint)","pmids":["bio_10.1101_2024.07.11.603126"],"confidence":"Medium","gaps":["Preprint, not peer reviewed; single study","Supercomplex existence in cells not demonstrated","Stoichiometry and regulation of VARP-mediated assembly unresolved"]},{"year":null,"claim":"How SNX2 cargo selectivity is partitioned from SNX1, and how its retrograde, contact-site, and supercomplex functions are coordinated in cells, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No cargo specificity map distinguishing SNX2 from SNX1","In-cell evidence for the SNX27/ESCPE-1/Retromer supercomplex lacking","Regulation switching SNX2 between retrieval and ER-contact roles unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[5]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0,1,4]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[4]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[4]}],"complexes":["Retromer (SNX1/SNX2-Vps26-Vps29-Vps35)","ESCPE-1 (SNX2/SNX6)"],"partners":["SNX1","SNX6","VPS35","VPS26","VPS29","VAPB","VARP","FBP17"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O60749","full_name":"Sorting nexin-2","aliases":["Transformation-related gene 9 protein","TRG-9"],"length_aa":519,"mass_kda":58.5,"function":"Involved in several stages of intracellular trafficking. Interacts with membranes containing phosphatidylinositol 3-phosphate (PtdIns(3P)) or phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2) (PubMed:16179610). Acts in part as component of the retromer membrane-deforming SNX-BAR subcomplex (PubMed:17101778). The SNX-BAR retromer mediates retrograde transport of cargo proteins from endosomes to the trans-Golgi network (TGN) and is involved in endosome-to-plasma membrane transport for cargo protein recycling. The SNX-BAR subcomplex functions to deform the donor membrane into a tubular profile called endosome-to-TGN transport carrier (ETC) (Probable). Can sense membrane curvature and has in vitro vesicle-to-membrane remodeling activity (PubMed:23085988). Required for retrograde endosome-to-TGN transport of TGN38 (PubMed:20138391). Promotes KALRN- and RHOG-dependent but retromer-independent membrane remodeling such as lamellipodium formation; the function is dependent on GEF activity of KALRN (PubMed:20604901)","subcellular_location":"Early endosome membrane; Cell projection, lamellipodium","url":"https://www.uniprot.org/uniprotkb/O60749/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SNX2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000205302","cell_line_id":"CID000679","localizations":[{"compartment":"vesicles","grade":3},{"compartment":"cytoplasmic","grade":1}],"interactors":[{"gene":"SNX1","stoichiometry":10.0},{"gene":"SNX5","stoichiometry":10.0},{"gene":"SNX6","stoichiometry":10.0},{"gene":"TPP2","stoichiometry":4.0},{"gene":"SAR1B","stoichiometry":0.2},{"gene":"IKBIP","stoichiometry":0.2},{"gene":"DNAJB11","stoichiometry":0.2},{"gene":"SDF2L1","stoichiometry":0.2},{"gene":"KIAA0368;ECM29","stoichiometry":0.2},{"gene":"SNX4","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000679","total_profiled":1310},"omim":[{"mim_id":"620961","title":"SORTING NEXIN 25; SNX25","url":"https://www.omim.org/entry/620961"},{"mim_id":"615740","title":"TBC1 DOMAIN FAMILY, MEMBER 5; TBC1D5","url":"https://www.omim.org/entry/615740"},{"mim_id":"614905","title":"SORTING NEXIN 8; SNX8","url":"https://www.omim.org/entry/614905"},{"mim_id":"606932","title":"VPS29 RETROMER COMPLEX COMPONENT; VPS29","url":"https://www.omim.org/entry/606932"},{"mim_id":"606191","title":"FORMIN-BINDING PROTEIN 1; FNBP1","url":"https://www.omim.org/entry/606191"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Endosomes","reliability":"Enhanced"},{"location":"Lysosomes","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SNX2"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"O60749","domains":[{"cath_id":"3.30.1520.10","chopping":"138-269","consensus_level":"medium","plddt":85.6159,"start":138,"end":269},{"cath_id":"1.20.1270.60","chopping":"289-519","consensus_level":"medium","plddt":93.0039,"start":289,"end":519}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O60749","model_url":"https://alphafold.ebi.ac.uk/files/AF-O60749-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O60749-F1-predicted_aligned_error_v6.png","plddt_mean":75.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SNX2","jax_strain_url":"https://www.jax.org/strain/search?query=SNX2"},"sequence":{"accession":"O60749","fasta_url":"https://rest.uniprot.org/uniprotkb/O60749.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O60749/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O60749"}},"corpus_meta":[{"pmid":"17101778","id":"PMC_17101778","title":"Interchangeable but essential functions of SNX1 and SNX2 in the association of retromer with endosomes and the trafficking of mannose 6-phosphate receptors.","date":"2006","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17101778","citation_count":197,"is_preprint":false},{"pmid":"11438682","id":"PMC_11438682","title":"The human formin-binding protein 17 (FBP17) interacts with sorting nexin, SNX2, and is an MLL-fusion partner in acute myelogeneous leukemia.","date":"2001","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/11438682","citation_count":71,"is_preprint":false},{"pmid":"17498660","id":"PMC_17498660","title":"SNX1 and SNX2 mediate retrograde transport of Shiga toxin.","date":"2007","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/17498660","citation_count":50,"is_preprint":false},{"pmid":"21391972","id":"PMC_21391972","title":"Identification of FOXP1 and SNX2 as novel ABL1 fusion partners in acute lymphoblastic leukaemia.","date":"2011","source":"British journal of haematology","url":"https://pubmed.ncbi.nlm.nih.gov/21391972","citation_count":36,"is_preprint":false},{"pmid":"36535076","id":"PMC_36535076","title":"Cancer-associated fibroblast-derived exosome miR-181b-3p promotes the occurrence and development of colorectal cancer by regulating SNX2 expression.","date":"2022","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/36535076","citation_count":30,"is_preprint":false},{"pmid":"24215620","id":"PMC_24215620","title":"Poor responses to tyrosine kinase inhibitors in a child with precursor B-cell acute lymphoblastic leukemia with SNX2-ABL1 chimeric transcript.","date":"2013","source":"European journal of haematology","url":"https://pubmed.ncbi.nlm.nih.gov/24215620","citation_count":23,"is_preprint":false},{"pmid":"24367893","id":"PMC_24367893","title":"Sensitivity of SNX2-ABL1 toward tyrosine kinase inhibitors distinct from that of BCR-ABL1.","date":"2013","source":"Leukemia research","url":"https://pubmed.ncbi.nlm.nih.gov/24367893","citation_count":17,"is_preprint":false},{"pmid":"36585258","id":"PMC_36585258","title":"A SNX1-SNX2-VAPB partnership regulates endosomal membrane rewiring in response to nutritional stress.","date":"2022","source":"Life science alliance","url":"https://pubmed.ncbi.nlm.nih.gov/36585258","citation_count":14,"is_preprint":false},{"pmid":"38033809","id":"PMC_38033809","title":"Canonical and Non-Canonical Roles of SNX1 and SNX2 in Endosomal Membrane Dynamics.","date":"2023","source":"Contact (Thousand Oaks (Ventura County, Calif.))","url":"https://pubmed.ncbi.nlm.nih.gov/38033809","citation_count":8,"is_preprint":false},{"pmid":"23531855","id":"PMC_23531855","title":"Sorting Nexin 2 (SNX2): a potential marker of active thyrocytes in normal and hyperfunctioning thyroid disorders.","date":"2014","source":"Applied immunohistochemistry & molecular morphology : AIMM","url":"https://pubmed.ncbi.nlm.nih.gov/23531855","citation_count":3,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.23.677992","title":"Identification of Novel Fusion Genes in Pediatric B-ALL patients Using Whole Transcriptome Sequencing","date":"2025-09-25","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.23.677992","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.07.11.603126","title":"VARP binds SNX27 to promote endosomal supercomplex formation on membranes","date":"2024-07-11","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.11.603126","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7629,"output_tokens":1674,"usd":0.023998,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8405,"output_tokens":2625,"usd":0.053825,"stage2_stop_reason":"end_turn"},"total_usd":0.077823,"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\": 2006,\n      \"finding\": \"The mammalian retromer complex assembles as two autonomously assembling subcomplexes: a Vps26-Vps29-Vps35 obligate heterotrimer and a SNX1/SNX2 alternative heterodimer or homodimer. Association of Vps26-Vps29-Vps35 with endosomes requires the presence of either SNX1 or SNX2, whereas SNX1/2 can be recruited to endosomes independently of Vps26-Vps29-Vps35. Either SNX1 or SNX2 is essential for retrieval of the cation-independent mannose 6-phosphate receptor (CI-MPR) to the TGN.\",\n      \"method\": \"Biochemical fractionation, co-immunoprecipitation, siRNA knockdown, and trafficking assays in HeLa cells\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, siRNA knockdown with defined cargo trafficking readout, multiple orthogonal methods in a rigorous single study\",\n      \"pmids\": [\"17101778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"SNX1 and SNX2 are each required for efficient retrograde transport of Shiga toxin from early endosomes to the trans-Golgi network; combined depletion of both SNX1 and SNX2 by siRNA inhibits Shiga toxin transport to the Golgi by ~80%, and individual depletion of either causes ≥40% inhibition, indicating partial redundancy.\",\n      \"method\": \"siRNA knockdown of SNX1 and/or SNX2 in Vero cells followed by Shiga toxin trafficking assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with defined cargo trafficking readout, single lab, single method\",\n      \"pmids\": [\"17498660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"SNX2 was identified as a protein interaction partner of FBP17 (formin-binding protein 17) by yeast two-hybrid screening of a human kidney library, providing a link between the EGF receptor pathway and FBP17.\",\n      \"method\": \"Yeast two-hybrid screen\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single yeast two-hybrid result, no in-cell or in vitro validation reported\",\n      \"pmids\": [\"11438682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SNX2-ABL1 fusion protein (lacking SH3 and SH2 domains) confers IL-3-independent proliferation on Ba/F3 cells, demonstrating constitutive ABL1 kinase activity. SNX2-ABL1-expressing cells showed markedly reduced sensitivity to imatinib and dasatinib compared to BCR-ABL1-expressing cells.\",\n      \"method\": \"Retroviral expression of SNX2-ABL1 in murine Ba/F3 cells, IL-3 independence assay, TKI sensitivity assays\",\n      \"journal\": \"Leukemia research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional reconstitution in Ba/F3 cells with IL-3 independence and pharmacological readouts, single lab\",\n      \"pmids\": [\"24367893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"During nutritional stress (starvation), SNX2 regulates endosome-ER contact sites through interaction with VAPB, an ER protein. SNX1 and SNX2 cooperation induces tubulation of early endosomes toward VAPB-positive ER subdomains involved in autophagosome biogenesis.\",\n      \"method\": \"Live-cell imaging, siRNA knockdown, co-localization assays in mammalian cells under starvation conditions\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — localization and knockdown data with functional autophagy readout, single lab, limited biochemical validation described in abstract\",\n      \"pmids\": [\"36585258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SNX2, as part of the ESCPE-1 complex (SNX2/SNX6), deforms membranes enriched with Folch I lipids and CI-MPR cargo motifs in a fully reconstituted biochemical system. Notably, ESCPE-1 does not recruit Retromer to membranes on its own; rather, VARP is required to reconstitute the proposed endosomal supercomplex containing SNX27, ESCPE-1, and Retromer on PI(3)P-enriched membranes.\",\n      \"method\": \"In vitro membrane reconstitution with purified mammalian proteins, liposome tubulation assay, AlphaFold2 Multimer modeling\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — biochemical reconstitution with purified proteins, but preprint with no peer review and single study\",\n      \"pmids\": [\"bio_10.1101_2024.07.11.603126\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"SNX2 is a phosphoinositide (PI3P)-binding SNX-BAR protein that functions as part of the retromer complex on endosomal membranes: it forms alternative heterodimers or homodimers with SNX1, recruits the Vps26-Vps29-Vps35 subcomplex to endosomes, and is essential (redundantly with SNX1) for retrograde trafficking of CI-MPR and Shiga toxin from endosomes to the TGN; additionally, SNX2 participates in endosome-ER contact site formation via VAPB interaction during starvation to support autophagosome biogenesis, and as part of the ESCPE-1 (SNX2/SNX6) complex it can deform membranes containing physiological cargo motifs in a reconstituted system.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SNX2 is a sorting nexin that organizes endosomal retrograde trafficking as a membrane-recruitment module of the mammalian retromer pathway [#0]. It assembles into an alternative SNX1/SNX2 heterodimer (or homodimer) whose presence on endosomes is required to recruit the Vps26-Vps29-Vps35 heterotrimer, while SNX1/2 themselves localize to endosomes independently of that subcomplex; either SNX1 or SNX2 suffices to retrieve the cation-independent mannose 6-phosphate receptor to the trans-Golgi network [#0]. SNX1 and SNX2 act with partial redundancy in retrograde transport, as combined depletion blocks Shiga toxin delivery to the Golgi by ~80% whereas single depletion gives ≥40% inhibition [#1]. Beyond retrieval, SNX2 cooperates with SNX1 to tubulate early endosomes toward VAPB-positive ER subdomains, building endosome-ER contact sites that support autophagosome biogenesis during starvation [#4]. As part of the ESCPE-1 (SNX2/SNX6) complex, SNX2 deforms cargo-motif- and lipid-enriched membranes in a reconstituted system, with VARP required to assemble a larger endosomal supercomplex linking SNX27, ESCPE-1, and Retromer [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Before its endosomal role was defined, an unbiased interaction screen placed SNX2 in a protein network, linking it to FBP17 and the EGF receptor pathway.\",\n      \"evidence\": \"Yeast two-hybrid screen of a human kidney library\",\n      \"pmids\": [\"11438682\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single yeast two-hybrid hit with no in-cell or in vitro validation\", \"Functional consequence of the FBP17 interaction not established\", \"No link drawn to retromer function\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Established the architectural logic of mammalian retromer by showing SNX1/SNX2 form an autonomous membrane-recruitment dimer required to bring the Vps26-Vps29-Vps35 trimer to endosomes for CI-MPR retrieval.\",\n      \"evidence\": \"Biochemical fractionation, reciprocal Co-IP, siRNA knockdown and CI-MPR trafficking assays in HeLa cells\",\n      \"pmids\": [\"17101778\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve whether SNX1 and SNX2 have distinct cargo preferences\", \"Lipid/PI3P-binding determinants of recruitment not dissected here\", \"Structural basis of SNX1/2 dimer-trimer coupling not shown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Extended SNX2 function to a defined physiological/toxin cargo and quantified its redundancy with SNX1 in retrograde transport.\",\n      \"evidence\": \"Single and combined siRNA knockdown of SNX1/SNX2 with Shiga toxin trafficking assay in Vero cells\",\n      \"pmids\": [\"17498660\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, single method\", \"Does not distinguish direct cargo engagement from general retromer disruption\", \"Residual ~20% transport after double knockdown unexplained\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed that an SNX2-ABL1 gene fusion creates a constitutively active kinase, framing SNX2 as a fusion partner in a leukemogenic oncoprotein with altered TKI sensitivity.\",\n      \"evidence\": \"Retroviral expression of SNX2-ABL1 in Ba/F3 cells, IL-3 independence and imatinib/dasatinib sensitivity assays\",\n      \"pmids\": [\"24367893\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Contribution of the SNX2 portion to localization or signaling not dissected\", \"Single lab, model cell line only\", \"No patient-level functional validation described\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed a non-canonical SNX2 role beyond retrograde sorting: nucleating endosome-ER contact sites that support autophagy under nutrient stress.\",\n      \"evidence\": \"Live-cell imaging, siRNA knockdown and co-localization in starved mammalian cells; VAPB interaction\",\n      \"pmids\": [\"36585258\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Limited biochemical validation of the SNX2-VAPB interaction\", \"Direct vs indirect binding to VAPB not resolved\", \"Mechanistic link between tubulation and autophagosome formation incomplete\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Reconstituted SNX2 (in ESCPE-1) membrane-deforming activity with purified proteins and showed VARP, not ESCPE-1 alone, couples ESCPE-1 to Retromer in a proposed endosomal supercomplex.\",\n      \"evidence\": \"In vitro liposome tubulation with purified mammalian proteins and AlphaFold2-Multimer modeling (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.07.11.603126\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not peer reviewed; single study\", \"Supercomplex existence in cells not demonstrated\", \"Stoichiometry and regulation of VARP-mediated assembly unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SNX2 cargo selectivity is partitioned from SNX1, and how its retrograde, contact-site, and supercomplex functions are coordinated in cells, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No cargo specificity map distinguishing SNX2 from SNX1\", \"In-cell evidence for the SNX27/ESCPE-1/Retromer supercomplex lacking\", \"Regulation switching SNX2 between retrieval and ER-contact roles unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [\"Retromer (SNX1/SNX2-Vps26-Vps29-Vps35)\", \"ESCPE-1 (SNX2/SNX6)\"],\n    \"partners\": [\"SNX1\", \"SNX6\", \"VPS35\", \"VPS26\", \"VPS29\", \"VAPB\", \"VARP\", \"FBP17\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}