Affinage

SH3GL1

Endophilin-A2 · UniProt Q99961

Length
368 aa
Mass
41.5 kDa
Annotated
2026-04-28
25 papers in source corpus 14 papers cited in narrative 14 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1997 High

    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

    PMID:9238017

    Open questions at the time
    • Functional consequence of SH3GL1 loss on vesicle recycling not tested
    • BAR domain membrane-tubulating activity not yet assessed
  2. 1997 High

    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

    PMID:9122235

    Open questions at the time
    • Mechanism of leukemic transformation by MLL-EEN not yet defined
    • Frequency in leukemia cohorts not established
  3. 2000 High

    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

    PMID:10764144 PMID:10816441

    Open questions at the time
    • In vivo relevance of amphiphysin–EEN competition not demonstrated
    • Stoichiometry at endocytic sites unknown
  4. 2003 Medium

    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

    PMID:14551139

    Open questions at the time
    • Physiological context for EEN–EBP–Sos complex not defined
    • No genetic loss-of-function validation
  5. 2004 Medium

    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

    PMID:15214844

    Open questions at the time
    • Direct mitotic target or function not identified
    • Nuclear import/export signals not mapped
  6. 2004 Medium

    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

    PMID:15077184

    Open questions at the time
    • Target gene repertoire beyond HoxA7 not explored
    • In vivo leukemogenesis model not reported
  7. 2005 High

    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

    PMID:15944398

    Open questions at the time
    • Whether SH3GL1–BPGAP1 acts at clathrin-coated pits or later endocytic compartments not resolved
    • Structural basis of cooperativity unknown
  8. 2006 Medium

    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

    PMID:16990610

    Open questions at the time
    • Whether transformation depends on endocytic or nuclear functions of SH3GL1 not distinguished
    • No loss-of-function in AML1-ETO leukemia
  9. 2014 Medium

    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

    PMID:24704450

    Open questions at the time
    • Step in IGF-1 secretory pathway controlled by SH3GL1 not identified
    • Single myeloma cell line system
  10. 2016 Medium

    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

    PMID:27220321

    Open questions at the time
    • Direct molecular mechanism linking SH3GL1 to EGFR activation not resolved
    • Not tested whether the endocytic function is required
  11. 2025 Medium

    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

    PMID:40874628

    Open questions at the time
    • Endosomal sorting mechanism (e.g., Rab GTPase involvement) not defined
    • Not tested in other checkpoint molecules
  12. 2025 Medium

    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

    PMID:40038872

    Open questions at the time
    • Direct physical interaction between SH3GL1 and FTH1 not demonstrated
    • Mechanism linking endophilin to ferritinophagy regulation unknown
    • Single DLBCL model

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0005198 structural molecule activity 2
Localization
GO:0031410 cytoplasmic vesicle 3 GO:0005634 nucleus 2 GO:0005829 cytosol 1 GO:0005856 cytoskeleton 1
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-5653656 Vesicle-mediated transport 5 R-HSA-1643685 Disease 3 R-HSA-1640170 Cell Cycle 2 R-HSA-168256 Immune System 1 R-HSA-5357801 Programmed Cell Death 1
Partners
AMPHBPGAP1CD276DNM1EBPKMT2ASYNJ1

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 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. Yeast two-hybrid screen, co-immunoprecipitation from brain extracts, biochemical binding studies Proceedings of the National Academy of Sciences of the United States of America High 9238017
1997 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. Cloning of chromosomal translocation t(11;19)(q23;p13), sequence analysis of MLL/EEN fusion transcript Proceedings of the National Academy of Sciences of the United States of America High 9122235
2000 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. GST pull-down, yeast two-hybrid, in vitro competitive binding assays Leukemia High 10764144
2000 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. Binding affinity studies, competition assays with amphiphysin The Biochemical journal Medium 10816441
2003 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. Co-immunoprecipitation, yeast two-hybrid, reporter assay (Elk-1 activation), cellular transformation assay Blood Medium 14551139
2004 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. Immunofluorescence, cell fractionation, cell cycle synchronization, flow cytometry The Biochemical journal Medium 15214844
2004 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. Subcellular localization studies, deletion mutant analysis, reporter gene assay (HoxA7 promoter), oncogenic transformation assay Oncogene Medium 15077184
2005 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. Mass spectrometry, pull-down with deletion mutants, co-immunoprecipitation, EGFR endocytosis assay, ERK1/2 phosphorylation assay, dominant-negative analysis Journal of cell science High 15944398
2006 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. NIH3T3 transformation assay, retroviral transduction, reporter assay, ChIP-based promoter analysis, RNAi knockdown Blood Medium 16990610
2014 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. siRNA knockdown, overexpression, cell cycle analysis, apoptosis assay, IGF-1 measurement, pathway inhibition rescue experiments Biochemical and biophysical research communications Medium 24704450
2016 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. siRNA knockdown, overexpression, EGFR/ERK inhibitor treatment, MDR1 promoter activity assay, AP-1 binding assay, western blot Tumour biology Medium 27220321
2017 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. Adenovirus shRNA knockdown, cell cycle analysis, in vivo tumor xenograft, western blot for signaling intermediates Human cell Medium 28702842
2025 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. Co-immunoprecipitation, immunofluorescence, flow cytometry, confocal microscopy, T cell co-culture assay, in vivo tumor model The International journal of biological markers Medium 40874628
2025 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). CRISPR/Cas9 knockout, proteomics (Deep-DIA, LC-MS), xenograft models, molecular pathway analyses Clinical and translational medicine Medium 40038872

Source papers

Stage 0 corpus · 25 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 The SH3p4/Sh3p8/SH3p13 protein family: binding partners for synaptojanin and dynamin via a Grb2-like Src homology 3 domain. Proceedings of the National Academy of Sciences of the United States of America 334 9238017
1998 Phospholipid signalling in the nucleus. Een DAG uit het leven van de inositide signalering in de nucleus. Biochimica et biophysica acta 155 9838115
1997 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. Proceedings of the National Academy of Sciences of the United States of America 107 9122235
2005 Activation of EGF receptor endocytosis and ERK1/2 signaling by BPGAP1 requires direct interaction with EEN/endophilin II and a functional RhoGAP domain. Journal of cell science 42 15944398
2000 The interaction between EEN and Abi-1, two MLL fusion partners, and synaptojanin and dynamin: implications for leukaemogenesis. Leukemia 36 10764144
2003 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. Blood 33 14551139
2004 Functional contribution of EEN to leukemogenic transformation by MLL-EEN fusion protein. Oncogene 26 15077184
2013 miR-218 is downregulated and directly targets SH3GL1 in childhood medulloblastoma. Molecular medicine reports 23 23970061
2000 Expression and protein-binding studies of the EEN gene family, new interacting partners for dynamin, synaptojanin and huntingtin proteins. The Biochemical journal 22 10816441
2021 MiR-3663-3p participates in the anti-hepatocellular carcinoma proliferation activity of baicalein by targeting SH3GL1 and negatively regulating EGFR/ERK/NF-κB signaling. Toxicology and applied pharmacology 18 33838155
2016 SH3GL1 inhibition reverses multidrug resistance in colorectal cancer cells by downregulation of MDR1/P-glycoprotein via EGFR/ERK/AP-1 pathway. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 18 27220321
2017 Essential role of SH3GL1 in interleukin-6(IL-6)- and vascular endothelial growth factor (VEGF)-triggered p130cas-mediated proliferation and migration of osteosarcoma cells. Human cell 17 28702842
2004 Subcellular localization of EEN/endophilin A2, a fusion partner gene in leukaemia. The Biochemical journal 16 15214844
2006 The Mll-Een knockin fusion gene enhances proliferation of myeloid progenitors derived from mouse embryonic stem cells and causes myeloid leukaemia in chimeric mice. Leukemia 14 16888613
2006 Aberrant transcriptional regulation of the MLL fusion partner EEN by AML1-ETO and its implication in leukemogenesis. Blood 11 16990610
2025 SH3GL1-activated FTH1 inhibits ferroptosis and confers doxorubicin resistance in diffuse large B-cell lymphoma. Clinical and translational medicine 7 40038872
2022 Exploring Different Effects of Exclusive Enteral Nutrition (EEN) and Corticosteroids on the Gut Microbiome in Crohn's Disease Based on a Three-Stage Strategy. Gastroenterology research and practice 7 35935714
2014 EEN regulates the proliferation and survival of multiple myeloma cells by potentiating IGF-1 secretion. Biochemical and biophysical research communications 6 24704450
2007 Aberrant dendritic cell differentiation initiated by the Mll-Een fusion gene does not require leukemic transformation. Journal of leukocyte biology 3 17895399
2010 [Comparative analysis of sequence alignment of SH3GL1 gene as a disease candidate gene of adolescent idiopathic scoliosis]. Zhonghua wai ke za zhi [Chinese journal of surgery] 2 20627007
2023 Efficacy of short-chain polypeptide-based EEN formulas in alleviating intestinal injury in children with Crohn's disease: a single-center study in China. Frontiers in nutrition 1 37215203
2025 SH3GL1 mediates B7-H3 recycling and enhances the immune escape in non-small cell lung cancer. The International journal of biological markers 0 40874628
2003 [Establishment of transgenic mice for HRX-EEN fusion gene]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 0 14669223
2001 Klinefelter syndroom en psychiatrische stoornissen: Twee gevalsbeschrijvingen en een literatuuroverzicht. Acta neuropsychiatrica 0 26983763
1999 Positron emissie tomografie (PET) bij stemmingsstoornissen: een overzicht. Acta neuropsychiatrica 0 26976369