{"gene":"SH3GL3","run_date":"2026-04-28T20:42:07","timeline":{"discoveries":[{"year":1997,"finding":"SH3GL3 (SH3p13) binds to both synaptojanin and dynamin I via its SH3 domain, which is closely related to the SH3 domain of Grb2; pools of synaptojanin and dynamin I were co-precipitated from brain extracts with anti-SH3p4/8/13 antibodies, and the proteins are concentrated in nerve terminals, implicating SH3GL3 in synaptic vesicle recycling.","method":"Yeast two-hybrid screen, co-immunoprecipitation from rat brain extracts, immunofluorescence localization","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP from native brain tissue plus localization, foundational paper with 334 citations replicated across family members","pmids":["9238017"],"is_preprint":false},{"year":1998,"finding":"SH3GL3 selectively interacts with huntingtin exon 1 protein (HDex1p) containing a polyglutamine repeat in the pathological range and promotes formation of insoluble polyglutamine-containing aggregates in vivo; the C-terminal SH3 domain of SH3GL3 and the proline-rich region of HDex1p are essential for this interaction; full-length huntingtin was co-immunoprecipitated from HD human brain extract with anti-SH3GL3 antibody.","method":"Co-immunoprecipitation, immunofluorescence co-localization in transfected COS cells, domain-deletion mutagenesis, filter retardation aggregation assay","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP from human brain extract plus mutagenesis of essential domains, 177 citations","pmids":["9809064"],"is_preprint":false},{"year":2009,"finding":"SH3GL3 (SH3P13) BAR domain interacts with DYDC1 (identified by yeast two-hybrid using BAR domain as bait); SH3P13 assists in regulating clathrin-coated vesicle traffic crucial for acrosome biogenesis during spermatogenesis in the testis.","method":"Yeast two-hybrid with BAR domain as bait, co-expression/localization analysis, RNAi knockdown in germ cells, germ cell transplantation","journal":"European journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 — yeast two-hybrid plus in vivo RNAi phenotype, single lab","pmids":["19545932"],"is_preprint":false},{"year":2012,"finding":"Knockdown of SH3GL3 inhibits glioma cell invasion in vitro, establishing a functional role for SH3GL3 in glioma cell invasiveness.","method":"shRNA knockdown, in vitro invasion assay (Matrigel transwell)","journal":"Neuropathology and applied neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with defined cellular phenotype, single lab","pmids":["21722156"],"is_preprint":false},{"year":2016,"finding":"SH3GL3 promotes myeloma cell migration/invasion, stemness, and chemo-resistance through the FAK/PI3K signaling pathway; overexpression of SH3GL3 increased p-FAK and p-PI3K, and pharmacological inhibition of FAK or PI3K attenuated SH3GL3-mediated migration/invasion.","method":"shRNA knockdown, cDNA overexpression, pharmacological inhibition (FAK inhibitor 14, LY294002), migration/invasion assays, Western blot","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 — gain- and loss-of-function with pathway inhibitor rescue, single lab","pmids":["27683032"],"is_preprint":false},{"year":2020,"finding":"SH3GL3 inhibits lung cancer cell proliferation and migration, arrests the cell cycle at G0/G1, induces apoptosis, and suppresses cancer stem cell self-renewal in a manner dependent on its SH3 domain; it up-regulates p21 at the transcriptional level.","method":"Overexpression with SH3 domain deletion mutants, cell proliferation/migration assays, flow cytometry, qRT-PCR for p21","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2/3 — domain-dependent functional assays with transcriptional readout, single lab","pmids":["33168185"],"is_preprint":false},{"year":2021,"finding":"SH3GL3 physically interacts with STAT3 and inhibits STAT3 nuclear localization in glioblastoma cells; constitutively active STAT3 (STAT3-C) rescues the anti-proliferative and anti-stemness effects of SH3GL3 overexpression, placing SH3GL3 upstream of STAT3 nuclear translocation.","method":"Co-immunoprecipitation, immunofluorescence, overexpression + epistasis rescue with STAT3-C construct","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP plus genetic epistasis rescue, single lab","pmids":["33524871"],"is_preprint":false},{"year":2023,"finding":"MIR210HG lncRNA inhibits SH3GL3 transcription by recruiting DNMT1 to the SH3GL3 promoter region, leading to promoter methylation and reduced SH3GL3 expression in lung cancer cells; knockdown of MIR210HG or overexpression of SH3GL3 suppresses lung cancer cell proliferation, migration, and invasion.","method":"Chromatin immunoprecipitation (ChIP) showing DNMT1 binding to SH3GL3 promoter, RNA immunoprecipitation showing MIR210HG-DNMT1 interaction, methylation-specific PCR, shRNA knockdown, overexpression assays","journal":"The Kaohsiung journal of medical sciences","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and RIP with functional rescue, single lab","pmids":["37916731"],"is_preprint":false}],"current_model":"SH3GL3 is a BAR/SH3 domain-containing endophilin-family protein concentrated in nerve terminals, where its SH3 domain directly binds the proline-rich tails of dynamin I and synaptojanin to facilitate synaptic vesicle recycling; the same SH3 domain mediates interaction with the polyglutamine-expanded huntingtin protein to promote aggregate formation, and in non-neuronal contexts SH3GL3 suppresses tumor cell invasion, proliferation, and stemness by interacting with and restraining STAT3 nuclear localization and by modulating FAK/PI3K signaling, while its expression is epigenetically silenced via DNMT1 recruitment to its promoter by the lncRNA MIR210HG."},"narrative":{"teleology":[{"year":1997,"claim":"Establishing SH3GL3 as a synaptic vesicle recycling component resolved the question of whether all three endophilin-family SH3 domains engage dynamin I and synaptojanin at nerve terminals.","evidence":"Yeast two-hybrid, co-immunoprecipitation from rat brain extracts, and immunofluorescence showing nerve-terminal enrichment","pmids":["9238017"],"confidence":"High","gaps":["No direct demonstration that SH3GL3 loss impairs synaptic vesicle endocytosis in neurons","Relative contribution of SH3GL3 versus SH3GL1/SH3GL2 at the synapse is undefined"]},{"year":1998,"claim":"Demonstrating that SH3GL3 selectively binds pathological-length polyglutamine huntingtin and promotes its aggregation identified a novel molecular partner in Huntington disease aggregate formation.","evidence":"Co-immunoprecipitation from HD human brain, domain-deletion mutagenesis, and filter retardation aggregation assay in COS cells","pmids":["9809064"],"confidence":"High","gaps":["Whether SH3GL3–huntingtin interaction contributes to neurodegeneration in vivo is untested","Stoichiometry and structural basis of SH3-domain/polyproline interaction with huntingtin are unresolved"]},{"year":2009,"claim":"Identifying DYDC1 as a BAR-domain interactor and linking SH3GL3 to clathrin-coated vesicle traffic during acrosome biogenesis extended its membrane-trafficking role beyond neurons.","evidence":"Yeast two-hybrid with BAR domain bait, RNAi knockdown in germ cells, and germ cell transplantation","pmids":["19545932"],"confidence":"Medium","gaps":["Interaction awaits validation by reciprocal co-immunoprecipitation from endogenous testis extracts","Whether BAR-domain–mediated membrane tubulation is required for acrosome formation is unknown"]},{"year":2012,"claim":"Showing that SH3GL3 knockdown inhibits glioma cell invasion provided the first evidence that SH3GL3 has tumor-suppressive activity, opening its characterization in cancer biology.","evidence":"shRNA knockdown with Matrigel transwell invasion assay in glioma cells","pmids":["21722156"],"confidence":"Medium","gaps":["Mechanism by which SH3GL3 restrains invasion was not identified","No in vivo tumor model used"]},{"year":2016,"claim":"Linking SH3GL3 overexpression to FAK/PI3K activation in myeloma identified a context where SH3GL3 paradoxically promotes migration and stemness, contrasting with its tumor-suppressive role in glioma.","evidence":"Gain- and loss-of-function in myeloma cells with FAK/PI3K pharmacological inhibitor rescue and Western blot","pmids":["27683032"],"confidence":"Medium","gaps":["Direct physical interaction between SH3GL3 and FAK or PI3K was not demonstrated","Context-dependent pro- versus anti-tumorigenic roles remain mechanistically unexplained"]},{"year":2020,"claim":"Demonstrating SH3-domain dependence for SH3GL3's anti-proliferative, pro-apoptotic, and p21-inducing activities in lung cancer established that its tumor-suppressive function requires the same domain used in endocytic partner binding.","evidence":"Overexpression of full-length versus SH3-deletion mutants in lung cancer cells with proliferation, flow cytometry, and qRT-PCR readouts","pmids":["33168185"],"confidence":"Medium","gaps":["The SH3-domain binding partner responsible for p21 upregulation is unidentified","Transcriptional mechanism linking SH3GL3 to p21 promoter activation is unknown"]},{"year":2021,"claim":"Identifying STAT3 as a direct SH3GL3-interacting protein whose nuclear translocation is blocked by SH3GL3 provided a mechanistic explanation for its tumor-suppressive effects in glioblastoma.","evidence":"Co-immunoprecipitation, immunofluorescence for STAT3 localization, and epistasis rescue with constitutively active STAT3-C in glioblastoma cells","pmids":["33524871"],"confidence":"Medium","gaps":["Domain on SH3GL3 that mediates STAT3 binding is not mapped","Whether STAT3 sequestration explains the lung cancer phenotype or p21 induction is untested"]},{"year":2023,"claim":"Revealing that the lncRNA MIR210HG recruits DNMT1 to methylate the SH3GL3 promoter explained how SH3GL3 expression is epigenetically silenced in lung cancer.","evidence":"ChIP for DNMT1 at SH3GL3 promoter, RNA immunoprecipitation for MIR210HG–DNMT1, methylation-specific PCR, and functional rescue in lung cancer cells","pmids":["37916731"],"confidence":"Medium","gaps":["Whether MIR210HG-mediated silencing operates in other cancer types is unknown","No in vivo demonstration that restoring SH3GL3 expression reverses tumor growth"]},{"year":null,"claim":"The structural basis for SH3GL3's context-dependent pro- versus anti-tumorigenic activities, the identity of the SH3-domain partner responsible for p21 transcriptional induction, and the in vivo physiological consequence of SH3GL3 loss in neurons remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No knockout or conditional deletion mouse model phenotype reported","No structural determination of SH3GL3 BAR or SH3 domains","Relationship between endocytic function and tumor-suppressive role is mechanistically unconnected"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,6]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[0,2]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,2]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,6]}],"complexes":[],"partners":["DNM1","SYNJ1","HTT","STAT3","DYDC1"],"other_free_text":[]},"mechanistic_narrative":"SH3GL3 is a BAR- and SH3-domain-containing endophilin-family protein that participates in membrane trafficking at nerve terminals and functions as a tumor suppressor in multiple cancer contexts. Its SH3 domain directly binds the proline-rich regions of dynamin I and synaptojanin, concentrating these endocytic effectors at synaptic terminals to facilitate synaptic vesicle recycling [PMID:9238017]; the same SH3 domain mediates interaction with polyglutamine-expanded huntingtin, promoting aggregate formation relevant to Huntington disease pathology [PMID:9809064]. In cancer cells, SH3GL3 suppresses proliferation, migration, stemness, and cell-cycle progression through SH3-domain-dependent mechanisms that include physical interaction with STAT3 to restrain its nuclear translocation [PMID:33524871, PMID:33168185] and modulation of FAK/PI3K signaling [PMID:27683032], while its expression is epigenetically silenced by DNMT1-mediated promoter methylation recruited by the lncRNA MIR210HG [PMID:37916731]."},"prefetch_data":{"uniprot":{"accession":"Q99963","full_name":"Endophilin-A3","aliases":["EEN-B2","Endophilin-3","SH3 domain protein 2C","SH3 domain-containing GRB2-like protein 3"],"length_aa":347,"mass_kda":39.3,"function":"Implicated in endocytosis. May recruit other proteins to membranes with high curvature (By similarity)","subcellular_location":"Cytoplasm; Early endosome membrane","url":"https://www.uniprot.org/uniprotkb/Q99963/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SH3GL3","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"SH3GL1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SH3GL3","total_profiled":1310},"omim":[{"mim_id":"615154","title":"DPY30 DOMAIN-CONTAINING PROTEIN 1; DYDC1","url":"https://www.omim.org/entry/615154"},{"mim_id":"613004","title":"HUNTINGTIN; HTT","url":"https://www.omim.org/entry/613004"},{"mim_id":"611540","title":"SH3-DOMAIN GRB2-LIKE (ENDOPHILIN)-INTERACTING PROTEIN 1; SGIP1","url":"https://www.omim.org/entry/611540"},{"mim_id":"604465","title":"SH3 DOMAIN, GRB2-LIKE, 2; SH3GL2","url":"https://www.omim.org/entry/604465"},{"mim_id":"603362","title":"SH3 DOMAIN, GRB2-LIKE, 3; SH3GL3","url":"https://www.omim.org/entry/603362"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Mitochondria","reliability":"Approved"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":56.9},{"tissue":"testis","ntpm":24.8}],"url":"https://www.proteinatlas.org/search/SH3GL3"},"hgnc":{"alias_symbol":["SH3D2C","SH3P13","CNSA3","EEN-B2","HsT19371"],"prev_symbol":[]},"alphafold":{"accession":"Q99963","domains":[{"cath_id":"1.20.1270.60","chopping":"9-75_84-250","consensus_level":"high","plddt":94.9541,"start":9,"end":250},{"cath_id":"2.30.30.40","chopping":"290-344","consensus_level":"high","plddt":91.6607,"start":290,"end":344}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99963","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q99963-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q99963-F1-predicted_aligned_error_v6.png","plddt_mean":88.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SH3GL3","jax_strain_url":"https://www.jax.org/strain/search?query=SH3GL3"},"sequence":{"accession":"Q99963","fasta_url":"https://rest.uniprot.org/uniprotkb/Q99963.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q99963/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99963"}},"corpus_meta":[{"pmid":"9238017","id":"PMC_9238017","title":"The SH3p4/Sh3p8/SH3p13 protein family: binding partners for synaptojanin and dynamin via a Grb2-like Src homology 3 domain.","date":"1997","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/9238017","citation_count":334,"is_preprint":false},{"pmid":"9809064","id":"PMC_9809064","title":"SH3GL3 associates with the Huntingtin exon 1 protein and promotes the formation of polygln-containing protein aggregates.","date":"1998","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/9809064","citation_count":177,"is_preprint":false},{"pmid":"21722156","id":"PMC_21722156","title":"Identification and functional validation of CDH11, PCSK6 and SH3GL3 as novel glioma invasion-associated candidate genes.","date":"2012","source":"Neuropathology and applied neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/21722156","citation_count":40,"is_preprint":false},{"pmid":"19545932","id":"PMC_19545932","title":"Interaction of SH3P13 and DYDC1 protein: a germ cell component that regulates acrosome biogenesis during spermiogenesis.","date":"2009","source":"European journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/19545932","citation_count":23,"is_preprint":false},{"pmid":"27683032","id":"PMC_27683032","title":"The role of SH3GL3 in myeloma cell migration/invasion, stemness and chemo-resistance.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27683032","citation_count":19,"is_preprint":false},{"pmid":"33168185","id":"PMC_33168185","title":"SH3GL3 functions as a potent tumor suppressor in lung cancer in a SH3 domain dependent manner.","date":"2020","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/33168185","citation_count":17,"is_preprint":false},{"pmid":"37916731","id":"PMC_37916731","title":"LncRNA MIR210HG promotes the proliferation, migration, and invasion of lung cancer cells by inhibiting the transcription of SH3GL3.","date":"2023","source":"The Kaohsiung journal of medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37916731","citation_count":10,"is_preprint":false},{"pmid":"9878254","id":"PMC_9878254","title":"Characterization of the mouse Src homology 3 domain gene Sh3d2c on Chr 7 demonstrates coexpression with huntingtin in the brain and identifies the processed pseudogene Sh3d2c-ps1 on Chr 2.","date":"1998","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/9878254","citation_count":7,"is_preprint":false},{"pmid":"33524871","id":"PMC_33524871","title":"SH3GL3 acts as a novel tumor suppressor in glioblastoma tumorigenesis by inhibiting STAT3 signaling.","date":"2021","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/33524871","citation_count":7,"is_preprint":false},{"pmid":"40120906","id":"PMC_40120906","title":"Molecular mechanism of SH3GL3 recombinant protein and attenuates the acute lung inflammation in Klebsiella pneumonia rats by mollugin treatment by regulating STAT3/ROS signaling pathway.","date":"2025","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/40120906","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6273,"output_tokens":2022,"usd":0.024574},"stage2":{"model":"claude-opus-4-6","input_tokens":5294,"output_tokens":2272,"usd":0.124905},"total_usd":0.149479,"stage1_batch_id":"msgbatch_011rkcQdVV1RaFq9XhcG6df6","stage2_batch_id":"msgbatch_01RzgrJafdF4EWHhj5mNi6dh","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"SH3GL3 (SH3p13) binds to both synaptojanin and dynamin I via its SH3 domain, which is closely related to the SH3 domain of Grb2; pools of synaptojanin and dynamin I were co-precipitated from brain extracts with anti-SH3p4/8/13 antibodies, and the proteins are concentrated in nerve terminals, implicating SH3GL3 in synaptic vesicle recycling.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation from rat brain extracts, immunofluorescence localization\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP from native brain tissue plus localization, foundational paper with 334 citations replicated across family members\",\n      \"pmids\": [\"9238017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"SH3GL3 selectively interacts with huntingtin exon 1 protein (HDex1p) containing a polyglutamine repeat in the pathological range and promotes formation of insoluble polyglutamine-containing aggregates in vivo; the C-terminal SH3 domain of SH3GL3 and the proline-rich region of HDex1p are essential for this interaction; full-length huntingtin was co-immunoprecipitated from HD human brain extract with anti-SH3GL3 antibody.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization in transfected COS cells, domain-deletion mutagenesis, filter retardation aggregation assay\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP from human brain extract plus mutagenesis of essential domains, 177 citations\",\n      \"pmids\": [\"9809064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SH3GL3 (SH3P13) BAR domain interacts with DYDC1 (identified by yeast two-hybrid using BAR domain as bait); SH3P13 assists in regulating clathrin-coated vesicle traffic crucial for acrosome biogenesis during spermatogenesis in the testis.\",\n      \"method\": \"Yeast two-hybrid with BAR domain as bait, co-expression/localization analysis, RNAi knockdown in germ cells, germ cell transplantation\",\n      \"journal\": \"European journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — yeast two-hybrid plus in vivo RNAi phenotype, single lab\",\n      \"pmids\": [\"19545932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Knockdown of SH3GL3 inhibits glioma cell invasion in vitro, establishing a functional role for SH3GL3 in glioma cell invasiveness.\",\n      \"method\": \"shRNA knockdown, in vitro invasion assay (Matrigel transwell)\",\n      \"journal\": \"Neuropathology and applied neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with defined cellular phenotype, single lab\",\n      \"pmids\": [\"21722156\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SH3GL3 promotes myeloma cell migration/invasion, stemness, and chemo-resistance through the FAK/PI3K signaling pathway; overexpression of SH3GL3 increased p-FAK and p-PI3K, and pharmacological inhibition of FAK or PI3K attenuated SH3GL3-mediated migration/invasion.\",\n      \"method\": \"shRNA knockdown, cDNA overexpression, pharmacological inhibition (FAK inhibitor 14, LY294002), migration/invasion assays, Western blot\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain- and loss-of-function with pathway inhibitor rescue, single lab\",\n      \"pmids\": [\"27683032\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SH3GL3 inhibits lung cancer cell proliferation and migration, arrests the cell cycle at G0/G1, induces apoptosis, and suppresses cancer stem cell self-renewal in a manner dependent on its SH3 domain; it up-regulates p21 at the transcriptional level.\",\n      \"method\": \"Overexpression with SH3 domain deletion mutants, cell proliferation/migration assays, flow cytometry, qRT-PCR for p21\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — domain-dependent functional assays with transcriptional readout, single lab\",\n      \"pmids\": [\"33168185\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SH3GL3 physically interacts with STAT3 and inhibits STAT3 nuclear localization in glioblastoma cells; constitutively active STAT3 (STAT3-C) rescues the anti-proliferative and anti-stemness effects of SH3GL3 overexpression, placing SH3GL3 upstream of STAT3 nuclear translocation.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, overexpression + epistasis rescue with STAT3-C construct\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus genetic epistasis rescue, single lab\",\n      \"pmids\": [\"33524871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MIR210HG lncRNA inhibits SH3GL3 transcription by recruiting DNMT1 to the SH3GL3 promoter region, leading to promoter methylation and reduced SH3GL3 expression in lung cancer cells; knockdown of MIR210HG or overexpression of SH3GL3 suppresses lung cancer cell proliferation, migration, and invasion.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) showing DNMT1 binding to SH3GL3 promoter, RNA immunoprecipitation showing MIR210HG-DNMT1 interaction, methylation-specific PCR, shRNA knockdown, overexpression assays\",\n      \"journal\": \"The Kaohsiung journal of medical sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and RIP with functional rescue, single lab\",\n      \"pmids\": [\"37916731\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SH3GL3 is a BAR/SH3 domain-containing endophilin-family protein concentrated in nerve terminals, where its SH3 domain directly binds the proline-rich tails of dynamin I and synaptojanin to facilitate synaptic vesicle recycling; the same SH3 domain mediates interaction with the polyglutamine-expanded huntingtin protein to promote aggregate formation, and in non-neuronal contexts SH3GL3 suppresses tumor cell invasion, proliferation, and stemness by interacting with and restraining STAT3 nuclear localization and by modulating FAK/PI3K signaling, while its expression is epigenetically silenced via DNMT1 recruitment to its promoter by the lncRNA MIR210HG.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SH3GL3 is a BAR- and SH3-domain-containing endophilin-family protein that participates in membrane trafficking at nerve terminals and functions as a tumor suppressor in multiple cancer contexts. Its SH3 domain directly binds the proline-rich regions of dynamin I and synaptojanin, concentrating these endocytic effectors at synaptic terminals to facilitate synaptic vesicle recycling [PMID:9238017]; the same SH3 domain mediates interaction with polyglutamine-expanded huntingtin, promoting aggregate formation relevant to Huntington disease pathology [PMID:9809064]. In cancer cells, SH3GL3 suppresses proliferation, migration, stemness, and cell-cycle progression through SH3-domain-dependent mechanisms that include physical interaction with STAT3 to restrain its nuclear translocation [PMID:33524871, PMID:33168185] and modulation of FAK/PI3K signaling [PMID:27683032], while its expression is epigenetically silenced by DNMT1-mediated promoter methylation recruited by the lncRNA MIR210HG [PMID:37916731].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Establishing SH3GL3 as a synaptic vesicle recycling component resolved the question of whether all three endophilin-family SH3 domains engage dynamin I and synaptojanin at nerve terminals.\",\n      \"evidence\": \"Yeast two-hybrid, co-immunoprecipitation from rat brain extracts, and immunofluorescence showing nerve-terminal enrichment\",\n      \"pmids\": [\"9238017\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No direct demonstration that SH3GL3 loss impairs synaptic vesicle endocytosis in neurons\",\n        \"Relative contribution of SH3GL3 versus SH3GL1/SH3GL2 at the synapse is undefined\"\n      ]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Demonstrating that SH3GL3 selectively binds pathological-length polyglutamine huntingtin and promotes its aggregation identified a novel molecular partner in Huntington disease aggregate formation.\",\n      \"evidence\": \"Co-immunoprecipitation from HD human brain, domain-deletion mutagenesis, and filter retardation aggregation assay in COS cells\",\n      \"pmids\": [\"9809064\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether SH3GL3–huntingtin interaction contributes to neurodegeneration in vivo is untested\",\n        \"Stoichiometry and structural basis of SH3-domain/polyproline interaction with huntingtin are unresolved\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identifying DYDC1 as a BAR-domain interactor and linking SH3GL3 to clathrin-coated vesicle traffic during acrosome biogenesis extended its membrane-trafficking role beyond neurons.\",\n      \"evidence\": \"Yeast two-hybrid with BAR domain bait, RNAi knockdown in germ cells, and germ cell transplantation\",\n      \"pmids\": [\"19545932\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Interaction awaits validation by reciprocal co-immunoprecipitation from endogenous testis extracts\",\n        \"Whether BAR-domain–mediated membrane tubulation is required for acrosome formation is unknown\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showing that SH3GL3 knockdown inhibits glioma cell invasion provided the first evidence that SH3GL3 has tumor-suppressive activity, opening its characterization in cancer biology.\",\n      \"evidence\": \"shRNA knockdown with Matrigel transwell invasion assay in glioma cells\",\n      \"pmids\": [\"21722156\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which SH3GL3 restrains invasion was not identified\",\n        \"No in vivo tumor model used\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Linking SH3GL3 overexpression to FAK/PI3K activation in myeloma identified a context where SH3GL3 paradoxically promotes migration and stemness, contrasting with its tumor-suppressive role in glioma.\",\n      \"evidence\": \"Gain- and loss-of-function in myeloma cells with FAK/PI3K pharmacological inhibitor rescue and Western blot\",\n      \"pmids\": [\"27683032\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct physical interaction between SH3GL3 and FAK or PI3K was not demonstrated\",\n        \"Context-dependent pro- versus anti-tumorigenic roles remain mechanistically unexplained\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrating SH3-domain dependence for SH3GL3's anti-proliferative, pro-apoptotic, and p21-inducing activities in lung cancer established that its tumor-suppressive function requires the same domain used in endocytic partner binding.\",\n      \"evidence\": \"Overexpression of full-length versus SH3-deletion mutants in lung cancer cells with proliferation, flow cytometry, and qRT-PCR readouts\",\n      \"pmids\": [\"33168185\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The SH3-domain binding partner responsible for p21 upregulation is unidentified\",\n        \"Transcriptional mechanism linking SH3GL3 to p21 promoter activation is unknown\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identifying STAT3 as a direct SH3GL3-interacting protein whose nuclear translocation is blocked by SH3GL3 provided a mechanistic explanation for its tumor-suppressive effects in glioblastoma.\",\n      \"evidence\": \"Co-immunoprecipitation, immunofluorescence for STAT3 localization, and epistasis rescue with constitutively active STAT3-C in glioblastoma cells\",\n      \"pmids\": [\"33524871\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Domain on SH3GL3 that mediates STAT3 binding is not mapped\",\n        \"Whether STAT3 sequestration explains the lung cancer phenotype or p21 induction is untested\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealing that the lncRNA MIR210HG recruits DNMT1 to methylate the SH3GL3 promoter explained how SH3GL3 expression is epigenetically silenced in lung cancer.\",\n      \"evidence\": \"ChIP for DNMT1 at SH3GL3 promoter, RNA immunoprecipitation for MIR210HG–DNMT1, methylation-specific PCR, and functional rescue in lung cancer cells\",\n      \"pmids\": [\"37916731\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether MIR210HG-mediated silencing operates in other cancer types is unknown\",\n        \"No in vivo demonstration that restoring SH3GL3 expression reverses tumor growth\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis for SH3GL3's context-dependent pro- versus anti-tumorigenic activities, the identity of the SH3-domain partner responsible for p21 transcriptional induction, and the in vivo physiological consequence of SH3GL3 loss in neurons remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No knockout or conditional deletion mouse model phenotype reported\",\n        \"No structural determination of SH3GL3 BAR or SH3 domains\",\n        \"Relationship between endocytic function and tumor-suppressive role is mechanistically unconnected\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"DNM1\",\n      \"SYNJ1\",\n      \"HTT\",\n      \"STAT3\",\n      \"DYDC1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}