{"gene":"TOM1L1","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2001,"finding":"Srcasm (TOM1L1) was identified as a novel substrate and binding partner of Fyn kinase; association requires cooperative binding between Fyn SH2 and SH3 domains and canonical binding sites in Srcasm. Fyn phosphorylates Srcasm on tyrosine residues. Phosphorylated Srcasm interacts with Grb2 and the p85 regulatory subunit of PI3K in a phosphorylation-dependent manner.","method":"Yeast two-hybrid screen, co-immunoprecipitation, in vitro kinase assay, domain-binding mutants","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding experiments with domain mutants, in vitro phosphorylation, and multiple orthogonal methods in a dedicated study; replicated in subsequent papers","pmids":["11711534"],"is_preprint":false},{"year":2004,"finding":"EGF receptor ligands promote tyrosine phosphorylation of endogenous TOM1L1/Srcasm in keratinocytes; increased Srcasm levels activate endogenous Fyn and Src (preferentially) and potentiate EGF-dependent SFK signaling, enhancing p44/42 MAPK activity and Elk-1-dependent transcription while inhibiting proliferation and promoting differentiation.","method":"Adenoviral overexpression, Western blotting, kinase activity assays, reporter assays (Elk-1), EGFR and SFK inhibitors","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD/OE with defined cellular phenotypes and multiple pathway readouts in a single lab","pmids":["15579470"],"is_preprint":false},{"year":2004,"finding":"The VHS domain of Tom1L1 interacts with Hrs (HGF-regulated tyrosine kinase substrate); a PTAP motif between the VHS and GAT domains binds TSG101. Tom1L1 is recruited from cytosol to endosomes upon Hrs overexpression. Tyrosine motifs in the C-terminal region mediate interactions with Src family kinases (including Fyn), Grb2, and p85. Constitutively active Fyn promotes Tom1L1 recruitment to enlarged endosomes.","method":"Co-immunoprecipitation, GST pulldown, epitope-tagged constructs with confocal imaging, domain-deletion mutants","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple binding partners mapped to specific domains, reciprocal IPs, localization experiments with mechanistic follow-up; independently consistent with other papers","pmids":["15611048"],"is_preprint":false},{"year":2006,"finding":"Tom1L1 is a negative regulator of SFK mitogenic signaling induced by PDGF: it inhibits DNA synthesis, reduces Src association with the PDGF receptor, and its inactivation potentiates receptor-SFK complex formation and DNA synthesis. Inhibition is overcome by c-Myc expression or p53 inactivation. Tom1L1 does not inhibit actin assembly induced by PDGF, nor DNA synthesis from constitutively active SrcY527F.","method":"Overexpression and dominant-negative studies, DNA synthesis assay (BrdU/thymidine), co-immunoprecipitation, genetic epistasis (c-Myc, p53, Src/Fyn co-expression)","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis combined with biochemical receptor-SFK association assays and multiple rescue experiments; mechanistic pathway placement established","pmids":["16479011"],"is_preprint":false},{"year":2006,"finding":"In vivo and in vitro, Srcasm (TOM1L1) promotes Fyn down-regulation in a phosphorylation-dependent manner requiring Fyn kinase activity and the Srcasm GAT domain. A nonphosphorylatable Srcasm mutant fails to down-regulate Fyn, and the down-regulation resolves epidermal hyperproliferation caused by Fyn overexpression in transgenic mice.","method":"Double transgenic mouse model (K14-Fyn/K14-Srcasm), primary keratinocytes, cell lines, Western blotting with phosphorylation mutants and GAT domain mutants","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic model complemented by biochemical dissection with domain and phosphorylation mutants, multiple experimental systems","pmids":["17046829"],"is_preprint":false},{"year":2007,"finding":"Tom1L1 forms a complex with clathrin heavy chain (CHC); this complex reduces the level of SFK in caveolae, preventing Src association with the PDGF receptor required for mitogenesis. When not associated with CHC, Tom1L1 accumulates in caveolae and promotes Src-driven DNA synthesis. The Tom1L1-CHC complex also reduces oncogenic Src in cholesterol-enriched microdomains, impairing DNA synthesis and cell transformation.","method":"Co-immunoprecipitation, subcellular fractionation (caveolae isolation), overexpression/dominant-negative constructs, DNA synthesis and transformation assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — biochemical fractionation, direct binding demonstrated by Co-IP, functional consequences (mitogenesis, transformation) tested in multiple assays","pmids":["17785434"],"is_preprint":false},{"year":2007,"finding":"TOM1L1 is a substrate of Lyn kinase in mast cells; co-transfection of TOM1L1 and Lyn (but not Syk) results in TOM1L1 tyrosine phosphorylation. In RBL-2H3 mast cells, TOM1L1 phosphorylation is enhanced by FcεRI aggregation. Overexpression of TOM1L1 enhances antigen-induced TNFα generation and release; both VHS and coiled-coil domains are required for enhanced TNFα release (but not generation).","method":"Bacterial expression library screen with baculoviral Lyn/Syk, co-transfection and phosphorylation assays, subcellular fractionation, deletion mutants, TNFα ELISA","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro phosphorylation screen combined with cell-based domain-deletion analysis; single lab, multiple orthogonal methods","pmids":["17977829"],"is_preprint":false},{"year":2008,"finding":"Tom1L1 contains both a PTAP and a PSAP sequence that interact with the UEV domain of Tsg101 and compete with HIV-1 Gag for Tsg101 binding. Via Tsg101, Tom1L1 is recruited to the midbody during cytokinesis as well as to endosomes, implicating it in MVB formation, viral egress, and cytokinesis.","method":"Co-immunoprecipitation, PTAP/PSAP motif mutagenesis, competition binding assays, confocal immunofluorescence during cytokinesis","journal":"Cell structure and function","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — binding mapped to specific motifs by mutagenesis, localization confirmed by imaging; single lab","pmids":["18367816"],"is_preprint":false},{"year":2009,"finding":"EGF stimulates transient tyrosine phosphorylation of Tom1L1 by Src family kinases, enabling Tom1L1 to interact with activated EGFR through a Grb2/Shc bridge. Cytosolic Tom1L1 is recruited to the plasma membrane and then redistributes to early endosomes. Tom1L1 mutants defective in Tyr-phosphorylation or Grb2 interaction cannot interact with EGFR and act as dominant negatives to inhibit EGFR endocytosis. RNAi knockdown of Tom1L1 inhibits EGFR endocytosis. The C-terminal tail contains a novel clathrin-interacting motif that binds clathrin heavy chain C-terminal region, required for rescue of endocytosis in knockdown cells.","method":"RNAi knockdown, dominant-negative mutants, co-immunoprecipitation, GST pulldown (clathrin-interacting motif), live-cell fluorescence microscopy, endocytosis assay (125I-EGF or fluorescent EGF)","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — RNAi knockdown with rescue, dominant-negative analysis, direct binding mapped by domain mutants, and live-imaging; multiple orthogonal methods","pmids":["19798056"],"is_preprint":false},{"year":2009,"finding":"Increasing Srcasm levels in K14-Fyn Y528F/K14-Srcasm double transgenic mice markedly inhibits cutaneous neoplasia, decreases levels of Fyn, activated SFKs, ERK1/2, PDK1, and phospho-STAT3, and increases Notch1/NICD and p53 levels. A nonphosphorylatable Srcasm mutant fails to suppress neoplasia, confirming phosphorylation dependence.","method":"Double transgenic mouse model, Western blotting, immunohistochemistry, quantitative analysis of signaling pathway components","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic model with phosphorylation-deficient mutant control and comprehensive downstream signaling analysis","pmids":["19934324"],"is_preprint":false},{"year":2016,"finding":"TOM1L1 upregulation enhances invasiveness of ERBB2-transformed breast cancer cells through MT1-MMP-dependent invadopodia activation. ERBB2 elicits indirect phosphorylation of TOM1L1 on Ser321, which promotes GAT domain-dependent association of TOM1L1 with TOLLIP and trafficking of MT1-MMP from endocytic compartments to invadopodia for matrix degradation. This pro-invasive function is independent of SRC.","method":"Co-immunoprecipitation, phosphorylation-deficient mutants (Ser321), GAT domain mutants, invadopodia assays, MT1-MMP trafficking/localization, RNAi knockdown, cell invasion assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic pathway mapped with phosphorylation mutants, domain mutants, direct binding to TOLLIP, and functional invasion/trafficking assays; multiple orthogonal methods in one study","pmids":["26899482"],"is_preprint":false},{"year":2021,"finding":"Srcasm (TOM1L1) downregulates native Fyn and Src more effectively than c-Cbl, while c-Cbl preferentially downregulates activated SFK mutants (e.g., Fyn Y528F). Srcasm-mediated SFK downregulation occurs through a lysosomal-dependent mechanism (not proteasomal), whereas c-Cbl utilizes a proteasomal mechanism. Phosphorylation of Srcasm and its GAT domain are required for this downregulation.","method":"Co-transfection in HaCaT cells, Western blotting, pharmacological inhibition of proteasome and lysosome, Srcasm and c-Cbl mutants","journal":"Journal of carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic dissection using pathway inhibitors and mutants in a single lab with multiple readouts","pmids":["34729053"],"is_preprint":false},{"year":2022,"finding":"TOM1L1 and Fyn are enriched within a subset of clathrin-coated pits (CCPs) with unique lifetimes and protein composition. Perturbation of TOM1L1 or Fyn impairs EGF-stimulated phosphorylation of Akt2 but not Akt1. EGF stimulation triggers TOM1L1- and Fyn-dependent recruitment of the phosphoinositide 5-phosphatase SHIP2 to CCPs.","method":"Total internal reflection fluorescence (TIRF) microscopy for CCP tracking, RNAi knockdown, phospho-specific Western blotting for Akt1/Akt2, co-localization and live-cell imaging","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization with functional consequence (isoform-selective Akt signaling), genetic perturbation (knockdown), and live-cell imaging of CCPs; multiple orthogonal methods","pmids":["35238864"],"is_preprint":false}],"current_model":"TOM1L1/Srcasm is a VHS-GAT domain adaptor protein that is phosphorylated on tyrosines by Src-family kinases (Fyn, Src, Lyn) downstream of growth factor receptors (EGFR, PDGFR) and immune receptors (FcεRI); once phosphorylated, it bridges activated receptors to endocytic machinery (via Grb2/Shc, clathrin heavy chain, Hrs, and TSG101) to promote receptor internalization, negatively regulates SFK mitogenic signaling by reducing SFK levels in caveolae through a Tom1L1-clathrin heavy chain complex, promotes lysosomal degradation of active SFKs (Fyn, Src) via its GAT domain in a phosphorylation-dependent manner, and in the context of ERBB2 amplification undergoes ERBB2-driven Ser321 phosphorylation that triggers GAT-dependent association with TOLLIP to traffic MT1-MMP from endosomes to invadopodia for matrix degradation and tumour invasion; additionally, within a subset of clathrin-coated pits, TOM1L1 and Fyn cooperate to recruit SHIP2 and selectively support EGF-stimulated Akt2 (but not Akt1) phosphorylation."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2001,"claim":"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","pmids":["11711534"],"confidence":"High","gaps":["Cellular consequence of Fyn-TOM1L1 interaction not yet defined","Tyrosine phosphosites not individually mapped"]},{"year":2004,"claim":"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","pmids":["15579470"],"confidence":"Medium","gaps":["Overexpression-based, endogenous loss-of-function not tested","Mechanism linking SFK activation to anti-proliferative outcome unresolved"]},{"year":2004,"claim":"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","pmids":["15611048"],"confidence":"High","gaps":["Functional consequence of endosomal recruitment not directly tested here","Stoichiometry within ESCRT machinery unknown"]},{"year":2006,"claim":"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","pmids":["16479011"],"confidence":"High","gaps":["Did not resolve how TOM1L1 physically reduces receptor-SFK association","Effect specific to mitogenesis but not actin assembly unexplained"]},{"year":2006,"claim":"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","pmids":["17046829"],"confidence":"High","gaps":["Degradative route (lysosomal vs other) not yet specified at this stage","Generality beyond Fyn unaddressed here"]},{"year":2007,"claim":"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","pmids":["17785434"],"confidence":"High","gaps":["How CHC association is regulated to switch between caveolar accumulation and SFK depletion unclear"]},{"year":2007,"claim":"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","pmids":["17977829"],"confidence":"Medium","gaps":["Endogenous requirement not tested by knockdown","Mechanism linking VHS/coiled-coil domains to TNFα release unresolved"]},{"year":2008,"claim":"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","pmids":["18367816"],"confidence":"Medium","gaps":["Functional role in cytokinesis/viral budding not tested by loss-of-function","Single-lab observation"]},{"year":2009,"claim":"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","pmids":["19798056"],"confidence":"High","gaps":["Selectivity for EGFR versus other receptors not delineated","Relationship between endocytic role and SFK downregulation not unified"]},{"year":2009,"claim":"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","pmids":["19934324"],"confidence":"High","gaps":["Whether downstream changes are direct or secondary to SFK loss unresolved","Human tumor relevance not addressed"]},{"year":2016,"claim":"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","pmids":["26899482"],"confidence":"High","gaps":["Identity of the Ser321 kinase not established","How the same GAT domain selects TOLLIP versus SFK-degradation cargo unknown"]},{"year":2021,"claim":"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","pmids":["34729053"],"confidence":"Medium","gaps":["Lysosomal targeting machinery for SFK cargo not identified","Single-lab, overexpression-based"]},{"year":2022,"claim":"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","pmids":["35238864"],"confidence":"High","gaps":["Molecular basis for Akt2-versus-Akt1 selectivity unresolved","Compositional determinants of the specialized CCP subset undefined"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2,8]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[5,8]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[2,8]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2,8]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5,8,12]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[8,12]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,3,9]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[4,10,11]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[9,10]}],"complexes":["TOM1L1-clathrin heavy chain complex"],"partners":["FYN","SRC","GRB2","HGS","TSG101","CLTC","TOLLIP","INPPL1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O75674","full_name":"TOM1-like protein 1","aliases":["Src-activating and signaling molecule protein","Target of Myb-like protein 1"],"length_aa":476,"mass_kda":53.0,"function":"Probable adapter protein involved in signaling pathways. Interacts with the SH2 and SH3 domains of various signaling proteins when it is phosphorylated. May promote FYN activation, possibly by disrupting intramolecular SH3-dependent interactions (By similarity)","subcellular_location":"Golgi apparatus, Golgi stack; Endosome membrane; Cytoplasm; Membrane","url":"https://www.uniprot.org/uniprotkb/O75674/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TOM1L1","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"TOLLIP","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/search/TOM1L1","total_profiled":1310},"omim":[{"mim_id":"615519","title":"TARGET OF MYB1-LIKE 2 MEMBRANE TRAFFICKING PROTEIN; TOM1L2","url":"https://www.omim.org/entry/615519"},{"mim_id":"608880","title":"ZINC FINGER FYVE DOMAIN-CONTAINING PROTEIN 16; ZFYVE16","url":"https://www.omim.org/entry/608880"},{"mim_id":"604701","title":"TARGET OF MYB1-LIKE 1 MEMBRANE TRAFFICKING PROTEIN; TOM1L1","url":"https://www.omim.org/entry/604701"},{"mim_id":"604700","title":"TARGET OF MYB1 MEMBRANE TRAFFICKING PROTEIN; TOM1","url":"https://www.omim.org/entry/604700"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TOM1L1"},"hgnc":{"alias_symbol":["SRCASM"],"prev_symbol":[]},"alphafold":{"accession":"O75674","domains":[{"cath_id":"1.25.40.90","chopping":"15-162","consensus_level":"high","plddt":92.338,"start":15,"end":162},{"cath_id":"1.20.58.160","chopping":"200-302","consensus_level":"high","plddt":86.401,"start":200,"end":302}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O75674","model_url":"https://alphafold.ebi.ac.uk/files/AF-O75674-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O75674-F1-predicted_aligned_error_v6.png","plddt_mean":67.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TOM1L1","jax_strain_url":"https://www.jax.org/strain/search?query=TOM1L1"},"sequence":{"accession":"O75674","fasta_url":"https://rest.uniprot.org/uniprotkb/O75674.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O75674/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O75674"}},"corpus_meta":[{"pmid":"15611048","id":"PMC_15611048","title":"Interactions of TOM1L1 with the multivesicular body sorting machinery.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15611048","citation_count":60,"is_preprint":false},{"pmid":"19934324","id":"PMC_19934324","title":"Srcasm inhibits Fyn-induced cutaneous carcinogenesis with modulation of Notch1 and p53.","date":"2009","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/19934324","citation_count":46,"is_preprint":false},{"pmid":"11711534","id":"PMC_11711534","title":"'Srcasm: a novel Src activating and signaling molecule.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11711534","citation_count":43,"is_preprint":false},{"pmid":"15579470","id":"PMC_15579470","title":"Srcasm modulates EGF and Src-kinase signaling in keratinocytes.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15579470","citation_count":41,"is_preprint":false},{"pmid":"26899482","id":"PMC_26899482","title":"TOM1L1 drives membrane delivery of MT1-MMP to promote ERBB2-induced breast cancer cell invasion.","date":"2016","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/26899482","citation_count":37,"is_preprint":false},{"pmid":"16479011","id":"PMC_16479011","title":"The adaptor protein Tom1L1 is a negative regulator of Src mitogenic signaling induced by growth factors.","date":"2006","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/16479011","citation_count":35,"is_preprint":false},{"pmid":"17046829","id":"PMC_17046829","title":"Srcasm corrects Fyn-induced epidermal hyperplasia by kinase down-regulation.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17046829","citation_count":30,"is_preprint":false},{"pmid":"19798056","id":"PMC_19798056","title":"Participation of Tom1L1 in EGF-stimulated endocytosis of EGF receptor.","date":"2009","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/19798056","citation_count":28,"is_preprint":false},{"pmid":"35238864","id":"PMC_35238864","title":"Fyn and TOM1L1 are recruited to clathrin-coated pits and regulate Akt signaling.","date":"2022","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/35238864","citation_count":21,"is_preprint":false},{"pmid":"17785434","id":"PMC_17785434","title":"The Tom1L1-clathrin heavy chain complex regulates membrane partitioning of the tyrosine kinase Src required for mitogenic and transforming activities.","date":"2007","source":"Molecular and cellular 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breast cancer progression: Role of TOM1L1 in ERBB2-dependent invasion.","date":"2016","source":"Molecular & cellular oncology","url":"https://pubmed.ncbi.nlm.nih.gov/27652326","citation_count":7,"is_preprint":false},{"pmid":"20944134","id":"PMC_20944134","title":"Decreased Srcasm expression in esophageal squamous cell carcinoma in a Chinese population.","date":"2010","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/20944134","citation_count":3,"is_preprint":false},{"pmid":"34729053","id":"PMC_34729053","title":"Downregulation of Src-family tyrosine kinases by Srcasm and c-Cbl: A comparative analysis.","date":"2021","source":"Journal of carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/34729053","citation_count":2,"is_preprint":false},{"pmid":"17244028","id":"PMC_17244028","title":"Srcasm overexpression in psoriasis-insights into pathogenesis.","date":"2007","source":"Journal of cutaneous pathology","url":"https://pubmed.ncbi.nlm.nih.gov/17244028","citation_count":2,"is_preprint":false},{"pmid":"40123000","id":"PMC_40123000","title":"TOM1L1 mediated the sort of tumor suppressive miR-378a-3p into exosomes and the excretion out of cells to promote ESCC progression.","date":"2025","source":"Cancer gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/40123000","citation_count":1,"is_preprint":false},{"pmid":"39548458","id":"PMC_39548458","title":"Exploring the correlation between Tom1L1 and the efficacy of neoadjuvant chemotherapy for locally progressive mid-low rectal cancer.","date":"2024","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/39548458","citation_count":0,"is_preprint":false},{"pmid":"30471750","id":"PMC_30471750","title":"Srcasm Regulates Tyrosine Kinases in Skin Cancer: Implications for Precision Medicine.","date":"2018","source":"The journal of investigative dermatology. Symposium proceedings","url":"https://pubmed.ncbi.nlm.nih.gov/30471750","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.11.07.25339560","title":"Genome-wide survival study identifies a novel non-HLA donor-recipient genetic mismatch associated with kidney allograft survival","date":"2025-11-09","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.07.25339560","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12099,"output_tokens":3936,"usd":0.047669,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11769,"output_tokens":4517,"usd":0.085885,"stage2_stop_reason":"end_turn"},"total_usd":0.133554,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"Srcasm (TOM1L1) was identified as a novel substrate and binding partner of Fyn kinase; association requires cooperative binding between Fyn SH2 and SH3 domains and canonical binding sites in Srcasm. Fyn phosphorylates Srcasm on tyrosine residues. Phosphorylated Srcasm interacts with Grb2 and the p85 regulatory subunit of PI3K in a phosphorylation-dependent manner.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, in vitro kinase assay, domain-binding mutants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding experiments with domain mutants, in vitro phosphorylation, and multiple orthogonal methods in a dedicated study; replicated in subsequent papers\",\n      \"pmids\": [\"11711534\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"EGF receptor ligands promote tyrosine phosphorylation of endogenous TOM1L1/Srcasm in keratinocytes; increased Srcasm levels activate endogenous Fyn and Src (preferentially) and potentiate EGF-dependent SFK signaling, enhancing p44/42 MAPK activity and Elk-1-dependent transcription while inhibiting proliferation and promoting differentiation.\",\n      \"method\": \"Adenoviral overexpression, Western blotting, kinase activity assays, reporter assays (Elk-1), EGFR and SFK inhibitors\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD/OE with defined cellular phenotypes and multiple pathway readouts in a single lab\",\n      \"pmids\": [\"15579470\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The VHS domain of Tom1L1 interacts with Hrs (HGF-regulated tyrosine kinase substrate); a PTAP motif between the VHS and GAT domains binds TSG101. Tom1L1 is recruited from cytosol to endosomes upon Hrs overexpression. Tyrosine motifs in the C-terminal region mediate interactions with Src family kinases (including Fyn), Grb2, and p85. Constitutively active Fyn promotes Tom1L1 recruitment to enlarged endosomes.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown, epitope-tagged constructs with confocal imaging, domain-deletion mutants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple binding partners mapped to specific domains, reciprocal IPs, localization experiments with mechanistic follow-up; independently consistent with other papers\",\n      \"pmids\": [\"15611048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Tom1L1 is a negative regulator of SFK mitogenic signaling induced by PDGF: it inhibits DNA synthesis, reduces Src association with the PDGF receptor, and its inactivation potentiates receptor-SFK complex formation and DNA synthesis. Inhibition is overcome by c-Myc expression or p53 inactivation. Tom1L1 does not inhibit actin assembly induced by PDGF, nor DNA synthesis from constitutively active SrcY527F.\",\n      \"method\": \"Overexpression and dominant-negative studies, DNA synthesis assay (BrdU/thymidine), co-immunoprecipitation, genetic epistasis (c-Myc, p53, Src/Fyn co-expression)\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis combined with biochemical receptor-SFK association assays and multiple rescue experiments; mechanistic pathway placement established\",\n      \"pmids\": [\"16479011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"In vivo and in vitro, Srcasm (TOM1L1) promotes Fyn down-regulation in a phosphorylation-dependent manner requiring Fyn kinase activity and the Srcasm GAT domain. A nonphosphorylatable Srcasm mutant fails to down-regulate Fyn, and the down-regulation resolves epidermal hyperproliferation caused by Fyn overexpression in transgenic mice.\",\n      \"method\": \"Double transgenic mouse model (K14-Fyn/K14-Srcasm), primary keratinocytes, cell lines, Western blotting with phosphorylation mutants and GAT domain mutants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic model complemented by biochemical dissection with domain and phosphorylation mutants, multiple experimental systems\",\n      \"pmids\": [\"17046829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Tom1L1 forms a complex with clathrin heavy chain (CHC); this complex reduces the level of SFK in caveolae, preventing Src association with the PDGF receptor required for mitogenesis. When not associated with CHC, Tom1L1 accumulates in caveolae and promotes Src-driven DNA synthesis. The Tom1L1-CHC complex also reduces oncogenic Src in cholesterol-enriched microdomains, impairing DNA synthesis and cell transformation.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation (caveolae isolation), overexpression/dominant-negative constructs, DNA synthesis and transformation assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — biochemical fractionation, direct binding demonstrated by Co-IP, functional consequences (mitogenesis, transformation) tested in multiple assays\",\n      \"pmids\": [\"17785434\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"TOM1L1 is a substrate of Lyn kinase in mast cells; co-transfection of TOM1L1 and Lyn (but not Syk) results in TOM1L1 tyrosine phosphorylation. In RBL-2H3 mast cells, TOM1L1 phosphorylation is enhanced by FcεRI aggregation. Overexpression of TOM1L1 enhances antigen-induced TNFα generation and release; both VHS and coiled-coil domains are required for enhanced TNFα release (but not generation).\",\n      \"method\": \"Bacterial expression library screen with baculoviral Lyn/Syk, co-transfection and phosphorylation assays, subcellular fractionation, deletion mutants, TNFα ELISA\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro phosphorylation screen combined with cell-based domain-deletion analysis; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"17977829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Tom1L1 contains both a PTAP and a PSAP sequence that interact with the UEV domain of Tsg101 and compete with HIV-1 Gag for Tsg101 binding. Via Tsg101, Tom1L1 is recruited to the midbody during cytokinesis as well as to endosomes, implicating it in MVB formation, viral egress, and cytokinesis.\",\n      \"method\": \"Co-immunoprecipitation, PTAP/PSAP motif mutagenesis, competition binding assays, confocal immunofluorescence during cytokinesis\",\n      \"journal\": \"Cell structure and function\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — binding mapped to specific motifs by mutagenesis, localization confirmed by imaging; single lab\",\n      \"pmids\": [\"18367816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"EGF stimulates transient tyrosine phosphorylation of Tom1L1 by Src family kinases, enabling Tom1L1 to interact with activated EGFR through a Grb2/Shc bridge. Cytosolic Tom1L1 is recruited to the plasma membrane and then redistributes to early endosomes. Tom1L1 mutants defective in Tyr-phosphorylation or Grb2 interaction cannot interact with EGFR and act as dominant negatives to inhibit EGFR endocytosis. RNAi knockdown of Tom1L1 inhibits EGFR endocytosis. The C-terminal tail contains a novel clathrin-interacting motif that binds clathrin heavy chain C-terminal region, required for rescue of endocytosis in knockdown cells.\",\n      \"method\": \"RNAi knockdown, dominant-negative mutants, co-immunoprecipitation, GST pulldown (clathrin-interacting motif), live-cell fluorescence microscopy, endocytosis assay (125I-EGF or fluorescent EGF)\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RNAi knockdown with rescue, dominant-negative analysis, direct binding mapped by domain mutants, and live-imaging; multiple orthogonal methods\",\n      \"pmids\": [\"19798056\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Increasing Srcasm levels in K14-Fyn Y528F/K14-Srcasm double transgenic mice markedly inhibits cutaneous neoplasia, decreases levels of Fyn, activated SFKs, ERK1/2, PDK1, and phospho-STAT3, and increases Notch1/NICD and p53 levels. A nonphosphorylatable Srcasm mutant fails to suppress neoplasia, confirming phosphorylation dependence.\",\n      \"method\": \"Double transgenic mouse model, Western blotting, immunohistochemistry, quantitative analysis of signaling pathway components\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic model with phosphorylation-deficient mutant control and comprehensive downstream signaling analysis\",\n      \"pmids\": [\"19934324\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TOM1L1 upregulation enhances invasiveness of ERBB2-transformed breast cancer cells through MT1-MMP-dependent invadopodia activation. ERBB2 elicits indirect phosphorylation of TOM1L1 on Ser321, which promotes GAT domain-dependent association of TOM1L1 with TOLLIP and trafficking of MT1-MMP from endocytic compartments to invadopodia for matrix degradation. This pro-invasive function is independent of SRC.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation-deficient mutants (Ser321), GAT domain mutants, invadopodia assays, MT1-MMP trafficking/localization, RNAi knockdown, cell invasion assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic pathway mapped with phosphorylation mutants, domain mutants, direct binding to TOLLIP, and functional invasion/trafficking assays; multiple orthogonal methods in one study\",\n      \"pmids\": [\"26899482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Srcasm (TOM1L1) downregulates native Fyn and Src more effectively than c-Cbl, while c-Cbl preferentially downregulates activated SFK mutants (e.g., Fyn Y528F). Srcasm-mediated SFK downregulation occurs through a lysosomal-dependent mechanism (not proteasomal), whereas c-Cbl utilizes a proteasomal mechanism. Phosphorylation of Srcasm and its GAT domain are required for this downregulation.\",\n      \"method\": \"Co-transfection in HaCaT cells, Western blotting, pharmacological inhibition of proteasome and lysosome, Srcasm and c-Cbl mutants\",\n      \"journal\": \"Journal of carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic dissection using pathway inhibitors and mutants in a single lab with multiple readouts\",\n      \"pmids\": [\"34729053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TOM1L1 and Fyn are enriched within a subset of clathrin-coated pits (CCPs) with unique lifetimes and protein composition. Perturbation of TOM1L1 or Fyn impairs EGF-stimulated phosphorylation of Akt2 but not Akt1. EGF stimulation triggers TOM1L1- and Fyn-dependent recruitment of the phosphoinositide 5-phosphatase SHIP2 to CCPs.\",\n      \"method\": \"Total internal reflection fluorescence (TIRF) microscopy for CCP tracking, RNAi knockdown, phospho-specific Western blotting for Akt1/Akt2, co-localization and live-cell imaging\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization with functional consequence (isoform-selective Akt signaling), genetic perturbation (knockdown), and live-cell imaging of CCPs; multiple orthogonal methods\",\n      \"pmids\": [\"35238864\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TOM1L1/Srcasm is a VHS-GAT domain adaptor protein that is phosphorylated on tyrosines by Src-family kinases (Fyn, Src, Lyn) downstream of growth factor receptors (EGFR, PDGFR) and immune receptors (FcεRI); once phosphorylated, it bridges activated receptors to endocytic machinery (via Grb2/Shc, clathrin heavy chain, Hrs, and TSG101) to promote receptor internalization, negatively regulates SFK mitogenic signaling by reducing SFK levels in caveolae through a Tom1L1-clathrin heavy chain complex, promotes lysosomal degradation of active SFKs (Fyn, Src) via its GAT domain in a phosphorylation-dependent manner, and in the context of ERBB2 amplification undergoes ERBB2-driven Ser321 phosphorylation that triggers GAT-dependent association with TOLLIP to traffic MT1-MMP from endosomes to invadopodia for matrix degradation and tumour invasion; additionally, within a subset of clathrin-coated pits, TOM1L1 and Fyn cooperate to recruit SHIP2 and selectively support EGF-stimulated Akt2 (but not Akt1) phosphorylation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #2]. 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 [#0]. 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 [#2, #7]. 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 [#8]. 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 [#3, #5], and it promotes phosphorylation- and GAT-domain-dependent lysosomal downregulation of active Fyn and Src [#4, #11]. In vivo, raising Srcasm levels suppresses Fyn-driven epidermal hyperproliferation and cutaneous neoplasia in a phosphorylation-dependent manner [#4, #9]. 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 [#10]. 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 [#12].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Establishing that TOM1L1/Srcasm is a direct Fyn substrate and SFK-coupled adaptor defined its entry point into tyrosine-kinase signaling.\",\n      \"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\",\n      \"pmids\": [\"11711534\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular consequence of Fyn-TOM1L1 interaction not yet defined\", \"Tyrosine phosphosites not individually mapped\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Linking TOM1L1 to EGFR ligands and SFK activation in keratinocytes connected the adaptor to growth-factor signaling and differentiation control.\",\n      \"evidence\": \"Adenoviral overexpression with kinase activity and Elk-1 reporter assays under EGFR/SFK inhibition in keratinocytes\",\n      \"pmids\": [\"15579470\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Overexpression-based, endogenous loss-of-function not tested\", \"Mechanism linking SFK activation to anti-proliferative outcome unresolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Mapping VHS-Hrs, PTAP-TSG101, and C-terminal SFK/Grb2/p85 interactions placed TOM1L1 on the endosomal/ESCRT trafficking pathway.\",\n      \"evidence\": \"Co-IP, GST pulldown, and confocal imaging with domain-deletion constructs showing Hrs/active-Fyn-driven endosomal recruitment\",\n      \"pmids\": [\"15611048\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of endosomal recruitment not directly tested here\", \"Stoichiometry within ESCRT machinery unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"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.\",\n      \"evidence\": \"Overexpression/dominant-negative DNA synthesis assays with Co-IP and c-Myc/p53/Src epistasis\",\n      \"pmids\": [\"16479011\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how TOM1L1 physically reduces receptor-SFK association\", \"Effect specific to mitogenesis but not actin assembly unexplained\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"An in vivo double-transgenic model demonstrated that Srcasm drives phosphorylation- and GAT-domain-dependent Fyn downregulation, resolving Fyn-induced epidermal hyperproliferation.\",\n      \"evidence\": \"K14-Fyn/K14-Srcasm mice and keratinocytes with phosphorylation and GAT-domain mutants\",\n      \"pmids\": [\"17046829\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Degradative route (lysosomal vs other) not yet specified at this stage\", \"Generality beyond Fyn unaddressed here\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identifying a TOM1L1-clathrin heavy chain complex that depletes SFK from caveolae provided the spatial mechanism for negative regulation of Src-driven transformation.\",\n      \"evidence\": \"Co-IP, caveolae fractionation, and DNA synthesis/transformation assays with dominant-negative constructs\",\n      \"pmids\": [\"17785434\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CHC association is regulated to switch between caveolar accumulation and SFK depletion unclear\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrating TOM1L1 as a Lyn substrate downstream of FcεRI extended its SFK-coupled adaptor role to mast-cell immune signaling.\",\n      \"evidence\": \"Bacterial expression library screen with baculoviral Lyn/Syk, co-transfection phosphorylation assays, and TNFα ELISA with domain deletions\",\n      \"pmids\": [\"17977829\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous requirement not tested by knockdown\", \"Mechanism linking VHS/coiled-coil domains to TNFα release unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showing dual PTAP/PSAP-TSG101 motifs and TSG101-dependent midbody recruitment implicated TOM1L1 in MVB formation, viral egress, and cytokinesis.\",\n      \"evidence\": \"Co-IP, PTAP/PSAP mutagenesis, HIV-1 Gag competition assays, and cytokinesis imaging\",\n      \"pmids\": [\"18367816\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role in cytokinesis/viral budding not tested by loss-of-function\", \"Single-lab observation\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"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.\",\n      \"evidence\": \"RNAi knockdown with rescue, dominant-negative mutants, GST pulldown, and live-cell EGF endocytosis assays\",\n      \"pmids\": [\"19798056\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Selectivity for EGFR versus other receptors not delineated\", \"Relationship between endocytic role and SFK downregulation not unified\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"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.\",\n      \"evidence\": \"K14-Fyn Y528F/K14-Srcasm double transgenic mice with IHC and pathway Western blotting plus nonphosphorylatable mutant control\",\n      \"pmids\": [\"19934324\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether downstream changes are direct or secondary to SFK loss unresolved\", \"Human tumor relevance not addressed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defining ERBB2-driven Ser321 phosphorylation, GAT-TOLLIP binding, and MT1-MMP trafficking revealed an SRC-independent pro-invasive function in breast cancer.\",\n      \"evidence\": \"Co-IP, Ser321 and GAT-domain mutants, MT1-MMP trafficking, invadopodia and invasion assays with RNAi\",\n      \"pmids\": [\"26899482\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the Ser321 kinase not established\", \"How the same GAT domain selects TOLLIP versus SFK-degradation cargo unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Comparative analysis distinguished Srcasm from c-Cbl by showing it preferentially downregulates native SFKs via a lysosomal, not proteasomal, route.\",\n      \"evidence\": \"Co-transfection in HaCaT cells with proteasome/lysosome inhibitors and Srcasm/c-Cbl mutants\",\n      \"pmids\": [\"34729053\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Lysosomal targeting machinery for SFK cargo not identified\", \"Single-lab, overexpression-based\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identifying a TOM1L1/Fyn-enriched CCP subset that recruits SHIP2 explained isoform-selective control of EGF-stimulated Akt2 signaling.\",\n      \"evidence\": \"TIRF CCP tracking, RNAi, SHIP2 recruitment imaging, and phospho-Akt1/Akt2 Western blotting\",\n      \"pmids\": [\"35238864\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis for Akt2-versus-Akt1 selectivity unresolved\", \"Compositional determinants of the specialized CCP subset undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2, 8]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [5, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [2, 8]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 8]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5, 8, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [8, 12]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 3, 9]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [4, 10, 11]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [9, 10]}\n    ],\n    \"complexes\": [\n      \"TOM1L1-clathrin heavy chain complex\"\n    ],\n    \"partners\": [\n      \"FYN\",\n      \"SRC\",\n      \"GRB2\",\n      \"HGS\",\n      \"TSG101\",\n      \"CLTC\",\n      \"TOLLIP\",\n      \"INPPL1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}