{"gene":"SH3BP5L","run_date":"2026-06-10T07:46:31","timeline":{"discoveries":[{"year":2021,"finding":"SH3BP5L is a guanine nucleotide exchange factor (GEF) for RAB11, required for activation of Rab11a and epithelial cyst lumen formation. SH3BP5L (and its paralogue SH3BP5) are substrates of the poly-ADP-ribose polymerase Tankyrase and the E3 ubiquitin ligase RNF146; Tankyrase suppresses SH3BP5L to inhibit Rab11a activation, while RNF146 reduces Tankyrase abundance to restore Rab11a activation and lumen formation.","method":"Proximity-dependent biotin identification (BioID) interaction proteomics, loss-of-function experiments in epithelial cyst lumen formation assays, genetic epistasis (RNF146 → Tankyrase → SH3BP5L → Rab11a pathway)","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — BioID proteomics, functional epistasis across multiple pathway nodes, loss-of-function phenotypic readout (lumen formation), replicated with two paralogues","pmids":["34128958"],"is_preprint":false},{"year":2024,"finding":"SH3BP5L acts as a GEF for RAB11A on early endosomes and is recruited by RAB22A to activate RAB11A, thereby redirecting EGFR from early endosomes to recycling endosomes for incorporation into microvesicles shed from the plasma membrane.","method":"RAB GTPase family screening, co-immunoprecipitation/interaction assays, functional vesicle formation assays","journal":"Journal of extracellular vesicles","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional screening plus interaction data and vesicle release readout, single lab","pmids":["39051763"],"is_preprint":false},{"year":2026,"finding":"SH3BP5L activates RAB11A via its GEF activity and promotes assembly of a RAB11A–KIF5B anterograde motor complex on recycling endosomes; this trafficking axis drives β1 integrin recycling and α3β1 integrin surface exposure, promoting breast cancer cell spreading and lung metastasis. Inhibition of SH3BP5L or its GEF catalytic activity reduces metastatic dissemination in zebrafish and mouse models.","method":"FRET sensors for RAB11A activation, AI-assisted microscopy, loss-of-function (SH3BP5L knockdown/GEF-dead mutants), integrin recycling assays, zebrafish spreading assay, mouse lung metastasis model","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — FRET-based activity measurement, GEF-dead mutagenesis, multiple orthogonal functional readouts (integrin recycling, in vivo metastasis models), single lab but multiple rigorous methods","pmids":["41623179"],"is_preprint":false}],"current_model":"SH3BP5L is a guanine nucleotide exchange factor (GEF) for RAB11A that, when recruited to early/recycling endosomes (e.g., by RAB22A), activates RAB11A and drives assembly of a RAB11A–KIF5B motor complex to recycle cargo (including integrins and EGFR) to the plasma membrane; this activity is negatively regulated by Tankyrase-mediated suppression (itself countered by RNF146), and SH3BP5L-dependent RAB11A activation is required for epithelial lumen formation, microvesicle biogenesis, and integrin-driven cancer metastasis."},"narrative":{"mechanistic_narrative":"SH3BP5L is a guanine nucleotide exchange factor (GEF) for the small GTPase RAB11A that controls endosomal recycling and the routing of cargo to the plasma membrane [PMID:34128958, PMID:39051763]. Recruited to early endosomes (in part by RAB22A), SH3BP5L activates RAB11A to redirect cargo such as EGFR from early endosomes into recycling endosomes destined for microvesicle shedding [PMID:39051763], and it nucleates assembly of a RAB11A–KIF5B anterograde motor complex that drives β1 integrin recycling and α3β1 surface exposure [PMID:41623179]. Through these activities SH3BP5L-dependent RAB11A activation supports epithelial cyst lumen formation [PMID:34128958], microvesicle biogenesis [PMID:39051763], and integrin-driven cell spreading and metastasis, such that loss of SH3BP5L or its GEF catalytic activity reduces metastatic dissemination in vivo [PMID:41623179]. Its GEF activity is held in check by Tankyrase-mediated suppression, which is itself relieved by the E3 ubiquitin ligase RNF146 acting to reduce Tankyrase abundance [PMID:34128958].","teleology":[{"year":2021,"claim":"Established SH3BP5L as a RAB11A GEF and embedded it in a regulatory circuit, answering both what activates RAB11A in lumen formation and how that activation is controlled.","evidence":"BioID interaction proteomics with loss-of-function epithelial cyst lumen assays and genetic epistasis (RNF146 → Tankyrase → SH3BP5L → RAB11A)","pmids":["34128958"],"confidence":"High","gaps":["No structural basis for nucleotide exchange on RAB11A defined","Direct biochemical demonstration of RNF146/Tankyrase modification of SH3BP5L not detailed in the readout","Cargo recycled during lumen formation not specified"]},{"year":2024,"claim":"Defined how SH3BP5L is recruited to act, showing RAB22A brings it to early endosomes to activate RAB11A and reroute EGFR into microvesicles, linking the GEF to cargo sorting and extracellular vesicle biogenesis.","evidence":"RAB GTPase family screening, co-immunoprecipitation/interaction assays, and functional microvesicle formation assays","pmids":["39051763"],"confidence":"Medium","gaps":["Single-lab interaction data without reciprocal in vivo validation","Whether RAB22A recruitment generalizes beyond EGFR cargo unknown","Mechanism coupling RAB11A activation to microvesicle shedding not resolved"]},{"year":2026,"claim":"Connected SH3BP5L GEF activity to a defined effector output and disease phenotype, showing it assembles a RAB11A–KIF5B motor complex driving integrin recycling and metastasis.","evidence":"FRET RAB11A activation sensors, GEF-dead mutagenesis, integrin recycling assays, and zebrafish/mouse metastasis models","pmids":["41623179"],"confidence":"High","gaps":["Structural detail of the RAB11A–KIF5B complex assembly not resolved","Whether Tankyrase/RNF146 regulation operates in the metastatic context untested","Selectivity of GEF inhibition for therapeutic use not established"]},{"year":null,"claim":"How SH3BP5L catalytic and recruitment activities are integrated across distinct cellular contexts (lumen formation, microvesicle biogenesis, metastasis) and structurally executed remains open.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of SH3BP5L or its RAB11A complex","Full cargo repertoire beyond EGFR and integrins unknown","Interplay between RAB22A recruitment and Tankyrase/RNF146 regulation uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,2]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[1,2]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,1,2]}],"complexes":[],"partners":["RAB11A","RAB22A","KIF5B","TANKYRASE","RNF146"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q7L8J4","full_name":"SH3 domain-binding protein 5-like","aliases":[],"length_aa":393,"mass_kda":43.5,"function":"Functions as a guanine nucleotide exchange factor (GEF) for RAB11A","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q7L8J4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SH3BP5L","classification":"Not Classified","n_dependent_lines":51,"n_total_lines":1208,"dependency_fraction":0.042218543046357616},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SH3BP5L","total_profiled":1310},"omim":[{"mim_id":"620652","title":"SH3 DOMAIN-BINDING PROTEIN 5-LIKE; SH3BP5L","url":"https://www.omim.org/entry/620652"},{"mim_id":"605612","title":"SH3 DOMAIN-BINDING PROTEIN 5; SH3BP5","url":"https://www.omim.org/entry/605612"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Golgi apparatus","reliability":"Approved"},{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SH3BP5L"},"hgnc":{"alias_symbol":["KIAA1720"],"prev_symbol":[]},"alphafold":{"accession":"Q7L8J4","domains":[{"cath_id":"-","chopping":"59-275","consensus_level":"medium","plddt":94.452,"start":59,"end":275}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7L8J4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q7L8J4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q7L8J4-F1-predicted_aligned_error_v6.png","plddt_mean":72.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SH3BP5L","jax_strain_url":"https://www.jax.org/strain/search?query=SH3BP5L"},"sequence":{"accession":"Q7L8J4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q7L8J4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q7L8J4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7L8J4"}},"corpus_meta":[{"pmid":"39051763","id":"PMC_39051763","title":"RAB22A sorts epithelial growth factor receptor (EGFR) from early endosomes to recycling endosomes for microvesicles release.","date":"2024","source":"Journal of extracellular vesicles","url":"https://pubmed.ncbi.nlm.nih.gov/39051763","citation_count":11,"is_preprint":false},{"pmid":"34128958","id":"PMC_34128958","title":"Tankyrase regulates epithelial lumen formation via suppression of Rab11 GEFs.","date":"2021","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/34128958","citation_count":11,"is_preprint":false},{"pmid":"39753851","id":"PMC_39753851","title":"Integrated Mendelian Randomization and Single-Cell Transcriptomics Analysis Identifies Critical Blood Biomarkers and Potential Mechanisms in Epilepsy.","date":"2025","source":"CNS neuroscience & therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/39753851","citation_count":4,"is_preprint":false},{"pmid":"40759305","id":"PMC_40759305","title":"Whole-transcriptome sequencing analysis of spinal neuronal ferroptosis in aggravating neuropathic pain.","date":"2025","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40759305","citation_count":1,"is_preprint":false},{"pmid":"41623179","id":"PMC_41623179","title":"SH3BP5L triggers the RAB11A-regulated integrin recycling network implicated in breast cancer metastasis.","date":"2026","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/41623179","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":4508,"output_tokens":1024,"usd":0.014442,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7537,"output_tokens":1715,"usd":0.04028,"stage2_stop_reason":"end_turn"},"total_usd":0.054722,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2021,\n      \"finding\": \"SH3BP5L is a guanine nucleotide exchange factor (GEF) for RAB11, required for activation of Rab11a and epithelial cyst lumen formation. SH3BP5L (and its paralogue SH3BP5) are substrates of the poly-ADP-ribose polymerase Tankyrase and the E3 ubiquitin ligase RNF146; Tankyrase suppresses SH3BP5L to inhibit Rab11a activation, while RNF146 reduces Tankyrase abundance to restore Rab11a activation and lumen formation.\",\n      \"method\": \"Proximity-dependent biotin identification (BioID) interaction proteomics, loss-of-function experiments in epithelial cyst lumen formation assays, genetic epistasis (RNF146 → Tankyrase → SH3BP5L → Rab11a pathway)\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — BioID proteomics, functional epistasis across multiple pathway nodes, loss-of-function phenotypic readout (lumen formation), replicated with two paralogues\",\n      \"pmids\": [\"34128958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SH3BP5L acts as a GEF for RAB11A on early endosomes and is recruited by RAB22A to activate RAB11A, thereby redirecting EGFR from early endosomes to recycling endosomes for incorporation into microvesicles shed from the plasma membrane.\",\n      \"method\": \"RAB GTPase family screening, co-immunoprecipitation/interaction assays, functional vesicle formation assays\",\n      \"journal\": \"Journal of extracellular vesicles\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional screening plus interaction data and vesicle release readout, single lab\",\n      \"pmids\": [\"39051763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SH3BP5L activates RAB11A via its GEF activity and promotes assembly of a RAB11A–KIF5B anterograde motor complex on recycling endosomes; this trafficking axis drives β1 integrin recycling and α3β1 integrin surface exposure, promoting breast cancer cell spreading and lung metastasis. Inhibition of SH3BP5L or its GEF catalytic activity reduces metastatic dissemination in zebrafish and mouse models.\",\n      \"method\": \"FRET sensors for RAB11A activation, AI-assisted microscopy, loss-of-function (SH3BP5L knockdown/GEF-dead mutants), integrin recycling assays, zebrafish spreading assay, mouse lung metastasis model\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — FRET-based activity measurement, GEF-dead mutagenesis, multiple orthogonal functional readouts (integrin recycling, in vivo metastasis models), single lab but multiple rigorous methods\",\n      \"pmids\": [\"41623179\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SH3BP5L is a guanine nucleotide exchange factor (GEF) for RAB11A that, when recruited to early/recycling endosomes (e.g., by RAB22A), activates RAB11A and drives assembly of a RAB11A–KIF5B motor complex to recycle cargo (including integrins and EGFR) to the plasma membrane; this activity is negatively regulated by Tankyrase-mediated suppression (itself countered by RNF146), and SH3BP5L-dependent RAB11A activation is required for epithelial lumen formation, microvesicle biogenesis, and integrin-driven cancer metastasis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SH3BP5L is a guanine nucleotide exchange factor (GEF) for the small GTPase RAB11A that controls endosomal recycling and the routing of cargo to the plasma membrane [#0, #1]. Recruited to early endosomes (in part by RAB22A), SH3BP5L activates RAB11A to redirect cargo such as EGFR from early endosomes into recycling endosomes destined for microvesicle shedding [#1], and it nucleates assembly of a RAB11A\\u2013KIF5B anterograde motor complex that drives \\u03b21 integrin recycling and \\u03b13\\u03b21 surface exposure [#2]. Through these activities SH3BP5L-dependent RAB11A activation supports epithelial cyst lumen formation [#0], microvesicle biogenesis [#1], and integrin-driven cell spreading and metastasis, such that loss of SH3BP5L or its GEF catalytic activity reduces metastatic dissemination in vivo [#2]. Its GEF activity is held in check by Tankyrase-mediated suppression, which is itself relieved by the E3 ubiquitin ligase RNF146 acting to reduce Tankyrase abundance [#0].\",\n  \"teleology\": [\n    {\n      \"year\": 2021,\n      \"claim\": \"Established SH3BP5L as a RAB11A GEF and embedded it in a regulatory circuit, answering both what activates RAB11A in lumen formation and how that activation is controlled.\",\n      \"evidence\": \"BioID interaction proteomics with loss-of-function epithelial cyst lumen assays and genetic epistasis (RNF146 \\u2192 Tankyrase \\u2192 SH3BP5L \\u2192 RAB11A)\",\n      \"pmids\": [\"34128958\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural basis for nucleotide exchange on RAB11A defined\", \"Direct biochemical demonstration of RNF146/Tankyrase modification of SH3BP5L not detailed in the readout\", \"Cargo recycled during lumen formation not specified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined how SH3BP5L is recruited to act, showing RAB22A brings it to early endosomes to activate RAB11A and reroute EGFR into microvesicles, linking the GEF to cargo sorting and extracellular vesicle biogenesis.\",\n      \"evidence\": \"RAB GTPase family screening, co-immunoprecipitation/interaction assays, and functional microvesicle formation assays\",\n      \"pmids\": [\"39051763\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab interaction data without reciprocal in vivo validation\", \"Whether RAB22A recruitment generalizes beyond EGFR cargo unknown\", \"Mechanism coupling RAB11A activation to microvesicle shedding not resolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Connected SH3BP5L GEF activity to a defined effector output and disease phenotype, showing it assembles a RAB11A\\u2013KIF5B motor complex driving integrin recycling and metastasis.\",\n      \"evidence\": \"FRET RAB11A activation sensors, GEF-dead mutagenesis, integrin recycling assays, and zebrafish/mouse metastasis models\",\n      \"pmids\": [\"41623179\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural detail of the RAB11A\\u2013KIF5B complex assembly not resolved\", \"Whether Tankyrase/RNF146 regulation operates in the metastatic context untested\", \"Selectivity of GEF inhibition for therapeutic use not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SH3BP5L catalytic and recruitment activities are integrated across distinct cellular contexts (lumen formation, microvesicle biogenesis, metastasis) and structurally executed remains open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of SH3BP5L or its RAB11A complex\", \"Full cargo repertoire beyond EGFR and integrins unknown\", \"Interplay between RAB22A recruitment and Tankyrase/RNF146 regulation uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RAB11A\", \"RAB22A\", \"KIF5B\", \"Tankyrase\", \"RNF146\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}