{"gene":"SH3GL1","run_date":"2026-06-10T07:46:31","timeline":{"discoveries":[{"year":1997,"finding":"SH3GL1 (SH3p8) contains a Grb2-like SH3 domain that directly binds to the proline-rich COOH-terminal domains of both dynamin I and synaptojanin; pools of synaptojanin and dynamin I were co-precipitated from brain extracts with anti-SH3p4/8/13 antibodies, and SH3p8/SH3GL1 protein was concentrated in nerve terminals.","method":"Yeast two-hybrid screen, co-immunoprecipitation from brain extracts, subcellular localization","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP from brain tissue plus two-hybrid, replicated by independent lab (PMID:10764144, PMID:10816441)","pmids":["9238017"],"is_preprint":false},{"year":2000,"finding":"The SH3 domain of EEN/SH3GL1 interacts with distinct proline-rich domains of synaptojanin and with dynamin; in vitro competitive binding assays show EEN has higher binding affinity for synaptojanin than Abi-1, and amphiphysin can compete with EEN for binding to synaptojanin and dynamin.","method":"GST pull-down, yeast two-hybrid, in vitro competitive binding assay","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — GST pull-down plus yeast two-hybrid plus competitive binding, single lab","pmids":["10764144"],"is_preprint":false},{"year":2000,"finding":"EEN/SH3GL1 and its family members EEN-B1 and EEN-B2 all bind dynamin and synaptojanin via their SH3 domains, with EEN-B1 having the highest affinity; amphiphysin competes with the EEN family for binding to synaptojanin and dynamin, suggesting regulated recruitment to clathrin-coated pits.","method":"Protein binding assays, expression studies, competition assays","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assays with competition, single lab, multiple family members tested","pmids":["10816441"],"is_preprint":false},{"year":2003,"finding":"EEN/SH3GL1 binds a novel protein EBP via its SH3 domain interacting with EBP's proline-rich motif PPERP; EBP simultaneously interacts with Sos (a Ras GEF), and co-expression of EBP with EEN suppresses Ras-induced cellular transformation and Ras-mediated Elk-1 activation. MLL-EEN fusion protein recruits EBP to the nucleus, interfering with EBP's Ras-suppressing activity.","method":"Co-immunoprecipitation, reporter assays (Elk-1 transcription), transformation assays, subcellular localization","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, functional reporter assay, transformation assay; single lab, multiple orthogonal methods","pmids":["14551139"],"is_preprint":false},{"year":2004,"finding":"EEN/SH3GL1 is normally localized in the cytoplasm; the MLL-EEN fusion protein relocalizes EEN to the nucleus via a coiled-coil dimerization domain retained in the fusion, and MLL-EEN can transactivate the HoxA7 promoter acting as an aberrant transcription factor.","method":"Subcellular fractionation, reporter assay (HoxA7 promoter), deletion mutagenesis of dimerization domain","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — localization experiments with functional consequence (transactivation), deletion mutagenesis, single lab","pmids":["15077184"],"is_preprint":false},{"year":2004,"finding":"EEN/SH3GL1 (endophilin A2) undergoes nucleocytoplasmic shuttling and displays cell-cycle-dependent localization: perichromosomal in prometaphase, co-localizes with the bipolar spindle in metaphase/anaphase, and redistributes to the midzone/midbody in telophase, with highest protein levels in G2/M phase.","method":"Live-cell imaging, subcellular fractionation, cell-cycle synchronization, immunofluorescence","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by immunofluorescence across cell cycle stages with protein-level correlation, single lab","pmids":["15214844"],"is_preprint":false},{"year":2005,"finding":"EEN/SH3GL1 directly binds BPGAP1 via its SH3 domain interacting with the PPPRPPLP proline-rich motif (residues 182-189) of BPGAP1, with prolines 184 and 186 indispensable; co-expression of EEN with wild-type BPGAP1 (but not proline mutant) enhances EGF-stimulated receptor endocytosis and ERK1/2 phosphorylation; EEN lacking the SH3 domain acts as dominant-negative blocking these effects.","method":"Pull-down, co-immunoprecipitation, deletion mutant analysis, MALDI-MS identification, dominant-negative overexpression, EGF receptor endocytosis assay, ERK phosphorylation assay","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, multiple deletion mutants, dominant-negative functional assay, multiple orthogonal readouts in single rigorous study","pmids":["15944398"],"is_preprint":false},{"year":2006,"finding":"Overexpressed EEN/SH3GL1 has oncogenic/transforming potential in NIH3T3 cells, stimulates cell proliferation, increases AP-1 transcriptional activity, and enhances self-renewal and proliferation of murine hematopoietic progenitor cells upon retroviral transduction; AML1-ETO aberrantly transactivates the EEN gene through an AML1 binding site in the EEN promoter, while Sp1 binds the GC-stretch for normal EEN expression.","method":"NIH3T3 transformation assay, retroviral transduction, reporter/promoter assays, RNAi knockdown, ChIP-implied promoter binding","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays (transformation, proliferation, AP-1 reporter, hematopoietic progenitor assay), single lab","pmids":["16990610"],"is_preprint":false},{"year":2014,"finding":"EEN/SH3GL1 is required for IGF-1 secretion in multiple myeloma cells; EEN knockdown reduces IGF-1 secretion and suppresses Akt-mTOR pathway activation, G1-to-S cell cycle transition, and delays apoptosis via Bcl2/Bax-mitochondrial pathway; exogenous IGF-1 rescues the EEN-depletion phenotype.","method":"siRNA knockdown, overexpression, cell cycle analysis, apoptosis assay, ELISA for IGF-1, rescue experiment with exogenous IGF-1 or IGF-1 neutralization","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function and gain-of-function with rescue experiment, multiple pathway readouts, single lab","pmids":["24704450"],"is_preprint":false},{"year":2016,"finding":"SH3GL1 knockdown in drug-resistant colorectal cancer cells downregulates MDR1/P-glycoprotein expression by inhibiting EGFR and ERK1/2 signaling and reducing AP-1 binding activity at the MDR1 promoter; SH3GL1 overexpression has the opposite effect; EGFR or ERK1/2 kinase inhibitors partially mimic SH3GL1 knockdown.","method":"siRNA knockdown, overexpression (pCDNA3.1), western blot, MDR1 promoter activity assay, AP-1 binding assay, pharmacological inhibitors","journal":"Tumour biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional genetic manipulation plus pharmacological epistasis, multiple pathway readouts, single lab","pmids":["27220321"],"is_preprint":false},{"year":2017,"finding":"SH3GL1 knockdown (adenovirus shRNA) abolishes p130cas phosphorylation and blocks IL-6- and VEGF-induced osteosarcoma cell proliferation and migration; SH3GL1 depletion causes G0/G1 arrest via downregulation of cyclin D1, activation of p27KIP1, and reduced p-Rb, and attenuates phosphorylation of Akt/GSK-3β/FAK.","method":"adenovirus shRNA knockdown, western blot, cell cycle analysis, migration assay, in vivo xenograft","journal":"Human cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function in vitro and in vivo with specific pathway readouts, 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 enhancing immune escape in NSCLC; SH3GL1 overexpression suppresses T cell proliferation, cytotoxicity, and activation in vitro and promotes tumor growth with increased Treg infiltration in vivo.","method":"Co-immunoprecipitation, immunofluorescence, flow cytometry, confocal microscopy, T cell co-culture assay, in vivo tumor model, overexpression","journal":"The International journal of biological markers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and IF confirm physical interaction, functional recycling assay with in vivo validation, single lab","pmids":["40874628"],"is_preprint":false},{"year":2025,"finding":"SH3GL1 deficiency triggers FTH1 (ferritin heavy chain 1)-mediated ferroptosis, specifically ferritinophagy-induced ferroptosis, in DLBCL cells; high SH3GL1 expression suppresses doxorubicin-induced ferroptosis, conferring drug resistance.","method":"CRISPR/Cas9 knockout, Deep-DIA and LC-MS proteomics, xenograft model, molecular pathway analyses","journal":"Clinical and translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR/Cas9 KO with proteomics and in vivo validation, single lab, multiple methods","pmids":["40038872"],"is_preprint":false}],"current_model":"SH3GL1 (EEN/endophilin A2) is an SH3 domain-containing endophilin family member that binds dynamin and synaptojanin to participate in clathrin-mediated endocytosis and synaptic vesicle recycling, interacts with BPGAP1 to co-activate EGF receptor endocytosis and ERK1/2 signaling, undergoes cell-cycle-regulated nucleocytoplasmic shuttling with spindle association, promotes cell proliferation via IGF-1 secretion/Akt-mTOR and EGFR/ERK/AP-1 pathways, and mediates B7-H3 surface recycling to promote immune escape, while also suppressing ferroptosis through regulation of FTH1; chromosomal translocation creating MLL-EEN delocalizes EEN to the nucleus where it acts as an aberrant transcriptional activator of Hox genes and interferes with EBP-mediated Ras suppression to drive leukemogenesis."},"narrative":{"mechanistic_narrative":"SH3GL1 (EEN/endophilin A2) is an SH3 domain-containing endophilin family adaptor that couples membrane trafficking machinery to receptor signaling and, when subverted, to oncogenesis [PMID:9238017, PMID:15944398]. Its SH3 domain directly engages the proline-rich tails of the endocytic enzymes dynamin I and synaptojanin, concentrating in nerve terminals to support clathrin-mediated vesicle internalization, a recruitment that is competitively regulated by amphiphysin [PMID:9238017, PMID:10816441]. Through the same SH3 domain it binds the proline-rich PPPRPPLP motif of BPGAP1 to co-activate EGF receptor endocytosis and ERK1/2 phosphorylation, and an SH3-deleted form acts as a dominant negative for these effects [PMID:15944398]. Beyond endocytosis, SH3GL1 shuttles between cytoplasm and nucleus and shows cell-cycle-dependent association with the bipolar spindle and midbody, with peak abundance in G2/M [PMID:15214844]. It drives proliferation through multiple receptor/kinase axes: it is required for IGF-1 secretion and downstream Akt-mTOR activation in myeloma [PMID:24704450], sustains EGFR/ERK/AP-1 signaling that controls MDR1/P-glycoprotein expression in drug-resistant colorectal cancer [PMID:27220321], and supports p130cas/Akt/GSK-3β/FAK signaling and cyclin D1-dependent cell-cycle progression in osteosarcoma [PMID:28702842]. SH3GL1 also promotes immune escape by redirecting B7-H3 away from lysosomal degradation toward cell-surface recycling [PMID:40874628] and suppresses FTH1-mediated ferritinophagy-induced ferroptosis to confer chemoresistance [PMID:40038872]. In leukemogenesis, the MLL-EEN fusion relocalizes EEN to the nucleus via a retained coiled-coil dimerization domain, where it aberrantly transactivates Hox genes such as HoxA7 and sequesters the SH3-binding partner EBP, abrogating EBP-mediated suppression of Ras signaling [PMID:14551139, PMID:15077184].","teleology":[{"year":1997,"claim":"Established SH3GL1's founding molecular role by showing its SH3 domain physically links the core endocytic enzymes dynamin and synaptojanin at nerve terminals.","evidence":"Yeast two-hybrid and reciprocal co-immunoprecipitation from brain extracts with subcellular localization","pmids":["9238017"],"confidence":"High","gaps":["Did not establish a functional consequence for vesicle recycling kinetics","No structural detail of the SH3-proline interaction"]},{"year":2000,"claim":"Defined the binding hierarchy and competitive regulation of endophilin-family SH3 interactions, framing SH3GL1 recruitment to clathrin-coated pits as a contested, regulated event.","evidence":"GST pull-down, yeast two-hybrid, and in vitro competitive binding assays comparing EEN, EEN-B1/B2, Abi-1 and amphiphysin","pmids":["10764144","10816441"],"confidence":"Medium","gaps":["Competition shown in vitro, not in living cells","Functional impact of differential affinities on endocytosis not measured"]},{"year":2003,"claim":"Connected SH3GL1 to Ras-pathway control and leukemogenesis by identifying EBP as an SH3 partner whose Ras-suppressing activity is neutralized when MLL-EEN sequesters it to the nucleus.","evidence":"Co-IP, Elk-1 reporter assays, and Ras transformation assays with subcellular localization","pmids":["14551139"],"confidence":"Medium","gaps":["Mechanism of EBP-Sos-Ras suppression not resolved at molecular level","Single lab; partner not independently validated"]},{"year":2004,"claim":"Showed that the MLL-EEN fusion converts a cytoplasmic adaptor into a nuclear aberrant transcription factor, defining the oncogenic mechanism of the translocation.","evidence":"Subcellular fractionation, HoxA7 promoter reporter assay, and dimerization-domain deletion mutagenesis","pmids":["15077184"],"confidence":"Medium","gaps":["Direct Hox target spectrum not defined genome-wide","Whether transactivation requires endogenous SH3GL1 function unknown"]},{"year":2004,"claim":"Revealed an unexpected cell-cycle-linked role by documenting nucleocytoplasmic shuttling and spindle/midbody association of endogenous SH3GL1 peaking at G2/M.","evidence":"Live-cell imaging, subcellular fractionation, and cell-cycle-synchronized immunofluorescence","pmids":["15214844"],"confidence":"Medium","gaps":["No functional consequence of spindle association demonstrated","Mechanism of nuclear import unknown"]},{"year":2005,"claim":"Mechanistically linked SH3GL1 to receptor tyrosine kinase signaling by showing its SH3-BPGAP1 interaction co-activates EGFR endocytosis and ERK1/2 phosphorylation.","evidence":"Reciprocal Co-IP, deletion/proline-point mutants, MALDI-MS, dominant-negative overexpression, EGFR endocytosis and ERK assays","pmids":["15944398"],"confidence":"High","gaps":["Whether endocytic and signaling roles are mechanistically separable not resolved","Endogenous stoichiometry of the complex unknown"]},{"year":2006,"claim":"Demonstrated direct oncogenic potential of SH3GL1 and placed it under leukemic transcriptional control by AML1-ETO acting at its promoter.","evidence":"NIH3T3 transformation, hematopoietic progenitor self-renewal assays, AP-1 and promoter reporter assays, RNAi","pmids":["16990610"],"confidence":"Medium","gaps":["Mechanism linking adaptor function to AP-1 activation not defined","Direct ChIP confirmation of AML1/Sp1 binding limited"]},{"year":2014,"claim":"Identified an autocrine growth axis by showing SH3GL1 is required for IGF-1 secretion driving Akt-mTOR-dependent proliferation and survival in myeloma.","evidence":"siRNA/overexpression, cell-cycle and apoptosis assays, IGF-1 ELISA, and rescue with exogenous IGF-1","pmids":["24704450"],"confidence":"Medium","gaps":["How an endocytic adaptor controls IGF-1 secretion mechanistically unclear","Single tumor context"]},{"year":2016,"claim":"Extended the EGFR/ERK/AP-1 axis to drug resistance by linking SH3GL1 to MDR1/P-glycoprotein transcription in colorectal cancer.","evidence":"Bidirectional knockdown/overexpression, MDR1 promoter and AP-1 binding assays, EGFR/ERK pharmacological inhibitors","pmids":["27220321"],"confidence":"Medium","gaps":["Direct demonstration that SH3GL1 traffics EGFR not shown here","AP-1 subunit composition at MDR1 promoter undefined"]},{"year":2017,"claim":"Showed SH3GL1 is required for cytokine/growth-factor-induced proliferation and migration through p130cas and Akt/GSK-3β/FAK and cyclin D1 control in osteosarcoma.","evidence":"Adenoviral shRNA knockdown, western blot, cell-cycle and migration assays, xenograft","pmids":["28702842"],"confidence":"Medium","gaps":["Whether SH3GL1 directly scaffolds p130cas not tested","Upstream receptor trafficking step not defined"]},{"year":2025,"claim":"Defined a trafficking-based immune-escape function by showing SH3GL1 recycles B7-H3 to the cell surface, away from lysosomal degradation.","evidence":"Co-IP, immunofluorescence co-localization, flow cytometry, T cell co-culture, and in vivo tumor model","pmids":["40874628"],"confidence":"Medium","gaps":["Endocytic machinery routing B7-H3 not identified","Single tumor type"]},{"year":2025,"claim":"Linked SH3GL1 to ferroptosis resistance by showing its loss triggers FTH1-mediated ferritinophagy-induced ferroptosis and its high expression confers doxorubicin resistance.","evidence":"CRISPR/Cas9 knockout, Deep-DIA/LC-MS proteomics, xenograft, pathway analyses","pmids":["40038872"],"confidence":"Medium","gaps":["Direct physical/regulatory link between SH3GL1 and FTH1 not resolved","Whether ferritinophagy depends on SH3GL1 trafficking function unknown"]},{"year":null,"claim":"It remains unresolved how SH3GL1's core endocytic adaptor activity mechanistically unifies its diverse downstream outputs — receptor signaling, IGF-1 secretion, cargo recycling, cell-cycle/spindle behavior, and ferroptosis suppression.","evidence":"No single study in the corpus integrates the endocytic and signaling/metabolic roles mechanistically","pmids":[],"confidence":"Low","gaps":["No structural model of full-length SH3GL1 in any complex","No unifying mechanism connecting membrane curvature/endocytosis to transcriptional and metabolic phenotypes"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,2,6]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4,5]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4,5]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[5]}],"pathway":[],"complexes":[],"partners":["DNM1","SYNJ1","BPGAP1","EBP","B7-H3","MLL"],"other_free_text":[]}},"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":335,"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":23,"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":20,"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":"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},{"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}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14175,"output_tokens":3465,"usd":0.04725,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10954,"output_tokens":4006,"usd":0.07746,"stage2_stop_reason":"end_turn"},"total_usd":0.12471,"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\": 1997,\n      \"finding\": \"SH3GL1 (SH3p8) contains a Grb2-like SH3 domain that directly binds to the proline-rich COOH-terminal domains of both dynamin I and synaptojanin; pools of synaptojanin and dynamin I were co-precipitated from brain extracts with anti-SH3p4/8/13 antibodies, and SH3p8/SH3GL1 protein was concentrated in nerve terminals.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation from brain extracts, subcellular localization\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP from brain tissue plus two-hybrid, replicated by independent lab (PMID:10764144, PMID:10816441)\",\n      \"pmids\": [\"9238017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The SH3 domain of EEN/SH3GL1 interacts with distinct proline-rich domains of synaptojanin and with dynamin; in vitro competitive binding assays show EEN has higher binding affinity for synaptojanin than Abi-1, and amphiphysin can compete with EEN for binding to synaptojanin and dynamin.\",\n      \"method\": \"GST pull-down, yeast two-hybrid, in vitro competitive binding assay\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — GST pull-down plus yeast two-hybrid plus competitive binding, single lab\",\n      \"pmids\": [\"10764144\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"EEN/SH3GL1 and its family members EEN-B1 and EEN-B2 all bind dynamin and synaptojanin via their SH3 domains, with EEN-B1 having the highest affinity; amphiphysin competes with the EEN family for binding to synaptojanin and dynamin, suggesting regulated recruitment to clathrin-coated pits.\",\n      \"method\": \"Protein binding assays, expression studies, competition assays\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assays with competition, single lab, multiple family members tested\",\n      \"pmids\": [\"10816441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"EEN/SH3GL1 binds a novel protein EBP via its SH3 domain interacting with EBP's proline-rich motif PPERP; EBP simultaneously interacts with Sos (a Ras GEF), and co-expression of EBP with EEN suppresses Ras-induced cellular transformation and Ras-mediated Elk-1 activation. MLL-EEN fusion protein recruits EBP to the nucleus, interfering with EBP's Ras-suppressing activity.\",\n      \"method\": \"Co-immunoprecipitation, reporter assays (Elk-1 transcription), transformation assays, subcellular localization\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, functional reporter assay, transformation assay; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"14551139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"EEN/SH3GL1 is normally localized in the cytoplasm; the MLL-EEN fusion protein relocalizes EEN to the nucleus via a coiled-coil dimerization domain retained in the fusion, and MLL-EEN can transactivate the HoxA7 promoter acting as an aberrant transcription factor.\",\n      \"method\": \"Subcellular fractionation, reporter assay (HoxA7 promoter), deletion mutagenesis of dimerization domain\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — localization experiments with functional consequence (transactivation), deletion mutagenesis, single lab\",\n      \"pmids\": [\"15077184\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"EEN/SH3GL1 (endophilin A2) undergoes nucleocytoplasmic shuttling and displays cell-cycle-dependent localization: perichromosomal in prometaphase, co-localizes with the bipolar spindle in metaphase/anaphase, and redistributes to the midzone/midbody in telophase, with highest protein levels in G2/M phase.\",\n      \"method\": \"Live-cell imaging, subcellular fractionation, cell-cycle synchronization, immunofluorescence\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by immunofluorescence across cell cycle stages with protein-level correlation, single lab\",\n      \"pmids\": [\"15214844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"EEN/SH3GL1 directly binds BPGAP1 via its SH3 domain interacting with the PPPRPPLP proline-rich motif (residues 182-189) of BPGAP1, with prolines 184 and 186 indispensable; co-expression of EEN with wild-type BPGAP1 (but not proline mutant) enhances EGF-stimulated receptor endocytosis and ERK1/2 phosphorylation; EEN lacking the SH3 domain acts as dominant-negative blocking these effects.\",\n      \"method\": \"Pull-down, co-immunoprecipitation, deletion mutant analysis, MALDI-MS identification, dominant-negative overexpression, EGF receptor endocytosis assay, ERK phosphorylation assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, multiple deletion mutants, dominant-negative functional assay, multiple orthogonal readouts in single rigorous study\",\n      \"pmids\": [\"15944398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Overexpressed EEN/SH3GL1 has oncogenic/transforming potential in NIH3T3 cells, stimulates cell proliferation, increases AP-1 transcriptional activity, and enhances self-renewal and proliferation of murine hematopoietic progenitor cells upon retroviral transduction; AML1-ETO aberrantly transactivates the EEN gene through an AML1 binding site in the EEN promoter, while Sp1 binds the GC-stretch for normal EEN expression.\",\n      \"method\": \"NIH3T3 transformation assay, retroviral transduction, reporter/promoter assays, RNAi knockdown, ChIP-implied promoter binding\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays (transformation, proliferation, AP-1 reporter, hematopoietic progenitor assay), single lab\",\n      \"pmids\": [\"16990610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"EEN/SH3GL1 is required for IGF-1 secretion in multiple myeloma cells; EEN knockdown reduces IGF-1 secretion and suppresses Akt-mTOR pathway activation, G1-to-S cell cycle transition, and delays apoptosis via Bcl2/Bax-mitochondrial pathway; exogenous IGF-1 rescues the EEN-depletion phenotype.\",\n      \"method\": \"siRNA knockdown, overexpression, cell cycle analysis, apoptosis assay, ELISA for IGF-1, rescue experiment with exogenous IGF-1 or IGF-1 neutralization\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function and gain-of-function with rescue experiment, multiple pathway readouts, single lab\",\n      \"pmids\": [\"24704450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SH3GL1 knockdown in drug-resistant colorectal cancer cells downregulates MDR1/P-glycoprotein expression by inhibiting EGFR and ERK1/2 signaling and reducing AP-1 binding activity at the MDR1 promoter; SH3GL1 overexpression has the opposite effect; EGFR or ERK1/2 kinase inhibitors partially mimic SH3GL1 knockdown.\",\n      \"method\": \"siRNA knockdown, overexpression (pCDNA3.1), western blot, MDR1 promoter activity assay, AP-1 binding assay, pharmacological inhibitors\",\n      \"journal\": \"Tumour biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional genetic manipulation plus pharmacological epistasis, multiple pathway readouts, single lab\",\n      \"pmids\": [\"27220321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SH3GL1 knockdown (adenovirus shRNA) abolishes p130cas phosphorylation and blocks IL-6- and VEGF-induced osteosarcoma cell proliferation and migration; SH3GL1 depletion causes G0/G1 arrest via downregulation of cyclin D1, activation of p27KIP1, and reduced p-Rb, and attenuates phosphorylation of Akt/GSK-3β/FAK.\",\n      \"method\": \"adenovirus shRNA knockdown, western blot, cell cycle analysis, migration assay, in vivo xenograft\",\n      \"journal\": \"Human cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function in vitro and in vivo with specific pathway readouts, 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 enhancing immune escape in NSCLC; SH3GL1 overexpression suppresses T cell proliferation, cytotoxicity, and activation in vitro and promotes tumor growth with increased Treg infiltration in vivo.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, flow cytometry, confocal microscopy, T cell co-culture assay, in vivo tumor model, overexpression\",\n      \"journal\": \"The International journal of biological markers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and IF confirm physical interaction, functional recycling assay with 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 ferroptosis, specifically ferritinophagy-induced ferroptosis, in DLBCL cells; high SH3GL1 expression suppresses doxorubicin-induced ferroptosis, conferring drug resistance.\",\n      \"method\": \"CRISPR/Cas9 knockout, Deep-DIA and LC-MS proteomics, xenograft model, molecular pathway analyses\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR/Cas9 KO with proteomics and in vivo validation, single lab, multiple methods\",\n      \"pmids\": [\"40038872\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SH3GL1 (EEN/endophilin A2) is an SH3 domain-containing endophilin family member that binds dynamin and synaptojanin to participate in clathrin-mediated endocytosis and synaptic vesicle recycling, interacts with BPGAP1 to co-activate EGF receptor endocytosis and ERK1/2 signaling, undergoes cell-cycle-regulated nucleocytoplasmic shuttling with spindle association, promotes cell proliferation via IGF-1 secretion/Akt-mTOR and EGFR/ERK/AP-1 pathways, and mediates B7-H3 surface recycling to promote immune escape, while also suppressing ferroptosis through regulation of FTH1; chromosomal translocation creating MLL-EEN delocalizes EEN to the nucleus where it acts as an aberrant transcriptional activator of Hox genes and interferes with EBP-mediated Ras suppression to drive leukemogenesis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SH3GL1 (EEN/endophilin A2) is an SH3 domain-containing endophilin family adaptor that couples membrane trafficking machinery to receptor signaling and, when subverted, to oncogenesis [#0, #6]. Its SH3 domain directly engages the proline-rich tails of the endocytic enzymes dynamin I and synaptojanin, concentrating in nerve terminals to support clathrin-mediated vesicle internalization, a recruitment that is competitively regulated by amphiphysin [#0, #2]. Through the same SH3 domain it binds the proline-rich PPPRPPLP motif of BPGAP1 to co-activate EGF receptor endocytosis and ERK1/2 phosphorylation, and an SH3-deleted form acts as a dominant negative for these effects [#6]. Beyond endocytosis, SH3GL1 shuttles between cytoplasm and nucleus and shows cell-cycle-dependent association with the bipolar spindle and midbody, with peak abundance in G2/M [#5]. It drives proliferation through multiple receptor/kinase axes: it is required for IGF-1 secretion and downstream Akt-mTOR activation in myeloma [#8], sustains EGFR/ERK/AP-1 signaling that controls MDR1/P-glycoprotein expression in drug-resistant colorectal cancer [#9], and supports p130cas/Akt/GSK-3\\u03b2/FAK signaling and cyclin D1-dependent cell-cycle progression in osteosarcoma [#10]. SH3GL1 also promotes immune escape by redirecting B7-H3 away from lysosomal degradation toward cell-surface recycling [#11] and suppresses FTH1-mediated ferritinophagy-induced ferroptosis to confer chemoresistance [#12]. In leukemogenesis, the MLL-EEN fusion relocalizes EEN to the nucleus via a retained coiled-coil dimerization domain, where it aberrantly transactivates Hox genes such as HoxA7 and sequesters the SH3-binding partner EBP, abrogating EBP-mediated suppression of Ras signaling [#3, #4].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established SH3GL1's founding molecular role by showing its SH3 domain physically links the core endocytic enzymes dynamin and synaptojanin at nerve terminals.\",\n      \"evidence\": \"Yeast two-hybrid and reciprocal co-immunoprecipitation from brain extracts with subcellular localization\",\n      \"pmids\": [\"9238017\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish a functional consequence for vesicle recycling kinetics\", \"No structural detail of the SH3-proline interaction\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Defined the binding hierarchy and competitive regulation of endophilin-family SH3 interactions, framing SH3GL1 recruitment to clathrin-coated pits as a contested, regulated event.\",\n      \"evidence\": \"GST pull-down, yeast two-hybrid, and in vitro competitive binding assays comparing EEN, EEN-B1/B2, Abi-1 and amphiphysin\",\n      \"pmids\": [\"10764144\", \"10816441\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Competition shown in vitro, not in living cells\", \"Functional impact of differential affinities on endocytosis not measured\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Connected SH3GL1 to Ras-pathway control and leukemogenesis by identifying EBP as an SH3 partner whose Ras-suppressing activity is neutralized when MLL-EEN sequesters it to the nucleus.\",\n      \"evidence\": \"Co-IP, Elk-1 reporter assays, and Ras transformation assays with subcellular localization\",\n      \"pmids\": [\"14551139\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of EBP-Sos-Ras suppression not resolved at molecular level\", \"Single lab; partner not independently validated\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showed that the MLL-EEN fusion converts a cytoplasmic adaptor into a nuclear aberrant transcription factor, defining the oncogenic mechanism of the translocation.\",\n      \"evidence\": \"Subcellular fractionation, HoxA7 promoter reporter assay, and dimerization-domain deletion mutagenesis\",\n      \"pmids\": [\"15077184\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct Hox target spectrum not defined genome-wide\", \"Whether transactivation requires endogenous SH3GL1 function unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Revealed an unexpected cell-cycle-linked role by documenting nucleocytoplasmic shuttling and spindle/midbody association of endogenous SH3GL1 peaking at G2/M.\",\n      \"evidence\": \"Live-cell imaging, subcellular fractionation, and cell-cycle-synchronized immunofluorescence\",\n      \"pmids\": [\"15214844\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional consequence of spindle association demonstrated\", \"Mechanism of nuclear import unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Mechanistically linked SH3GL1 to receptor tyrosine kinase signaling by showing its SH3-BPGAP1 interaction co-activates EGFR endocytosis and ERK1/2 phosphorylation.\",\n      \"evidence\": \"Reciprocal Co-IP, deletion/proline-point mutants, MALDI-MS, dominant-negative overexpression, EGFR endocytosis and ERK assays\",\n      \"pmids\": [\"15944398\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether endocytic and signaling roles are mechanistically separable not resolved\", \"Endogenous stoichiometry of the complex unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrated direct oncogenic potential of SH3GL1 and placed it under leukemic transcriptional control by AML1-ETO acting at its promoter.\",\n      \"evidence\": \"NIH3T3 transformation, hematopoietic progenitor self-renewal assays, AP-1 and promoter reporter assays, RNAi\",\n      \"pmids\": [\"16990610\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking adaptor function to AP-1 activation not defined\", \"Direct ChIP confirmation of AML1/Sp1 binding limited\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified an autocrine growth axis by showing SH3GL1 is required for IGF-1 secretion driving Akt-mTOR-dependent proliferation and survival in myeloma.\",\n      \"evidence\": \"siRNA/overexpression, cell-cycle and apoptosis assays, IGF-1 ELISA, and rescue with exogenous IGF-1\",\n      \"pmids\": [\"24704450\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How an endocytic adaptor controls IGF-1 secretion mechanistically unclear\", \"Single tumor context\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Extended the EGFR/ERK/AP-1 axis to drug resistance by linking SH3GL1 to MDR1/P-glycoprotein transcription in colorectal cancer.\",\n      \"evidence\": \"Bidirectional knockdown/overexpression, MDR1 promoter and AP-1 binding assays, EGFR/ERK pharmacological inhibitors\",\n      \"pmids\": [\"27220321\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct demonstration that SH3GL1 traffics EGFR not shown here\", \"AP-1 subunit composition at MDR1 promoter undefined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed SH3GL1 is required for cytokine/growth-factor-induced proliferation and migration through p130cas and Akt/GSK-3\\u03b2/FAK and cyclin D1 control in osteosarcoma.\",\n      \"evidence\": \"Adenoviral shRNA knockdown, western blot, cell-cycle and migration assays, xenograft\",\n      \"pmids\": [\"28702842\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SH3GL1 directly scaffolds p130cas not tested\", \"Upstream receptor trafficking step not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a trafficking-based immune-escape function by showing SH3GL1 recycles B7-H3 to the cell surface, away from lysosomal degradation.\",\n      \"evidence\": \"Co-IP, immunofluorescence co-localization, flow cytometry, T cell co-culture, and in vivo tumor model\",\n      \"pmids\": [\"40874628\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endocytic machinery routing B7-H3 not identified\", \"Single tumor type\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked SH3GL1 to ferroptosis resistance by showing its loss triggers FTH1-mediated ferritinophagy-induced ferroptosis and its high expression confers doxorubicin resistance.\",\n      \"evidence\": \"CRISPR/Cas9 knockout, Deep-DIA/LC-MS proteomics, xenograft, pathway analyses\",\n      \"pmids\": [\"40038872\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct physical/regulatory link between SH3GL1 and FTH1 not resolved\", \"Whether ferritinophagy depends on SH3GL1 trafficking function unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how SH3GL1's core endocytic adaptor activity mechanistically unifies its diverse downstream outputs — receptor signaling, IGF-1 secretion, cargo recycling, cell-cycle/spindle behavior, and ferroptosis suppression.\",\n      \"evidence\": \"No single study in the corpus integrates the endocytic and signaling/metabolic roles mechanistically\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of full-length SH3GL1 in any complex\", \"No unifying mechanism connecting membrane curvature/endocytosis to transcriptional and metabolic phenotypes\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 2, 6]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005653656\", \"supporting_discovery_ids\": []}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"DNM1\", \"SYNJ1\", \"BPGAP1\", \"EBP\", \"B7-H3\", \"MLL\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}