SH3GL1

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).

1. 1997 High

   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

   PMID:9238017

   Open questions at the time

   • Did not establish a functional consequence for vesicle recycling kinetics
   • No structural detail of the SH3-proline interaction
2. 2000 Medium

   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

   PMID:10764144 PMID:10816441

   Open questions at the time

   • Competition shown in vitro, not in living cells
   • Functional impact of differential affinities on endocytosis not measured
3. 2003 Medium

   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

   PMID:14551139

   Open questions at the time

   • Mechanism of EBP-Sos-Ras suppression not resolved at molecular level
   • Single lab; partner not independently validated
4. 2004 Medium

   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

   PMID:15077184

   Open questions at the time

   • Direct Hox target spectrum not defined genome-wide
   • Whether transactivation requires endogenous SH3GL1 function unknown
5. 2004 Medium

   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

   PMID:15214844

   Open questions at the time

   • No functional consequence of spindle association demonstrated
   • Mechanism of nuclear import unknown
6. 2005 High

   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

   PMID:15944398

   Open questions at the time

   • Whether endocytic and signaling roles are mechanistically separable not resolved
   • Endogenous stoichiometry of the complex unknown
7. 2006 Medium

   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

   PMID:16990610

   Open questions at the time

   • Mechanism linking adaptor function to AP-1 activation not defined
   • Direct ChIP confirmation of AML1/Sp1 binding limited
8. 2014 Medium

   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

   PMID:24704450

   Open questions at the time

   • How an endocytic adaptor controls IGF-1 secretion mechanistically unclear
   • Single tumor context
9. 2016 Medium

   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

   PMID:27220321

   Open questions at the time

   • Direct demonstration that SH3GL1 traffics EGFR not shown here
   • AP-1 subunit composition at MDR1 promoter undefined
10. 2017 Medium

    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

    PMID:28702842

    Open questions at the time

    • Whether SH3GL1 directly scaffolds p130cas not tested
    • Upstream receptor trafficking step not defined
11. 2025 Medium

    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

    PMID:40874628

    Open questions at the time

    • Endocytic machinery routing B7-H3 not identified
    • Single tumor type
12. 2025 Medium

    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

    PMID:40038872

    Open questions at the time

    • Direct physical/regulatory link between SH3GL1 and FTH1 not resolved
    • Whether ferritinophagy depends on SH3GL1 trafficking function unknown

• 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.
• No structural model of full-length SH3GL1 in any complex
• No unifying mechanism connecting membrane curvature/endocytosis to transcriptional and metabolic phenotypes