{"gene":"SH3GL1","run_date":"2026-04-28T20:42:07","timeline":{"discoveries":[{"year":1997,"finding":"SH3p13 (SH3GL1/EEN) was identified as a binding partner for both dynamin I and synaptojanin via its SH3 domain. The protein was co-precipitated with synaptojanin and dynamin I from brain extracts, and the interaction was mapped to the proline-rich tails of synaptojanin and dynamin I. SH3p4/8/13 family members were found concentrated in nerve terminals, implicating them in synaptic vesicle recycling.","method":"Yeast two-hybrid screen, co-immunoprecipitation from brain extracts, biochemical binding studies","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP and two-hybrid, replicated across family members, foundational paper with 334 citations","pmids":["9238017"],"is_preprint":false},{"year":1997,"finding":"EEN (SH3GL1) encodes a protein containing a central alpha-helical region and a C-terminal SH3 domain most similar to the Grb2/Sem-5/Drk family. It was identified as a fusion partner fused to MLL at exon 6, creating a chimeric protein that includes the major functional domain of EEN.","method":"Cloning of chromosomal translocation t(11;19)(q23;p13), sequence analysis of MLL/EEN fusion transcript","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — original cloning with domain characterization; 107 citations","pmids":["9122235"],"is_preprint":false},{"year":2000,"finding":"EEN SH3 domain binds to the proline-rich domain of synaptojanin and dynamin, with EEN showing higher binding affinity than Abi-1 for synaptojanin. The EEN SH3 domain interacts with a different proline-rich domain of synaptojanin than the EH domains of Eps15. Competitive binding assays showed EEN can compete with Abi-1 for synaptojanin binding.","method":"GST pull-down, yeast two-hybrid, in vitro competitive binding assays","journal":"Leukemia","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro pull-down with mutagenesis and competition assays, multiple orthogonal methods","pmids":["10764144"],"is_preprint":false},{"year":2000,"finding":"EEN, EEN-B1, and EEN-B2 all bind dynamin and synaptojanin, with EEN-B1 showing highest affinity, followed by EEN, then EEN-B2. Amphiphysin competes with EEN family members for binding to synaptojanin and dynamin, suggesting recruitment of EEN family to clathrin-coated pits is regulated by amphiphysin.","method":"Binding affinity studies, competition assays with amphiphysin","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2-3 — binding/competition assays in single study, moderate evidence for competitive mechanism","pmids":["10816441"],"is_preprint":false},{"year":2003,"finding":"EEN (SH3GL1) interacts with EBP (a novel EEN binding protein) via its SH3 domain binding to the proline-rich motif PPERP of EBP. EBP simultaneously interacts with EEN and Sos (a Ras GEF), and co-expression of EBP with EEN suppresses Ras-induced cellular transformation and Ras-mediated activation of Elk-1, suggesting EEN normally regulates Ras signaling via EBP.","method":"Co-immunoprecipitation, yeast two-hybrid, reporter assay (Elk-1 activation), cellular transformation assay","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal Co-IP plus functional assays, single lab","pmids":["14551139"],"is_preprint":false},{"year":2004,"finding":"EEN/EA2 (SH3GL1) is localized predominantly in nuclei of haemopoietic, fibroblast, and epithelial cell lines (in contrast to its cytoplasmic localization in neurons) and exhibits nucleocytoplasmic shuttling. During the cell cycle, EEN/EA2 is perichromosomal in prometaphase, co-localizes with the bipolar spindle in metaphase/anaphase, and redistributes to midzone/midbody in telophase, with highest protein levels in G2/M phase, indicating a role in cell cycle progression.","method":"Immunofluorescence, cell fractionation, cell cycle synchronization, flow cytometry","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization experiments with cell cycle functional link, single lab","pmids":["15214844"],"is_preprint":false},{"year":2004,"finding":"MLL-EEN fusion protein localizes to the nucleus and exerts a dominant-negative effect on wild-type EEN subcellular localization, delocalizing cytoplasmic EEN to the nucleus via a coiled-coil dimerization domain retained in the fusion. MLL-EEN can transactivate the HoxA7 promoter, with the MLL portion providing DNA-binding and EEN portion providing transcriptional activation.","method":"Subcellular localization studies, deletion mutant analysis, reporter gene assay (HoxA7 promoter), oncogenic transformation assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — multiple methods including mutagenesis and functional reporter assay, single lab","pmids":["15077184"],"is_preprint":false},{"year":2005,"finding":"EEN/endophilin II (SH3GL1) directly interacts with BPGAP1 via its SH3 domain binding to the proline-rich region 182-PPPRPPLP-189 of BPGAP1, with prolines 184 and 186 indispensable for the interaction. Co-expression of EEN and BPGAP1 synergistically promotes EGF-stimulated EGFR endocytosis and ERK1/2 phosphorylation; EEN lacking the SH3 domain acts as dominant negative blocking these effects.","method":"Mass spectrometry, pull-down with deletion mutants, co-immunoprecipitation, EGFR endocytosis assay, ERK1/2 phosphorylation assay, dominant-negative analysis","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1-2 — MS identification, reciprocal Co-IP, mutagenesis of binding motif, and functional readouts with multiple orthogonal methods","pmids":["15944398"],"is_preprint":false},{"year":2006,"finding":"Overexpressed EEN (SH3GL1) shows oncogenic properties including transforming potential in NIH3T3 cells, stimulation of cell proliferation, and increased AP-1 transcriptional activity. Retroviral transduction of EEN increased self-renewal and proliferation of murine hematopoietic progenitor cells. EEN expression is transcriptionally regulated by Sp1 binding to GC-rich promoter elements, and AML1-ETO aberrantly transactivates the EEN gene through an AML1 binding site.","method":"NIH3T3 transformation assay, retroviral transduction, reporter assay, ChIP-based promoter analysis, RNAi knockdown","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 — multiple functional assays in single lab with promoter mechanistic detail","pmids":["16990610"],"is_preprint":false},{"year":2014,"finding":"EEN (SH3GL1) regulates proliferation and survival of multiple myeloma cells by being indispensable for IGF-1 secretion and activation of the Akt-mTOR pathway. EEN depletion reduced IGF-1 secretion, and exogenous IGF-1 rescued the proliferative phenotype of EEN-depleted cells while IGF-1 neutralization overcame EEN overexpression effects.","method":"siRNA knockdown, overexpression, cell cycle analysis, apoptosis assay, IGF-1 measurement, pathway inhibition rescue experiments","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with defined pathway, rescue experiments with IGF-1, single lab","pmids":["24704450"],"is_preprint":false},{"year":2016,"finding":"SH3GL1 knockdown in chemotherapy-resistant colorectal cancer cells downregulates MDR1/P-glycoprotein expression by decreasing AP-1 binding activity and inhibiting EGFR and ERK1/2 signaling; EGFR or ERK inhibitors phenocopied SH3GL1 knockdown, placing SH3GL1 upstream of the EGFR/ERK/AP-1/MDR1 axis.","method":"siRNA knockdown, overexpression, EGFR/ERK inhibitor treatment, MDR1 promoter activity assay, AP-1 binding assay, western blot","journal":"Tumour biology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic and pharmacological epistasis with defined pathway readout, single lab","pmids":["27220321"],"is_preprint":false},{"year":2017,"finding":"SH3GL1 knockdown abrogates p130cas phosphorylation and blocks IL-6- and VEGF-induced osteosarcoma cell proliferation and migration, induces G0/G1 arrest via downregulation of cyclin D1 and activation of p27KIP, attenuates p-Rb, and reduces phosphorylation of Akt/GSK-3β/FAK; in vivo, SH3GL1 depletion inhibited tumor growth and p-p130cas expression.","method":"Adenovirus shRNA knockdown, cell cycle analysis, in vivo tumor xenograft, western blot for signaling intermediates","journal":"Human cell","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with multiple pathway readouts in vitro and in vivo, single lab","pmids":["28702842"],"is_preprint":false},{"year":2025,"finding":"SH3GL1 physically interacts with B7-H3 (confirmed by Co-IP and immunofluorescence co-localization) and promotes B7-H3 recycling to the cell surface by redirecting it away from lysosomal degradation, thereby sustaining B7-H3-mediated immune escape in non-small cell lung cancer; SH3GL1 overexpression suppressed T cell proliferation and cytotoxicity in co-culture assays.","method":"Co-immunoprecipitation, immunofluorescence, flow cytometry, confocal microscopy, T cell co-culture assay, in vivo tumor model","journal":"The International journal of biological markers","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal Co-IP, co-localization, functional endocytic recycling assay and in vivo validation, single lab","pmids":["40874628"],"is_preprint":false},{"year":2025,"finding":"SH3GL1 deficiency triggers FTH1 (ferritin heavy chain 1)-mediated ferritinophagy-induced ferroptosis in DLBCL cells; high SH3GL1 expression suppresses doxorubicin-induced ferroptosis, conferring drug resistance. Identified by CRISPR/Cas9 knockout combined with proteomics (Deep-DIA/LC-MS).","method":"CRISPR/Cas9 knockout, proteomics (Deep-DIA, LC-MS), xenograft models, molecular pathway analyses","journal":"Clinical and translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 — CRISPR KO with proteomics and in vivo validation, single lab","pmids":["40038872"],"is_preprint":false}],"current_model":"SH3GL1 (EEN/endophilin A2) is an SH3 domain-containing endophilin family protein that physically binds dynamin and synaptojanin to facilitate endocytic vesicle recycling, interacts with BPGAP1 to promote EGFR endocytosis and ERK/Ras signaling, regulates cell cycle progression with dynamic nuclear/cytoplasmic localization, controls B7-H3 surface recycling to mediate immune escape, and suppresses ferroptosis via FTH1; when fused to MLL, its coiled-coil domain drives nuclear mislocalization and aberrant HoxA7 transactivation to cause leukemic transformation."},"narrative":{"teleology":[{"year":1997,"claim":"Establishing that SH3GL1 is a core endocytic adaptor answered the initial question of what this SH3 domain protein does: it links dynamin and synaptojanin at nerve terminals to drive synaptic vesicle recycling.","evidence":"Yeast two-hybrid and reciprocal co-immunoprecipitation from brain extracts","pmids":["9238017"],"confidence":"High","gaps":["Functional consequence of SH3GL1 loss on vesicle recycling not tested","BAR domain membrane-tubulating activity not yet assessed"]},{"year":1997,"claim":"Cloning of the MLL-EEN fusion from a t(11;19) leukemia translocation revealed SH3GL1 as an oncogenic fusion partner, raising the question of how an endocytic protein contributes to leukemogenesis.","evidence":"Molecular cloning of the chromosomal breakpoint and sequence analysis of the chimeric transcript","pmids":["9122235"],"confidence":"High","gaps":["Mechanism of leukemic transformation by MLL-EEN not yet defined","Frequency in leukemia cohorts not established"]},{"year":2000,"claim":"Binding-specificity and competition studies showed that EEN family members and amphiphysin compete for dynamin/synaptojanin, establishing a regulated recruitment model at clathrin-coated pits.","evidence":"In vitro GST pull-down, competitive binding assays, and affinity comparisons across EEN paralogs","pmids":["10764144","10816441"],"confidence":"High","gaps":["In vivo relevance of amphiphysin–EEN competition not demonstrated","Stoichiometry at endocytic sites unknown"]},{"year":2003,"claim":"Discovery of EBP as an SH3GL1-interacting scaffold that also binds the Ras GEF Sos connected endophilin biology to Ras/Elk-1 signaling, showing that SH3GL1 is not purely an endocytic protein.","evidence":"Co-immunoprecipitation, yeast two-hybrid, and Elk-1 reporter assays; EEN+EBP suppressed Ras transformation","pmids":["14551139"],"confidence":"Medium","gaps":["Physiological context for EEN–EBP–Sos complex not defined","No genetic loss-of-function validation"]},{"year":2004,"claim":"Demonstration that SH3GL1 shuttles between cytoplasm and nucleus and dynamically associates with mitotic structures resolved the unexpected non-neuronal nuclear localization and linked SH3GL1 to cell cycle progression.","evidence":"Immunofluorescence, cell fractionation, and cell cycle synchronization in hematopoietic and epithelial lines","pmids":["15214844"],"confidence":"Medium","gaps":["Direct mitotic target or function not identified","Nuclear import/export signals not mapped"]},{"year":2004,"claim":"Mechanistic dissection of MLL-EEN showed that its coiled-coil domain mislocalizes wild-type EEN to the nucleus and the chimera transactivates HoxA7, answering how the fusion drives leukemia.","evidence":"Deletion mutant analysis, subcellular localization, and HoxA7 promoter reporter assays","pmids":["15077184"],"confidence":"Medium","gaps":["Target gene repertoire beyond HoxA7 not explored","In vivo leukemogenesis model not reported"]},{"year":2005,"claim":"Identification of BPGAP1 as a direct SH3 domain partner that synergizes with SH3GL1 to promote EGFR endocytosis and ERK1/2 activation provided the first receptor-level mechanism connecting SH3GL1 to growth factor signaling.","evidence":"Mass spectrometry identification, reciprocal Co-IP, proline mutagenesis, EGFR endocytosis and ERK phosphorylation assays","pmids":["15944398"],"confidence":"High","gaps":["Whether SH3GL1–BPGAP1 acts at clathrin-coated pits or later endocytic compartments not resolved","Structural basis of cooperativity unknown"]},{"year":2006,"claim":"Overexpression studies established SH3GL1 as having intrinsic oncogenic potential—transforming NIH3T3 cells and expanding hematopoietic progenitors—and revealed its transcriptional upregulation by AML1-ETO, linking it to the leukemic transcription program.","evidence":"NIH3T3 transformation, retroviral progenitor expansion, promoter–reporter and ChIP analysis","pmids":["16990610"],"confidence":"Medium","gaps":["Whether transformation depends on endocytic or nuclear functions of SH3GL1 not distinguished","No loss-of-function in AML1-ETO leukemia"]},{"year":2014,"claim":"SH3GL1 depletion in multiple myeloma impaired IGF-1 secretion and Akt-mTOR signaling, revealing a secretory trafficking function that sustains autocrine growth factor loops.","evidence":"siRNA knockdown, IGF-1 ELISA, rescue with exogenous IGF-1 and IGF-1 neutralizing antibody","pmids":["24704450"],"confidence":"Medium","gaps":["Step in IGF-1 secretory pathway controlled by SH3GL1 not identified","Single myeloma cell line system"]},{"year":2016,"claim":"Placing SH3GL1 upstream of the EGFR/ERK/AP-1/MDR1 axis in chemoresistant colorectal cancer answered how it contributes to multidrug resistance, extending the EGFR-signaling connection to a clinically relevant phenotype.","evidence":"siRNA knockdown combined with EGFR/ERK inhibitors phenocopying MDR1 downregulation","pmids":["27220321"],"confidence":"Medium","gaps":["Direct molecular mechanism linking SH3GL1 to EGFR activation not resolved","Not tested whether the endocytic function is required"]},{"year":2025,"claim":"Discovery that SH3GL1 physically interacts with B7-H3 and reroutes it from lysosomal degradation to cell-surface recycling connected its endocytic function to immune checkpoint biology and tumor immune escape.","evidence":"Reciprocal Co-IP, confocal co-localization, flow cytometry recycling assay, T cell co-culture, in vivo tumor model in NSCLC","pmids":["40874628"],"confidence":"Medium","gaps":["Endosomal sorting mechanism (e.g., Rab GTPase involvement) not defined","Not tested in other checkpoint molecules"]},{"year":2025,"claim":"CRISPR knockout revealed that SH3GL1 loss triggers FTH1-mediated ferritinophagy and ferroptosis, uncovering a previously unknown role in iron homeostasis and explaining how high SH3GL1 expression confers doxorubicin resistance in DLBCL.","evidence":"CRISPR/Cas9 KO with Deep-DIA proteomics, xenograft validation","pmids":["40038872"],"confidence":"Medium","gaps":["Direct physical interaction between SH3GL1 and FTH1 not demonstrated","Mechanism linking endophilin to ferritinophagy regulation unknown","Single DLBCL model"]},{"year":null,"claim":"How SH3GL1's BAR-domain membrane remodeling, SH3-mediated protein recruitment, and nuclear functions are coordinated across different cell types, and whether its endocytic versus non-endocytic roles are separable in disease contexts, remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of full-length SH3GL1 in a functional complex","Nuclear function substrates/targets undefined","Relative contribution of BAR versus SH3 domain to oncogenic phenotypes untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2,3,7]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,7]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[5]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5,6]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[0,7,12]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,2,3,7,12]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,7,9,10,11]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[5,11]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[13]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[12]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,6,8]}],"complexes":[],"partners":["DNM1","SYNJ1","BPGAP1","CD276","EBP","KMT2A","AMPH"],"other_free_text":[]},"mechanistic_narrative":"SH3GL1 (also known as EEN/endophilin A2) is an SH3 domain-containing BAR-domain family protein that functions at the intersection of endocytic membrane trafficking, receptor signaling, and cell cycle control. Its C-terminal SH3 domain directly engages the proline-rich regions of dynamin and synaptojanin to facilitate clathrin-mediated endocytosis and synaptic vesicle recycling [PMID:9238017, PMID:10764144], and it cooperates with BPGAP1 to promote EGFR internalization and downstream ERK1/2 activation [PMID:15944398], while also sustaining B7-H3 surface expression by redirecting it from lysosomal degradation to a recycling pathway that supports tumor immune evasion [PMID:40874628]. In non-neuronal cells SH3GL1 undergoes nucleocytoplasmic shuttling, associates with mitotic structures from prometaphase through cytokinesis, and peaks in G2/M, linking it to cell cycle progression [PMID:15214844]; its loss triggers FTH1-dependent ferritinophagy and ferroptosis in lymphoma cells, while its overexpression confers chemoresistance [PMID:40038872]. SH3GL1 was originally identified as a fusion partner of MLL in t(11;19)(q23;p13) acute leukemia, where its coiled-coil dimerization domain mislocalizes wild-type EEN to the nucleus and the MLL-EEN chimera transactivates HoxA7 to drive leukemic transformation [PMID:9122235, PMID:15077184]."},"prefetch_data":{"uniprot":{"accession":"Q99961","full_name":"Endophilin-A2","aliases":["EEN fusion partner of MLL","Endophilin-2","Extra eleven-nineteen leukemia fusion gene protein","EEN","SH3 domain protein 2B","SH3 domain-containing GRB2-like protein 1"],"length_aa":368,"mass_kda":41.5,"function":"Implicated in endocytosis. May recruit other proteins to membranes with high curvature (By similarity)","subcellular_location":"Cytoplasm; Early endosome membrane; Cell projection, podosome","url":"https://www.uniprot.org/uniprotkb/Q99961/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SH3GL1","classification":"Not Classified","n_dependent_lines":83,"n_total_lines":1208,"dependency_fraction":0.06870860927152318},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000141985","cell_line_id":"CID000669","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"membrane","grade":3},{"compartment":"cell_contact","grade":1}],"interactors":[{"gene":"GLRX3","stoichiometry":0.2},{"gene":"EML4","stoichiometry":0.2},{"gene":"SH3GL3","stoichiometry":0.2},{"gene":"SH3GL2","stoichiometry":0.2},{"gene":"HNRNPK","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000669","total_profiled":1310},"omim":[{"mim_id":"604465","title":"SH3 DOMAIN, GRB2-LIKE, 2; SH3GL2","url":"https://www.omim.org/entry/604465"},{"mim_id":"602544","title":"PARKIN RBR E3 UBIQUITIN PROTEIN LIGASE; PRKN","url":"https://www.omim.org/entry/602544"},{"mim_id":"601768","title":"SH3 DOMAIN, GRB2-LIKE, 1; SH3GL1","url":"https://www.omim.org/entry/601768"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SH3GL1"},"hgnc":{"alias_symbol":["SH3P8","SH3D2B","CNSA1","EEN","MGC111371"],"prev_symbol":[]},"alphafold":{"accession":"Q99961","domains":[{"cath_id":"1.20.1270.60","chopping":"9-73_88-250","consensus_level":"high","plddt":93.147,"start":9,"end":250},{"cath_id":"2.30.30.40","chopping":"311-365","consensus_level":"high","plddt":90.1782,"start":311,"end":365}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99961","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q99961-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q99961-F1-predicted_aligned_error_v6.png","plddt_mean":83.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SH3GL1","jax_strain_url":"https://www.jax.org/strain/search?query=SH3GL1"},"sequence":{"accession":"Q99961","fasta_url":"https://rest.uniprot.org/uniprotkb/Q99961.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q99961/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99961"}},"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":"9838115","id":"PMC_9838115","title":"Phospholipid signalling in the nucleus. Een DAG uit het leven van de inositide signalering in de nucleus.","date":"1998","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/9838115","citation_count":155,"is_preprint":false},{"pmid":"9122235","id":"PMC_9122235","title":"EEN encodes for a member of a new family of proteins containing an Src homology 3 domain and is the third gene located on chromosome 19p13 that fuses to MLL in human leukemia.","date":"1997","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/9122235","citation_count":107,"is_preprint":false},{"pmid":"15944398","id":"PMC_15944398","title":"Activation of EGF receptor endocytosis and ERK1/2 signaling by BPGAP1 requires direct interaction with EEN/endophilin II and a functional RhoGAP domain.","date":"2005","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/15944398","citation_count":42,"is_preprint":false},{"pmid":"10764144","id":"PMC_10764144","title":"The interaction between EEN and Abi-1, two MLL fusion partners, and synaptojanin and dynamin: implications for leukaemogenesis.","date":"2000","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/10764144","citation_count":36,"is_preprint":false},{"pmid":"14551139","id":"PMC_14551139","title":"Identification and characterization of EBP, a novel EEN binding protein that inhibits Ras signaling and is recruited into the nucleus by the MLL-EEN fusion protein.","date":"2003","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/14551139","citation_count":33,"is_preprint":false},{"pmid":"15077184","id":"PMC_15077184","title":"Functional contribution of EEN to leukemogenic transformation by MLL-EEN fusion protein.","date":"2004","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/15077184","citation_count":26,"is_preprint":false},{"pmid":"23970061","id":"PMC_23970061","title":"miR-218 is downregulated and directly targets SH3GL1 in childhood medulloblastoma.","date":"2013","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/23970061","citation_count":23,"is_preprint":false},{"pmid":"10816441","id":"PMC_10816441","title":"Expression and protein-binding studies of the EEN gene family, new interacting partners for dynamin, synaptojanin and huntingtin proteins.","date":"2000","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/10816441","citation_count":22,"is_preprint":false},{"pmid":"33838155","id":"PMC_33838155","title":"MiR-3663-3p participates in the anti-hepatocellular carcinoma proliferation activity of baicalein by targeting SH3GL1 and negatively regulating EGFR/ERK/NF-κB signaling.","date":"2021","source":"Toxicology and applied pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/33838155","citation_count":18,"is_preprint":false},{"pmid":"27220321","id":"PMC_27220321","title":"SH3GL1 inhibition reverses multidrug resistance in colorectal cancer cells by downregulation of MDR1/P-glycoprotein via EGFR/ERK/AP-1 pathway.","date":"2016","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/27220321","citation_count":18,"is_preprint":false},{"pmid":"28702842","id":"PMC_28702842","title":"Essential role of SH3GL1 in interleukin-6(IL-6)- and vascular endothelial growth factor (VEGF)-triggered p130cas-mediated proliferation and migration of osteosarcoma cells.","date":"2017","source":"Human cell","url":"https://pubmed.ncbi.nlm.nih.gov/28702842","citation_count":17,"is_preprint":false},{"pmid":"15214844","id":"PMC_15214844","title":"Subcellular localization of EEN/endophilin A2, a fusion partner gene in leukaemia.","date":"2004","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/15214844","citation_count":16,"is_preprint":false},{"pmid":"16888613","id":"PMC_16888613","title":"The Mll-Een knockin fusion gene enhances proliferation of myeloid progenitors derived from mouse embryonic stem cells and causes myeloid leukaemia in chimeric mice.","date":"2006","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/16888613","citation_count":14,"is_preprint":false},{"pmid":"16990610","id":"PMC_16990610","title":"Aberrant transcriptional regulation of the MLL fusion partner EEN by AML1-ETO and its implication in leukemogenesis.","date":"2006","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/16990610","citation_count":11,"is_preprint":false},{"pmid":"40038872","id":"PMC_40038872","title":"SH3GL1-activated FTH1 inhibits ferroptosis and confers doxorubicin resistance in diffuse large B-cell lymphoma.","date":"2025","source":"Clinical and translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40038872","citation_count":7,"is_preprint":false},{"pmid":"35935714","id":"PMC_35935714","title":"Exploring Different Effects of Exclusive Enteral Nutrition (EEN) and Corticosteroids on the Gut Microbiome in Crohn's Disease Based on a Three-Stage Strategy.","date":"2022","source":"Gastroenterology research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/35935714","citation_count":7,"is_preprint":false},{"pmid":"24704450","id":"PMC_24704450","title":"EEN regulates the proliferation and survival of multiple myeloma cells by potentiating IGF-1 secretion.","date":"2014","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/24704450","citation_count":6,"is_preprint":false},{"pmid":"17895399","id":"PMC_17895399","title":"Aberrant dendritic cell differentiation initiated by the Mll-Een fusion gene does not require leukemic transformation.","date":"2007","source":"Journal of leukocyte biology","url":"https://pubmed.ncbi.nlm.nih.gov/17895399","citation_count":3,"is_preprint":false},{"pmid":"20627007","id":"PMC_20627007","title":"[Comparative analysis of sequence alignment of SH3GL1 gene as a disease candidate gene of adolescent idiopathic scoliosis].","date":"2010","source":"Zhonghua wai ke za zhi [Chinese journal of surgery]","url":"https://pubmed.ncbi.nlm.nih.gov/20627007","citation_count":2,"is_preprint":false},{"pmid":"37215203","id":"PMC_37215203","title":"Efficacy of short-chain polypeptide-based EEN formulas in alleviating intestinal injury in children with Crohn's disease: a single-center study in China.","date":"2023","source":"Frontiers in nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/37215203","citation_count":1,"is_preprint":false},{"pmid":"40874628","id":"PMC_40874628","title":"SH3GL1 mediates B7-H3 recycling and enhances the immune escape in non-small cell lung cancer.","date":"2025","source":"The International journal of biological markers","url":"https://pubmed.ncbi.nlm.nih.gov/40874628","citation_count":0,"is_preprint":false},{"pmid":"14669223","id":"PMC_14669223","title":"[Establishment of transgenic mice for HRX-EEN fusion gene].","date":"2003","source":"Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/14669223","citation_count":0,"is_preprint":false},{"pmid":"26983763","id":"PMC_26983763","title":"Klinefelter syndroom en psychiatrische stoornissen: Twee gevalsbeschrijvingen en een literatuuroverzicht.","date":"2001","source":"Acta neuropsychiatrica","url":"https://pubmed.ncbi.nlm.nih.gov/26983763","citation_count":0,"is_preprint":false},{"pmid":"26976369","id":"PMC_26976369","title":"Positron emissie tomografie (PET) bij stemmingsstoornissen: een overzicht.","date":"1999","source":"Acta neuropsychiatrica","url":"https://pubmed.ncbi.nlm.nih.gov/26976369","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13394,"output_tokens":3627,"usd":0.047294},"stage2":{"model":"claude-opus-4-6","input_tokens":7011,"output_tokens":3143,"usd":0.170445},"total_usd":0.217739,"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\": \"SH3p13 (SH3GL1/EEN) was identified as a binding partner for both dynamin I and synaptojanin via its SH3 domain. The protein was co-precipitated with synaptojanin and dynamin I from brain extracts, and the interaction was mapped to the proline-rich tails of synaptojanin and dynamin I. SH3p4/8/13 family members were found concentrated in nerve terminals, implicating them in synaptic vesicle recycling.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation from brain extracts, biochemical binding studies\",\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 and two-hybrid, replicated across family members, foundational paper with 334 citations\",\n      \"pmids\": [\"9238017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"EEN (SH3GL1) encodes a protein containing a central alpha-helical region and a C-terminal SH3 domain most similar to the Grb2/Sem-5/Drk family. It was identified as a fusion partner fused to MLL at exon 6, creating a chimeric protein that includes the major functional domain of EEN.\",\n      \"method\": \"Cloning of chromosomal translocation t(11;19)(q23;p13), sequence analysis of MLL/EEN fusion transcript\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — original cloning with domain characterization; 107 citations\",\n      \"pmids\": [\"9122235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"EEN SH3 domain binds to the proline-rich domain of synaptojanin and dynamin, with EEN showing higher binding affinity than Abi-1 for synaptojanin. The EEN SH3 domain interacts with a different proline-rich domain of synaptojanin than the EH domains of Eps15. Competitive binding assays showed EEN can compete with Abi-1 for synaptojanin binding.\",\n      \"method\": \"GST pull-down, yeast two-hybrid, in vitro competitive binding assays\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro pull-down with mutagenesis and competition assays, multiple orthogonal methods\",\n      \"pmids\": [\"10764144\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"EEN, EEN-B1, and EEN-B2 all bind dynamin and synaptojanin, with EEN-B1 showing highest affinity, followed by EEN, then EEN-B2. Amphiphysin competes with EEN family members for binding to synaptojanin and dynamin, suggesting recruitment of EEN family to clathrin-coated pits is regulated by amphiphysin.\",\n      \"method\": \"Binding affinity studies, competition assays with amphiphysin\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — binding/competition assays in single study, moderate evidence for competitive mechanism\",\n      \"pmids\": [\"10816441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"EEN (SH3GL1) interacts with EBP (a novel EEN binding protein) via its SH3 domain binding to the proline-rich motif PPERP of EBP. EBP simultaneously interacts with EEN and Sos (a Ras GEF), and co-expression of EBP with EEN suppresses Ras-induced cellular transformation and Ras-mediated activation of Elk-1, suggesting EEN normally regulates Ras signaling via EBP.\",\n      \"method\": \"Co-immunoprecipitation, yeast two-hybrid, reporter assay (Elk-1 activation), cellular transformation assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus functional assays, single lab\",\n      \"pmids\": [\"14551139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"EEN/EA2 (SH3GL1) is localized predominantly in nuclei of haemopoietic, fibroblast, and epithelial cell lines (in contrast to its cytoplasmic localization in neurons) and exhibits nucleocytoplasmic shuttling. During the cell cycle, EEN/EA2 is perichromosomal in prometaphase, co-localizes with the bipolar spindle in metaphase/anaphase, and redistributes to midzone/midbody in telophase, with highest protein levels in G2/M phase, indicating a role in cell cycle progression.\",\n      \"method\": \"Immunofluorescence, cell fractionation, cell cycle synchronization, flow cytometry\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiments with cell cycle functional link, single lab\",\n      \"pmids\": [\"15214844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"MLL-EEN fusion protein localizes to the nucleus and exerts a dominant-negative effect on wild-type EEN subcellular localization, delocalizing cytoplasmic EEN to the nucleus via a coiled-coil dimerization domain retained in the fusion. MLL-EEN can transactivate the HoxA7 promoter, with the MLL portion providing DNA-binding and EEN portion providing transcriptional activation.\",\n      \"method\": \"Subcellular localization studies, deletion mutant analysis, reporter gene assay (HoxA7 promoter), oncogenic transformation assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods including mutagenesis and functional reporter assay, single lab\",\n      \"pmids\": [\"15077184\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"EEN/endophilin II (SH3GL1) directly interacts with BPGAP1 via its SH3 domain binding to the proline-rich region 182-PPPRPPLP-189 of BPGAP1, with prolines 184 and 186 indispensable for the interaction. Co-expression of EEN and BPGAP1 synergistically promotes EGF-stimulated EGFR endocytosis and ERK1/2 phosphorylation; EEN lacking the SH3 domain acts as dominant negative blocking these effects.\",\n      \"method\": \"Mass spectrometry, pull-down with deletion mutants, co-immunoprecipitation, EGFR endocytosis assay, ERK1/2 phosphorylation assay, dominant-negative analysis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — MS identification, reciprocal Co-IP, mutagenesis of binding motif, and functional readouts with multiple orthogonal methods\",\n      \"pmids\": [\"15944398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Overexpressed EEN (SH3GL1) shows oncogenic properties including transforming potential in NIH3T3 cells, stimulation of cell proliferation, and increased AP-1 transcriptional activity. Retroviral transduction of EEN increased self-renewal and proliferation of murine hematopoietic progenitor cells. EEN expression is transcriptionally regulated by Sp1 binding to GC-rich promoter elements, and AML1-ETO aberrantly transactivates the EEN gene through an AML1 binding site.\",\n      \"method\": \"NIH3T3 transformation assay, retroviral transduction, reporter assay, ChIP-based promoter analysis, RNAi knockdown\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple functional assays in single lab with promoter mechanistic detail\",\n      \"pmids\": [\"16990610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"EEN (SH3GL1) regulates proliferation and survival of multiple myeloma cells by being indispensable for IGF-1 secretion and activation of the Akt-mTOR pathway. EEN depletion reduced IGF-1 secretion, and exogenous IGF-1 rescued the proliferative phenotype of EEN-depleted cells while IGF-1 neutralization overcame EEN overexpression effects.\",\n      \"method\": \"siRNA knockdown, overexpression, cell cycle analysis, apoptosis assay, IGF-1 measurement, pathway inhibition rescue experiments\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with defined pathway, rescue experiments with IGF-1, single lab\",\n      \"pmids\": [\"24704450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SH3GL1 knockdown in chemotherapy-resistant colorectal cancer cells downregulates MDR1/P-glycoprotein expression by decreasing AP-1 binding activity and inhibiting EGFR and ERK1/2 signaling; EGFR or ERK inhibitors phenocopied SH3GL1 knockdown, placing SH3GL1 upstream of the EGFR/ERK/AP-1/MDR1 axis.\",\n      \"method\": \"siRNA knockdown, overexpression, EGFR/ERK inhibitor treatment, MDR1 promoter activity assay, AP-1 binding assay, western blot\",\n      \"journal\": \"Tumour biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic and pharmacological epistasis with defined pathway readout, single lab\",\n      \"pmids\": [\"27220321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SH3GL1 knockdown abrogates p130cas phosphorylation and blocks IL-6- and VEGF-induced osteosarcoma cell proliferation and migration, induces G0/G1 arrest via downregulation of cyclin D1 and activation of p27KIP, attenuates p-Rb, and reduces phosphorylation of Akt/GSK-3β/FAK; in vivo, SH3GL1 depletion inhibited tumor growth and p-p130cas expression.\",\n      \"method\": \"Adenovirus shRNA knockdown, cell cycle analysis, in vivo tumor xenograft, western blot for signaling intermediates\",\n      \"journal\": \"Human cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with multiple pathway readouts in vitro and in vivo, single lab\",\n      \"pmids\": [\"28702842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SH3GL1 physically interacts with B7-H3 (confirmed by Co-IP and immunofluorescence co-localization) and promotes B7-H3 recycling to the cell surface by redirecting it away from lysosomal degradation, thereby sustaining B7-H3-mediated immune escape in non-small cell lung cancer; SH3GL1 overexpression suppressed T cell proliferation and cytotoxicity in co-culture assays.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, flow cytometry, confocal microscopy, T cell co-culture assay, in vivo tumor model\",\n      \"journal\": \"The International journal of biological markers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, co-localization, functional endocytic recycling assay and in vivo validation, single lab\",\n      \"pmids\": [\"40874628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SH3GL1 deficiency triggers FTH1 (ferritin heavy chain 1)-mediated ferritinophagy-induced ferroptosis in DLBCL cells; high SH3GL1 expression suppresses doxorubicin-induced ferroptosis, conferring drug resistance. Identified by CRISPR/Cas9 knockout combined with proteomics (Deep-DIA/LC-MS).\",\n      \"method\": \"CRISPR/Cas9 knockout, proteomics (Deep-DIA, LC-MS), xenograft models, molecular pathway analyses\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR KO with proteomics and in vivo validation, single lab\",\n      \"pmids\": [\"40038872\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SH3GL1 (EEN/endophilin A2) is an SH3 domain-containing endophilin family protein that physically binds dynamin and synaptojanin to facilitate endocytic vesicle recycling, interacts with BPGAP1 to promote EGFR endocytosis and ERK/Ras signaling, regulates cell cycle progression with dynamic nuclear/cytoplasmic localization, controls B7-H3 surface recycling to mediate immune escape, and suppresses ferroptosis via FTH1; when fused to MLL, its coiled-coil domain drives nuclear mislocalization and aberrant HoxA7 transactivation to cause leukemic transformation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SH3GL1 (also known as EEN/endophilin A2) is an SH3 domain-containing BAR-domain family protein that functions at the intersection of endocytic membrane trafficking, receptor signaling, and cell cycle control. Its C-terminal SH3 domain directly engages the proline-rich regions of dynamin and synaptojanin to facilitate clathrin-mediated endocytosis and synaptic vesicle recycling [PMID:9238017, PMID:10764144], and it cooperates with BPGAP1 to promote EGFR internalization and downstream ERK1/2 activation [PMID:15944398], while also sustaining B7-H3 surface expression by redirecting it from lysosomal degradation to a recycling pathway that supports tumor immune evasion [PMID:40874628]. In non-neuronal cells SH3GL1 undergoes nucleocytoplasmic shuttling, associates with mitotic structures from prometaphase through cytokinesis, and peaks in G2/M, linking it to cell cycle progression [PMID:15214844]; its loss triggers FTH1-dependent ferritinophagy and ferroptosis in lymphoma cells, while its overexpression confers chemoresistance [PMID:40038872]. SH3GL1 was originally identified as a fusion partner of MLL in t(11;19)(q23;p13) acute leukemia, where its coiled-coil dimerization domain mislocalizes wild-type EEN to the nucleus and the MLL-EEN chimera transactivates HoxA7 to drive leukemic transformation [PMID:9122235, PMID:15077184].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Establishing that SH3GL1 is a core endocytic adaptor answered the initial question of what this SH3 domain protein does: it links dynamin and synaptojanin at nerve terminals to drive synaptic vesicle recycling.\",\n      \"evidence\": \"Yeast two-hybrid and reciprocal co-immunoprecipitation from brain extracts\",\n      \"pmids\": [\"9238017\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of SH3GL1 loss on vesicle recycling not tested\", \"BAR domain membrane-tubulating activity not yet assessed\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Cloning of the MLL-EEN fusion from a t(11;19) leukemia translocation revealed SH3GL1 as an oncogenic fusion partner, raising the question of how an endocytic protein contributes to leukemogenesis.\",\n      \"evidence\": \"Molecular cloning of the chromosomal breakpoint and sequence analysis of the chimeric transcript\",\n      \"pmids\": [\"9122235\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of leukemic transformation by MLL-EEN not yet defined\", \"Frequency in leukemia cohorts not established\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Binding-specificity and competition studies showed that EEN family members and amphiphysin compete for dynamin/synaptojanin, establishing a regulated recruitment model at clathrin-coated pits.\",\n      \"evidence\": \"In vitro GST pull-down, competitive binding assays, and affinity comparisons across EEN paralogs\",\n      \"pmids\": [\"10764144\", \"10816441\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of amphiphysin–EEN competition not demonstrated\", \"Stoichiometry at endocytic sites unknown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Discovery of EBP as an SH3GL1-interacting scaffold that also binds the Ras GEF Sos connected endophilin biology to Ras/Elk-1 signaling, showing that SH3GL1 is not purely an endocytic protein.\",\n      \"evidence\": \"Co-immunoprecipitation, yeast two-hybrid, and Elk-1 reporter assays; EEN+EBP suppressed Ras transformation\",\n      \"pmids\": [\"14551139\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological context for EEN–EBP–Sos complex not defined\", \"No genetic loss-of-function validation\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstration that SH3GL1 shuttles between cytoplasm and nucleus and dynamically associates with mitotic structures resolved the unexpected non-neuronal nuclear localization and linked SH3GL1 to cell cycle progression.\",\n      \"evidence\": \"Immunofluorescence, cell fractionation, and cell cycle synchronization in hematopoietic and epithelial lines\",\n      \"pmids\": [\"15214844\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct mitotic target or function not identified\", \"Nuclear import/export signals not mapped\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Mechanistic dissection of MLL-EEN showed that its coiled-coil domain mislocalizes wild-type EEN to the nucleus and the chimera transactivates HoxA7, answering how the fusion drives leukemia.\",\n      \"evidence\": \"Deletion mutant analysis, subcellular localization, and HoxA7 promoter reporter assays\",\n      \"pmids\": [\"15077184\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Target gene repertoire beyond HoxA7 not explored\", \"In vivo leukemogenesis model not reported\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identification of BPGAP1 as a direct SH3 domain partner that synergizes with SH3GL1 to promote EGFR endocytosis and ERK1/2 activation provided the first receptor-level mechanism connecting SH3GL1 to growth factor signaling.\",\n      \"evidence\": \"Mass spectrometry identification, reciprocal Co-IP, proline mutagenesis, EGFR endocytosis and ERK phosphorylation assays\",\n      \"pmids\": [\"15944398\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SH3GL1–BPGAP1 acts at clathrin-coated pits or later endocytic compartments not resolved\", \"Structural basis of cooperativity unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Overexpression studies established SH3GL1 as having intrinsic oncogenic potential—transforming NIH3T3 cells and expanding hematopoietic progenitors—and revealed its transcriptional upregulation by AML1-ETO, linking it to the leukemic transcription program.\",\n      \"evidence\": \"NIH3T3 transformation, retroviral progenitor expansion, promoter–reporter and ChIP analysis\",\n      \"pmids\": [\"16990610\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether transformation depends on endocytic or nuclear functions of SH3GL1 not distinguished\", \"No loss-of-function in AML1-ETO leukemia\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"SH3GL1 depletion in multiple myeloma impaired IGF-1 secretion and Akt-mTOR signaling, revealing a secretory trafficking function that sustains autocrine growth factor loops.\",\n      \"evidence\": \"siRNA knockdown, IGF-1 ELISA, rescue with exogenous IGF-1 and IGF-1 neutralizing antibody\",\n      \"pmids\": [\"24704450\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Step in IGF-1 secretory pathway controlled by SH3GL1 not identified\", \"Single myeloma cell line system\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placing SH3GL1 upstream of the EGFR/ERK/AP-1/MDR1 axis in chemoresistant colorectal cancer answered how it contributes to multidrug resistance, extending the EGFR-signaling connection to a clinically relevant phenotype.\",\n      \"evidence\": \"siRNA knockdown combined with EGFR/ERK inhibitors phenocopying MDR1 downregulation\",\n      \"pmids\": [\"27220321\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular mechanism linking SH3GL1 to EGFR activation not resolved\", \"Not tested whether the endocytic function is required\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Discovery that SH3GL1 physically interacts with B7-H3 and reroutes it from lysosomal degradation to cell-surface recycling connected its endocytic function to immune checkpoint biology and tumor immune escape.\",\n      \"evidence\": \"Reciprocal Co-IP, confocal co-localization, flow cytometry recycling assay, T cell co-culture, in vivo tumor model in NSCLC\",\n      \"pmids\": [\"40874628\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endosomal sorting mechanism (e.g., Rab GTPase involvement) not defined\", \"Not tested in other checkpoint molecules\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"CRISPR knockout revealed that SH3GL1 loss triggers FTH1-mediated ferritinophagy and ferroptosis, uncovering a previously unknown role in iron homeostasis and explaining how high SH3GL1 expression confers doxorubicin resistance in DLBCL.\",\n      \"evidence\": \"CRISPR/Cas9 KO with Deep-DIA proteomics, xenograft validation\",\n      \"pmids\": [\"40038872\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct physical interaction between SH3GL1 and FTH1 not demonstrated\", \"Mechanism linking endophilin to ferritinophagy regulation unknown\", \"Single DLBCL model\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SH3GL1's BAR-domain membrane remodeling, SH3-mediated protein recruitment, and nuclear functions are coordinated across different cell types, and whether its endocytic versus non-endocytic roles are separable in disease contexts, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of full-length SH3GL1 in a functional complex\", \"Nuclear function substrates/targets undefined\", \"Relative contribution of BAR versus SH3 domain to oncogenic phenotypes untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2, 3, 7]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [0, 7, 12]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 2, 3, 7, 12]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 7, 9, 10, 11]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [5, 11]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 6, 8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"DNM1\",\n      \"SYNJ1\",\n      \"BPGAP1\",\n      \"CD276\",\n      \"EBP\",\n      \"KMT2A\",\n      \"AMPH\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}