TOM1L1

TOM1L1/Srcasm is a VHS-GAT domain endocytic adaptor that couples Src-family kinase (SFK) and receptor tyrosine kinase signaling to membrane trafficking and lysosomal receptor turnover (PMID:11711534, PMID:15611048). It was identified as a Fyn substrate and binding partner, engaged through cooperative Fyn SH2/SH3 binding, and once tyrosine-phosphorylated it recruits Grb2 and the p85 subunit of PI3K (PMID:11711534). Through its VHS domain, an inter-domain PTAP/PSAP motif, and a C-terminal clathrin-interacting motif, TOM1L1 binds Hrs, TSG101, and clathrin heavy chain, and is recruited from cytosol onto endosomes (PMID:15611048, PMID:18367816). Downstream of EGFR, SFK-dependent phosphorylation of TOM1L1 enables a Grb2/Shc bridge to activated receptor, driving plasma-membrane recruitment, redistribution to early endosomes, and clathrin-dependent EGFR endocytosis (PMID:19798056). TOM1L1 acts as a negative regulator of SFK mitogenic signaling: it forms a complex with clathrin heavy chain that depletes SFK from caveolae/cholesterol-enriched microdomains, blocking Src association with the PDGF receptor and limiting DNA synthesis and transformation (PMID:16479011, PMID:17785434), and it promotes phosphorylation- and GAT-domain-dependent lysosomal downregulation of active Fyn and Src (PMID:17046829, PMID:34729053). In vivo, raising Srcasm levels suppresses Fyn-driven epidermal hyperproliferation and cutaneous neoplasia in a phosphorylation-dependent manner (PMID:17046829, PMID:19934324). In ERBB2-amplified breast cancer, ERBB2 drives Ser321 phosphorylation that triggers GAT-dependent binding to TOLLIP and trafficking of MT1-MMP to invadopodia for matrix degradation, a pro-invasive role independent of SRC (PMID:26899482). Within a distinct subset of clathrin-coated pits, TOM1L1 cooperates with Fyn to recruit the 5-phosphatase SHIP2 and selectively support EGF-stimulated Akt2 phosphorylation (PMID:35238864).

1. 2001 High

   Establishing that TOM1L1/Srcasm is a direct Fyn substrate and SFK-coupled adaptor defined its entry point into tyrosine-kinase signaling.

   Evidence Yeast two-hybrid, reciprocal Co-IP with domain mutants, and in vitro kinase assay showing Fyn SH2/SH3-dependent binding and phospho-dependent Grb2/p85 recruitment

   PMID:11711534

   Open questions at the time

   • Cellular consequence of Fyn-TOM1L1 interaction not yet defined
   • Tyrosine phosphosites not individually mapped
2. 2004 Medium

   Linking TOM1L1 to EGFR ligands and SFK activation in keratinocytes connected the adaptor to growth-factor signaling and differentiation control.

   Evidence Adenoviral overexpression with kinase activity and Elk-1 reporter assays under EGFR/SFK inhibition in keratinocytes

   PMID:15579470

   Open questions at the time

   • Overexpression-based, endogenous loss-of-function not tested
   • Mechanism linking SFK activation to anti-proliferative outcome unresolved
3. 2004 High

   Mapping VHS-Hrs, PTAP-TSG101, and C-terminal SFK/Grb2/p85 interactions placed TOM1L1 on the endosomal/ESCRT trafficking pathway.

   Evidence Co-IP, GST pulldown, and confocal imaging with domain-deletion constructs showing Hrs/active-Fyn-driven endosomal recruitment

   PMID:15611048

   Open questions at the time

   • Functional consequence of endosomal recruitment not directly tested here
   • Stoichiometry within ESCRT machinery unknown
4. 2006 High

   Genetic epistasis established TOM1L1 as a negative regulator of PDGF/SFK mitogenic signaling, situating it upstream of receptor-SFK complex formation and the c-Myc/p53 axis.

   Evidence Overexpression/dominant-negative DNA synthesis assays with Co-IP and c-Myc/p53/Src epistasis

   PMID:16479011

   Open questions at the time

   • Did not resolve how TOM1L1 physically reduces receptor-SFK association
   • Effect specific to mitogenesis but not actin assembly unexplained
5. 2006 High

   An in vivo double-transgenic model demonstrated that Srcasm drives phosphorylation- and GAT-domain-dependent Fyn downregulation, resolving Fyn-induced epidermal hyperproliferation.

   Evidence K14-Fyn/K14-Srcasm mice and keratinocytes with phosphorylation and GAT-domain mutants

   PMID:17046829

   Open questions at the time

   • Degradative route (lysosomal vs other) not yet specified at this stage
   • Generality beyond Fyn unaddressed here
6. 2007 High

   Identifying a TOM1L1-clathrin heavy chain complex that depletes SFK from caveolae provided the spatial mechanism for negative regulation of Src-driven transformation.

   Evidence Co-IP, caveolae fractionation, and DNA synthesis/transformation assays with dominant-negative constructs

   PMID:17785434

   Open questions at the time

   • How CHC association is regulated to switch between caveolar accumulation and SFK depletion unclear
7. 2007 Medium

   Demonstrating TOM1L1 as a Lyn substrate downstream of FcεRI extended its SFK-coupled adaptor role to mast-cell immune signaling.

   Evidence Bacterial expression library screen with baculoviral Lyn/Syk, co-transfection phosphorylation assays, and TNFα ELISA with domain deletions

   PMID:17977829

   Open questions at the time

   • Endogenous requirement not tested by knockdown
   • Mechanism linking VHS/coiled-coil domains to TNFα release unresolved
8. 2008 Medium

   Showing dual PTAP/PSAP-TSG101 motifs and TSG101-dependent midbody recruitment implicated TOM1L1 in MVB formation, viral egress, and cytokinesis.

   Evidence Co-IP, PTAP/PSAP mutagenesis, HIV-1 Gag competition assays, and cytokinesis imaging

   PMID:18367816

   Open questions at the time

   • Functional role in cytokinesis/viral budding not tested by loss-of-function
   • Single-lab observation
9. 2009 High

   Loss-of-function with rescue established TOM1L1 as a required adaptor for EGFR endocytosis, bridging phospho-EGFR to clathrin via Grb2/Shc and a novel clathrin-interacting motif.

   Evidence RNAi knockdown with rescue, dominant-negative mutants, GST pulldown, and live-cell EGF endocytosis assays

   PMID:19798056

   Open questions at the time

   • Selectivity for EGFR versus other receptors not delineated
   • Relationship between endocytic role and SFK downregulation not unified
10. 2009 High

    An in vivo neoplasia model confirmed that Srcasm suppresses cutaneous tumorigenesis with broad rebalancing of SFK/ERK/STAT3/Notch/p53 signaling, dependent on its phosphorylation.

    Evidence K14-Fyn Y528F/K14-Srcasm double transgenic mice with IHC and pathway Western blotting plus nonphosphorylatable mutant control

    PMID:19934324

    Open questions at the time

    • Whether downstream changes are direct or secondary to SFK loss unresolved
    • Human tumor relevance not addressed
11. 2016 High

    Defining ERBB2-driven Ser321 phosphorylation, GAT-TOLLIP binding, and MT1-MMP trafficking revealed an SRC-independent pro-invasive function in breast cancer.

    Evidence Co-IP, Ser321 and GAT-domain mutants, MT1-MMP trafficking, invadopodia and invasion assays with RNAi

    PMID:26899482

    Open questions at the time

    • Identity of the Ser321 kinase not established
    • How the same GAT domain selects TOLLIP versus SFK-degradation cargo unknown
12. 2021 Medium

    Comparative analysis distinguished Srcasm from c-Cbl by showing it preferentially downregulates native SFKs via a lysosomal, not proteasomal, route.

    Evidence Co-transfection in HaCaT cells with proteasome/lysosome inhibitors and Srcasm/c-Cbl mutants

    PMID:34729053

    Open questions at the time

    • Lysosomal targeting machinery for SFK cargo not identified
    • Single-lab, overexpression-based
13. 2022 High

    Identifying a TOM1L1/Fyn-enriched CCP subset that recruits SHIP2 explained isoform-selective control of EGF-stimulated Akt2 signaling.

    Evidence TIRF CCP tracking, RNAi, SHIP2 recruitment imaging, and phospho-Akt1/Akt2 Western blotting

    PMID:35238864

    Open questions at the time

    • Molecular basis for Akt2-versus-Akt1 selectivity unresolved
    • Compositional determinants of the specialized CCP subset undefined

• How TOM1L1 switches between opposing roles — negative SFK regulator/lysosomal degradation versus pro-invasive TOLLIP/MT1-MMP trafficking — through differential Tyr versus Ser321 phosphorylation and partner selection remains unresolved.
• No structural model of how the GAT domain discriminates TOLLIP from SFK-degradation cargo
• The Ser321 kinase downstream of ERBB2 is unidentified
• Endogenous balance of these functions across tissues untested