{"gene":"SH3YL1","run_date":"2026-04-28T20:42:07","timeline":{"discoveries":[{"year":2000,"finding":"Sh3yl1 was identified as a novel mouse gene encoding a protein with one SH3 domain at the carboxyl terminus and homology to yeast YHRO16c/Ysc84 (a meiosis-expressed SH3 domain protein), expressed specifically in the hair bulb, hair shaft, inner root sheath, and outer root sheath during mid and late anagen phases of the hair follicle cycle.","method":"Differential cDNA library screening, northern blot, in situ hybridization","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 — expression pattern tied to hair cycle with direct in situ localization, but functional mechanism not fully established","pmids":["10771491"],"is_preprint":false},{"year":2015,"finding":"SH3YL1 interacts with the N-terminal polyproline domain of androgen receptor (AR) to function as a coregulator; this interaction was required for androgen-mediated transcription of a subset of AR target genes (including UBN1), cell growth, and migration in prostate cancer cells.","method":"T7 phage display, Co-IP, siRNA knockdown with proliferation and migration assays, RNA expression analysis","journal":"Molecular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2-3 — phage display identification plus functional KD phenotypes, but interaction not confirmed by reciprocal Co-IP or reconstitution","pmids":["26305679"],"is_preprint":false},{"year":2014,"finding":"SH3YL1 (a phosphoinositide-binding protein) interacts with the C-terminal proline-rich region of Dock4 via its phosphoinositide-binding domain, promoting Dock4-mediated Rac1 activation and cancer cell migration; mutations in the phosphoinositide-binding domain of SH3YL1 abolished this activity, and SH3YL1 depletion suppressed cell migration in MDA-MB-231 breast cancer cells.","method":"Co-IP, pulldown, dominant-negative/point mutations, Rac1 activation assay (G-LISA or pulldown), siRNA knockdown with migration assay","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP with domain mutants, functional KD and rescue, phosphoinositide-binding domain identified as critical","pmids":["24508479"],"is_preprint":false},{"year":2020,"finding":"SH3YL1 acts as a cytosolic regulator of NADPH oxidase Nox4: the SYLF region and SH3 domain of SH3YL1 mediate formation of a ternary complex with Nox4 and p22phox. LPS triggers interaction of p22phox with SH3YL1, and the resulting complex drives H2O2 generation and pro-inflammatory cytokine expression in tubular epithelial cells. SH3YL1 knockout mice showed markedly reduced acute kidney injury, inflammatory cytokine secretion, macrophage infiltration, and tubular damage following LPS injection.","method":"Co-IP, domain deletion/mutation analysis, H2O2 measurement, SH3YL1 knockout mouse model, in vivo LPS injection with AKI biomarkers and histology","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, domain mapping, in vitro H2O2 assay, and KO mouse with multiple orthogonal readouts in a single study","pmids":["33086058"],"is_preprint":false},{"year":2024,"finding":"The SH3YL1-Nox4 complex regulates diabetic nephropathy: SH3YL1 functions as a Nox4 cytosolic activator in podocytes. Global and podocyte-specific (Nphs2-Cre/SH3YL1fl/fl) SH3YL1 KO in streptozotocin-induced diabetic mice suppressed Nox4-driven oxidative stress, fibrosis markers, inflammatory cytokines, and podocyte loss; SH3YL1 protein levels were elevated in diabetic nephropathy patients.","method":"Conditional knockout mouse (podocyte-specific Cre), whole-body KO mouse, STZ diabetes model, immunohistochemistry, oxidative stress and fibrosis assays, patient biopsy protein quantification","journal":"iScience","confidence":"High","confidence_rationale":"Tier 2 — cell-type-specific KO with multiple mechanistic readouts corroborated by whole-body KO and replicated findings from prior AKI paper","pmids":["38318360"],"is_preprint":false}],"current_model":"SH3YL1 is a SYLF- and SH3-domain-containing scaffold protein that functions as a cytosolic activator of NADPH oxidase Nox4 by forming a ternary complex with Nox4 and p22phox to drive H2O2 production, thereby mediating inflammatory kidney injury and diabetic nephropathy; it also promotes cancer cell migration by binding phosphoinositides and the proline-rich region of Dock4 to stimulate Rac1 activation, and acts as a coregulator of androgen receptor transcription via the AR N-terminal polyproline domain."},"narrative":{"teleology":[{"year":2000,"claim":"Identification of SH3YL1 as a novel SH3-domain protein with hair-follicle-restricted expression established the gene's existence and tissue context but left its molecular function unknown.","evidence":"Differential cDNA library screening, northern blot, and in situ hybridization in mouse hair follicles","pmids":["10771491"],"confidence":"Medium","gaps":["No biochemical activity or binding partners identified","Function of the SH3 domain not tested","Expression in non-skin tissues not characterized"]},{"year":2014,"claim":"Demonstration that SH3YL1 binds phosphoinositides and the Dock4 proline-rich region to activate Rac1 revealed a first mechanistic role as a signaling scaffold promoting cell migration.","evidence":"Co-IP, pulldown with domain mutants, Rac1 activation assay, siRNA knockdown with migration assay in MDA-MB-231 breast cancer cells","pmids":["24508479"],"confidence":"Medium","gaps":["No structural detail of the SH3YL1–Dock4 interface","Phosphoinositide specificity and membrane recruitment mechanism not resolved","In vivo relevance for migration or metastasis not tested"]},{"year":2015,"claim":"Identification of SH3YL1 as an androgen receptor coregulator expanded its functional repertoire to nuclear transcriptional control, but the interaction was detected by phage display and a single Co-IP direction.","evidence":"T7 phage display, Co-IP, siRNA knockdown with proliferation and migration assays in prostate cancer cells","pmids":["26305679"],"confidence":"Medium","gaps":["Interaction not confirmed by reciprocal Co-IP or reconstitution with purified proteins","Genome-wide AR target gene dependency on SH3YL1 not mapped","Whether SH3YL1 enters the nucleus or acts at the cytoplasm–nucleus interface not determined"]},{"year":2020,"claim":"Discovery that SH3YL1 forms a ternary complex with Nox4 and p22phox to drive H2O2 production established SH3YL1 as a cytosolic activator of NADPH oxidase, linking it to inflammatory kidney injury in vivo.","evidence":"Reciprocal Co-IP, domain deletion/mutation analysis, H2O2 measurement, SH3YL1 knockout mouse with LPS-induced AKI model and histology","pmids":["33086058"],"confidence":"High","gaps":["Stoichiometry and structure of the ternary complex not determined","Mechanism by which LPS triggers p22phox–SH3YL1 interaction not identified","Whether SH3YL1 activates other Nox family members untested"]},{"year":2024,"claim":"Podocyte-specific conditional knockout confirmed cell-type-autonomous SH3YL1–Nox4 function in diabetic nephropathy, with corroborating elevation of SH3YL1 protein in patient biopsies, extending the Nox4-activator role to chronic kidney disease.","evidence":"Podocyte-specific (Nphs2-Cre) and global SH3YL1 KO mice in STZ diabetes model, patient biopsy immunohistochemistry, oxidative stress and fibrosis assays","pmids":["38318360"],"confidence":"High","gaps":["Whether pharmacological disruption of SH3YL1–Nox4 is therapeutically feasible not tested","Post-translational regulation of SH3YL1 protein levels in disease not characterized","Relative contributions of the Dock4/Rac1 versus Nox4 axes in kidney pathology not dissected"]},{"year":null,"claim":"It remains unknown how SH3YL1's distinct scaffolding functions — Nox4 activation, Dock4/Rac1-mediated migration, and AR coregulation — are coordinated or segregated across cell types, and no structural model of any SH3YL1-containing complex exists.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal or cryo-EM structure of SH3YL1 or its complexes","No systematic interactome or unbiased proteomics for SH3YL1","Functional integration of its phosphoinositide-binding, SH3, and SYLF domains across signaling contexts undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,3,4]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[2]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3,4]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,4]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,3]}],"complexes":["SH3YL1–Nox4–p22phox"],"partners":["NOX4","CYBA","DOCK4","AR"],"other_free_text":[]},"mechanistic_narrative":"SH3YL1 is a SYLF- and SH3-domain-containing scaffold protein that activates NADPH oxidase Nox4 by forming a ternary complex with Nox4 and p22phox, driving H2O2 production and pro-inflammatory signaling in renal epithelial cells and podocytes; SH3YL1 knockout mice are protected from LPS-induced acute kidney injury and streptozotocin-induced diabetic nephropathy [PMID:33086058, PMID:38318360]. SH3YL1 also promotes cancer cell migration through its phosphoinositide-binding domain, which mediates interaction with the proline-rich region of Dock4 to stimulate Dock4-dependent Rac1 activation [PMID:24508479]. Additionally, SH3YL1 functions as an androgen receptor coregulator by binding the AR N-terminal polyproline domain, supporting androgen-dependent transcription and prostate cancer cell proliferation [PMID:26305679]."},"prefetch_data":{"uniprot":{"accession":"Q96HL8","full_name":"SH3 domain-containing YSC84-like protein 1","aliases":[],"length_aa":342,"mass_kda":37.1,"function":"","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q96HL8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SH3YL1","classification":"Not Classified","n_dependent_lines":8,"n_total_lines":1208,"dependency_fraction":0.006622516556291391},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SH3YL1","total_profiled":1310},"omim":[{"mim_id":"617314","title":"SH3 DOMAIN- AND SYLF DOMAIN-CONTAINING PROTEIN 1; SH3YL1","url":"https://www.omim.org/entry/617314"},{"mim_id":"607679","title":"DEDICATOR OF CYTOKINESIS 4; DOCK4","url":"https://www.omim.org/entry/607679"},{"mim_id":"600829","title":"INOSITOL POLYPHOSPHATE PHOSPHATASE-LIKE 1; INPPL1","url":"https://www.omim.org/entry/600829"},{"mim_id":"313700","title":"ANDROGEN RECEPTOR; AR","url":"https://www.omim.org/entry/313700"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SH3YL1"},"hgnc":{"alias_symbol":["Ray","DKFZP586F1318"],"prev_symbol":[]},"alphafold":{"accession":"Q96HL8","domains":[{"cath_id":"-","chopping":"8-29_37-133_145-214","consensus_level":"high","plddt":83.4828,"start":8,"end":214},{"cath_id":"2.30.30.40","chopping":"285-342","consensus_level":"medium","plddt":80.54,"start":285,"end":342}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96HL8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96HL8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96HL8-F1-predicted_aligned_error_v6.png","plddt_mean":72.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SH3YL1","jax_strain_url":"https://www.jax.org/strain/search?query=SH3YL1"},"sequence":{"accession":"Q96HL8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96HL8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96HL8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96HL8"}},"corpus_meta":[{"pmid":"21293373","id":"PMC_21293373","title":"Femtosecond X-ray protein nanocrystallography.","date":"2011","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/21293373","citation_count":1177,"is_preprint":false},{"pmid":"21293374","id":"PMC_21293374","title":"Single mimivirus particles intercepted and imaged with an X-ray laser.","date":"2011","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/21293374","citation_count":432,"is_preprint":false},{"pmid":"25416941","id":"PMC_25416941","title":"A glimpse of structural biology through X-ray crystallography.","date":"2014","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/25416941","citation_count":211,"is_preprint":false},{"pmid":"18235446","id":"PMC_18235446","title":"The X-ray crystal structure of RNA polymerase from Archaea.","date":"2008","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/18235446","citation_count":169,"is_preprint":false},{"pmid":"10884915","id":"PMC_10884915","title":"x ray crystallography.","date":"2000","source":"Molecular pathology : MP","url":"https://pubmed.ncbi.nlm.nih.gov/10884915","citation_count":140,"is_preprint":false},{"pmid":"20363295","id":"PMC_20363295","title":"X-ray structures of ferritins and related proteins.","date":"2010","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/20363295","citation_count":135,"is_preprint":false},{"pmid":"11104004","id":"PMC_11104004","title":"Automation of X-ray crystallography.","date":"2000","source":"Nature structural biology","url":"https://pubmed.ncbi.nlm.nih.gov/11104004","citation_count":127,"is_preprint":false},{"pmid":"22975810","id":"PMC_22975810","title":"X-ray lasers for structural and dynamic biology.","date":"2012","source":"Reports on progress in physics. 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LPS triggers interaction of p22phox with SH3YL1, and the resulting complex drives H2O2 generation and pro-inflammatory cytokine expression in tubular epithelial cells. SH3YL1 knockout mice showed markedly reduced acute kidney injury, inflammatory cytokine secretion, macrophage infiltration, and tubular damage following LPS injection.\",\n      \"method\": \"Co-IP, domain deletion/mutation analysis, H2O2 measurement, SH3YL1 knockout mouse model, in vivo LPS injection with AKI biomarkers and histology\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, domain mapping, in vitro H2O2 assay, and KO mouse with multiple orthogonal readouts in a single study\",\n      \"pmids\": [\"33086058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The SH3YL1-Nox4 complex regulates diabetic nephropathy: SH3YL1 functions as a Nox4 cytosolic activator in podocytes. Global and podocyte-specific (Nphs2-Cre/SH3YL1fl/fl) SH3YL1 KO in streptozotocin-induced diabetic mice suppressed Nox4-driven oxidative stress, fibrosis markers, inflammatory cytokines, and podocyte loss; SH3YL1 protein levels were elevated in diabetic nephropathy patients.\",\n      \"method\": \"Conditional knockout mouse (podocyte-specific Cre), whole-body KO mouse, STZ diabetes model, immunohistochemistry, oxidative stress and fibrosis assays, patient biopsy protein quantification\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-type-specific KO with multiple mechanistic readouts corroborated by whole-body KO and replicated findings from prior AKI paper\",\n      \"pmids\": [\"38318360\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SH3YL1 is a SYLF- and SH3-domain-containing scaffold protein that functions as a cytosolic activator of NADPH oxidase Nox4 by forming a ternary complex with Nox4 and p22phox to drive H2O2 production, thereby mediating inflammatory kidney injury and diabetic nephropathy; it also promotes cancer cell migration by binding phosphoinositides and the proline-rich region of Dock4 to stimulate Rac1 activation, and acts as a coregulator of androgen receptor transcription via the AR N-terminal polyproline domain.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SH3YL1 is a SYLF- and SH3-domain-containing scaffold protein that activates NADPH oxidase Nox4 by forming a ternary complex with Nox4 and p22phox, driving H2O2 production and pro-inflammatory signaling in renal epithelial cells and podocytes; SH3YL1 knockout mice are protected from LPS-induced acute kidney injury and streptozotocin-induced diabetic nephropathy [PMID:33086058, PMID:38318360]. SH3YL1 also promotes cancer cell migration through its phosphoinositide-binding domain, which mediates interaction with the proline-rich region of Dock4 to stimulate Dock4-dependent Rac1 activation [PMID:24508479]. Additionally, SH3YL1 functions as an androgen receptor coregulator by binding the AR N-terminal polyproline domain, supporting androgen-dependent transcription and prostate cancer cell proliferation [PMID:26305679].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Identification of SH3YL1 as a novel SH3-domain protein with hair-follicle-restricted expression established the gene's existence and tissue context but left its molecular function unknown.\",\n      \"evidence\": \"Differential cDNA library screening, northern blot, and in situ hybridization in mouse hair follicles\",\n      \"pmids\": [\"10771491\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No biochemical activity or binding partners identified\",\n        \"Function of the SH3 domain not tested\",\n        \"Expression in non-skin tissues not characterized\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstration that SH3YL1 binds phosphoinositides and the Dock4 proline-rich region to activate Rac1 revealed a first mechanistic role as a signaling scaffold promoting cell migration.\",\n      \"evidence\": \"Co-IP, pulldown with domain mutants, Rac1 activation assay, siRNA knockdown with migration assay in MDA-MB-231 breast cancer cells\",\n      \"pmids\": [\"24508479\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structural detail of the SH3YL1–Dock4 interface\",\n        \"Phosphoinositide specificity and membrane recruitment mechanism not resolved\",\n        \"In vivo relevance for migration or metastasis not tested\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identification of SH3YL1 as an androgen receptor coregulator expanded its functional repertoire to nuclear transcriptional control, but the interaction was detected by phage display and a single Co-IP direction.\",\n      \"evidence\": \"T7 phage display, Co-IP, siRNA knockdown with proliferation and migration assays in prostate cancer cells\",\n      \"pmids\": [\"26305679\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Interaction not confirmed by reciprocal Co-IP or reconstitution with purified proteins\",\n        \"Genome-wide AR target gene dependency on SH3YL1 not mapped\",\n        \"Whether SH3YL1 enters the nucleus or acts at the cytoplasm–nucleus interface not determined\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Discovery that SH3YL1 forms a ternary complex with Nox4 and p22phox to drive H2O2 production established SH3YL1 as a cytosolic activator of NADPH oxidase, linking it to inflammatory kidney injury in vivo.\",\n      \"evidence\": \"Reciprocal Co-IP, domain deletion/mutation analysis, H2O2 measurement, SH3YL1 knockout mouse with LPS-induced AKI model and histology\",\n      \"pmids\": [\"33086058\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Stoichiometry and structure of the ternary complex not determined\",\n        \"Mechanism by which LPS triggers p22phox–SH3YL1 interaction not identified\",\n        \"Whether SH3YL1 activates other Nox family members untested\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Podocyte-specific conditional knockout confirmed cell-type-autonomous SH3YL1–Nox4 function in diabetic nephropathy, with corroborating elevation of SH3YL1 protein in patient biopsies, extending the Nox4-activator role to chronic kidney disease.\",\n      \"evidence\": \"Podocyte-specific (Nphs2-Cre) and global SH3YL1 KO mice in STZ diabetes model, patient biopsy immunohistochemistry, oxidative stress and fibrosis assays\",\n      \"pmids\": [\"38318360\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether pharmacological disruption of SH3YL1–Nox4 is therapeutically feasible not tested\",\n        \"Post-translational regulation of SH3YL1 protein levels in disease not characterized\",\n        \"Relative contributions of the Dock4/Rac1 versus Nox4 axes in kidney pathology not dissected\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how SH3YL1's distinct scaffolding functions — Nox4 activation, Dock4/Rac1-mediated migration, and AR coregulation — are coordinated or segregated across cell types, and no structural model of any SH3YL1-containing complex exists.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No crystal or cryo-EM structure of SH3YL1 or its complexes\",\n        \"No systematic interactome or unbiased proteomics for SH3YL1\",\n        \"Functional integration of its phosphoinositide-binding, SH3, and SYLF domains across signaling contexts undefined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 3, 4]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"complexes\": [\n      \"SH3YL1–Nox4–p22phox\"\n    ],\n    \"partners\": [\n      \"NOX4\",\n      \"CYBA\",\n      \"DOCK4\",\n      \"AR\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}