{"gene":"CYRIA","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":2021,"finding":"CYRI-A is transiently recruited to nascent macropinosomes in a PI3K- and RAC1-dependent manner; its recruitment follows RAC1 and actin signaling but precedes RAB5A recruitment, consistent with CYRI-A acting as a local inhibitor of actin polymerization at macropinosomes.","method":"Live-cell imaging, subcellular fractionation/localization, pharmacological inhibition of PI3K and RAC1, depletion experiments","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct localization experiments with functional consequence, multiple orthogonal methods (live imaging, depletion, inhibitor treatments) in a single focused study","pmids":["34165494"],"is_preprint":false},{"year":2021,"finding":"Depletion of both CYRI-A and CYRI-B results in enhanced surface expression of α5β1 integrin via reduced integrin internalization, and co-depletion enhances cell migration, invasion, and anchorage-independent growth in 3D.","method":"siRNA knockdown, flow cytometry for surface integrin levels, Transwell migration and invasion assays, 3D growth assays","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean KD with defined cellular phenotype (integrin trafficking, migration), single lab, multiple readouts but no mechanistic dissection separating CYRI-A from CYRI-B contributions","pmids":["34165494"],"is_preprint":false},{"year":2020,"finding":"CYRI-A and CYRI-B can form autoinhibited hetero- or homodimers, adding an additional regulatory layer to RAC1 signaling. The CYRI protein family members share a domain architecture with an N-terminal RAC1-binding subdomain and a C-terminal Ratchet subdomain.","method":"Crystal structure of CYRI-B:RAC1Q61L complex; biochemical analysis of CYRI-A/B dimerization","journal":"Structure (London, England : 1993)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure of CYRI-B:Rac1 complex with direct demonstration of CYRI-A/B heterodimerization; structural and biochemical methods in single study","pmids":["33217330"],"is_preprint":false},{"year":2020,"finding":"CYRI proteins (including CYRI-A) compete with the Scar/WAVE complex for binding to active (GTP-bound) RAC1, providing a feedback mechanism that negatively regulates actin dynamics.","method":"Crystal structure of CYRI-B:RAC1Q61L complex; competitive binding assays","journal":"Structure (London, England : 1993)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure plus competitive binding assay establishing mechanism; CYRI-A included as family member with demonstrated dimerization behavior","pmids":["33217330"],"is_preprint":false},{"year":2022,"finding":"Cells lacking CYRI proteins (CYRI-A and CYRI-B) internalize less high-molecular-weight dextran compared to wild-type cells, confirming a role for CYRI proteins in macropinocytosis.","method":"Image-based dextran uptake assay in CYRI-depleted cultured cells, fluorescence microscopy quantification","journal":"Bio-protocol","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean KO/depletion with defined cellular phenotype (dextran uptake), single lab, single method; corroborates earlier finding","pmids":["35530513"],"is_preprint":false}],"current_model":"CYRI-A is a RAC1-interacting protein that is transiently recruited to nascent macropinosomes in a PI3K- and RAC1-dependent manner, where it acts as a local inhibitor of actin polymerization by competing with the Scar/WAVE complex for active RAC1; together with its paralog CYRI-B, it regulates macropinocytosis, integrin (α5β1) internalization, and thereby limits cell migration and invasion, with an additional regulatory layer provided by the ability of CYRI-A and CYRI-B to form autoinhibited hetero- or homodimers."},"narrative":{"mechanistic_narrative":"CYRI-A is a RAC1-interacting protein that negatively regulates actin dynamics to control macropinocytosis and integrin trafficking [PMID:34165494, PMID:33217330]. It is transiently recruited to nascent macropinosomes in a PI3K- and RAC1-dependent manner, arriving after RAC1 and actin signaling but before RAB5A, consistent with a role as a local inhibitor of actin polymerization at these sites [PMID:34165494]. Mechanistically, CYRI-family proteins bind active GTP-bound RAC1 through an N-terminal RAC1-binding subdomain and compete with the Scar/WAVE complex for this interaction, establishing a negative feedback loop on RAC1-driven actin assembly [PMID:33217330]. CYRI-A and its paralog CYRI-B can additionally form autoinhibited homo- and heterodimers, adding a further regulatory layer to RAC1 signaling [PMID:33217330]. Functionally, loss of CYRI proteins reduces internalization of high-molecular-weight dextran, confirming their requirement for macropinocytosis [PMID:35530513], while co-depletion of CYRI-A and CYRI-B elevates surface α5β1 integrin via reduced internalization and enhances cell migration, invasion, and anchorage-independent growth [PMID:34165494].","teleology":[{"year":2020,"claim":"Establishing how CYRI proteins act on RAC1 was needed to explain their effect on actin; the structure showed CYRI-B binds active RAC1 and competes with Scar/WAVE, defining a negative-feedback mechanism on actin dynamics.","evidence":"Crystal structure of CYRI-B:RAC1Q61L complex with competitive binding assays","pmids":["33217330"],"confidence":"High","gaps":["CYRI-A itself was characterized largely as a family member by dimerization behavior, not by an independent CYRI-A:RAC1 structure","the cellular consequence of dimerization on RAC1 binding was not functionally dissected","stoichiometry and dynamics of CYRI vs Scar/WAVE competition in cells not resolved"]},{"year":2020,"claim":"Beyond a single inhibitory mode, it was unknown how CYRI activity is itself regulated; demonstrating that CYRI-A and CYRI-B form autoinhibited homo- and heterodimers added an additional regulatory layer to RAC1 signaling.","evidence":"Biochemical analysis of CYRI-A/B dimerization alongside crystallographic domain architecture analysis","pmids":["33217330"],"confidence":"High","gaps":["trigger and kinetics of dimer assembly/disassembly in cells unknown","relative abundance and biological role of homodimers vs heterodimers not defined"]},{"year":2021,"claim":"Where and when CYRI-A acts in the cell was unknown; live imaging placed it transiently at nascent macropinosomes downstream of PI3K/RAC1/actin and before RAB5A, localizing its inhibitory function to an early macropinosome stage.","evidence":"Live-cell imaging, subcellular localization, PI3K/RAC1 pharmacological inhibition, and depletion in cultured cells","pmids":["34165494"],"confidence":"High","gaps":["molecular signal driving the transient recruitment and departure not identified","whether RAB5A timing is a direct consequence of CYRI-A action untested"]},{"year":2021,"claim":"The downstream physiological output of CYRI loss was unclear; co-depletion of CYRI-A and CYRI-B raised surface α5β1 integrin via reduced internalization and increased migration, invasion, and 3D growth, linking CYRI to integrin trafficking and invasive behavior.","evidence":"siRNA knockdown, surface integrin flow cytometry, Transwell migration/invasion and 3D growth assays","pmids":["34165494"],"confidence":"Medium","gaps":["CYRI-A-specific contribution not separated from CYRI-B in the co-depletion phenotype","direct mechanistic link between actin/macropinosome regulation and integrin internalization not established"]},{"year":2022,"claim":"A dedicated functional readout was needed to confirm the macropinocytosis role; CYRI-depleted cells internalized less high-molecular-weight dextran, directly confirming a requirement for CYRI proteins in macropinocytosis.","evidence":"Image-based dextran uptake assay with fluorescence quantification in CYRI-depleted cells","pmids":["35530513"],"confidence":"Medium","gaps":["single-method assay from one lab","does not separate CYRI-A from CYRI-B contributions to dextran uptake"]},{"year":null,"claim":"It remains unknown how CYRI-A and CYRI-B activities are individually apportioned across macropinocytosis, integrin trafficking, and migration, and how dimerization-based autoinhibition is dynamically controlled in living cells.","evidence":"","pmids":[],"confidence":"Low","gaps":["no CYRI-A-specific loss-of-function dissection separating it from CYRI-B","no characterization of the upstream signal that toggles dimer autoinhibition"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,3]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[3]}],"localization":[{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,4]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3]}],"complexes":[],"partners":["RAC1","CYRIB"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H0Q0","full_name":"CYFIP-related Rac1 interactor A","aliases":["Protein CYRIA"],"length_aa":323,"mass_kda":37.3,"function":"May negatively regulate RAC1 signaling and RAC1-driven cytoskeletal remodeling (Probable). May regulate chemotaxis, cell migration and epithelial polarization by controlling the polarity, plasticity, duration and extent of protrusions (Probable)","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q9H0Q0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CYRIA","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CYRIA","total_profiled":1310},"omim":[{"mim_id":"621448","title":"CYFIP-RELATED RAC1 INTERACTOR A; CYRIA","url":"https://www.omim.org/entry/621448"},{"mim_id":"617978","title":"CYFIP-RELATED RAC1 INTERACTOR B; CYRIB","url":"https://www.omim.org/entry/617978"},{"mim_id":"602878","title":"SOLUTE CARRIER FAMILY 30 (ZINC TRANSPORTER), MEMBER 3; SLC30A3","url":"https://www.omim.org/entry/602878"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":46.1}],"url":"https://www.proteinatlas.org/search/CYRIA"},"hgnc":{"alias_symbol":["DKFZP566A1524","FLJ11080","CYRI-A"],"prev_symbol":["FAM49A"]},"alphafold":{"accession":"Q9H0Q0","domains":[{"cath_id":"-","chopping":"19-128_147-192","consensus_level":"medium","plddt":95.2304,"start":19,"end":192},{"cath_id":"1.20.1050","chopping":"215-323","consensus_level":"medium","plddt":95.7026,"start":215,"end":323}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H0Q0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H0Q0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H0Q0-F1-predicted_aligned_error_v6.png","plddt_mean":92.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CYRIA","jax_strain_url":"https://www.jax.org/strain/search?query=CYRIA"},"sequence":{"accession":"Q9H0Q0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H0Q0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H0Q0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H0Q0"}},"corpus_meta":[{"pmid":"20631050","id":"PMC_20631050","title":"Gene amplification as double minutes or homogeneously staining regions in solid tumors: origin and structure.","date":"2010","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/20631050","citation_count":194,"is_preprint":false},{"pmid":"27033726","id":"PMC_27033726","title":"A multi-ethnic genome-wide association study identifies novel loci for non-syndromic cleft lip with or without cleft palate on 2p24.2, 17q23 and 19q13.","date":"2016","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27033726","citation_count":188,"is_preprint":false},{"pmid":"15659707","id":"PMC_15659707","title":"Effect of cryopreservation on sea bass sperm proteins.","date":"2005","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/15659707","citation_count":43,"is_preprint":false},{"pmid":"29654272","id":"PMC_29654272","title":"Identification of novel lncRNAs regulated by the TAL1 complex in T-cell acute lymphoblastic 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and RAC1-dependent manner; its recruitment follows RAC1 and actin signaling but precedes RAB5A recruitment, consistent with CYRI-A acting as a local inhibitor of actin polymerization at macropinosomes.\",\n      \"method\": \"Live-cell imaging, subcellular fractionation/localization, pharmacological inhibition of PI3K and RAC1, depletion experiments\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiments with functional consequence, multiple orthogonal methods (live imaging, depletion, inhibitor treatments) in a single focused study\",\n      \"pmids\": [\"34165494\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Depletion of both CYRI-A and CYRI-B results in enhanced surface expression of α5β1 integrin via reduced integrin internalization, and co-depletion enhances cell migration, invasion, and anchorage-independent growth in 3D.\",\n      \"method\": \"siRNA knockdown, flow cytometry for surface integrin levels, Transwell migration and invasion assays, 3D growth assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean KD with defined cellular phenotype (integrin trafficking, migration), single lab, multiple readouts but no mechanistic dissection separating CYRI-A from CYRI-B contributions\",\n      \"pmids\": [\"34165494\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CYRI-A and CYRI-B can form autoinhibited hetero- or homodimers, adding an additional regulatory layer to RAC1 signaling. The CYRI protein family members share a domain architecture with an N-terminal RAC1-binding subdomain and a C-terminal Ratchet subdomain.\",\n      \"method\": \"Crystal structure of CYRI-B:RAC1Q61L complex; biochemical analysis of CYRI-A/B dimerization\",\n      \"journal\": \"Structure (London, England : 1993)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure of CYRI-B:Rac1 complex with direct demonstration of CYRI-A/B heterodimerization; structural and biochemical methods in single study\",\n      \"pmids\": [\"33217330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CYRI proteins (including CYRI-A) compete with the Scar/WAVE complex for binding to active (GTP-bound) RAC1, providing a feedback mechanism that negatively regulates actin dynamics.\",\n      \"method\": \"Crystal structure of CYRI-B:RAC1Q61L complex; competitive binding assays\",\n      \"journal\": \"Structure (London, England : 1993)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus competitive binding assay establishing mechanism; CYRI-A included as family member with demonstrated dimerization behavior\",\n      \"pmids\": [\"33217330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cells lacking CYRI proteins (CYRI-A and CYRI-B) internalize less high-molecular-weight dextran compared to wild-type cells, confirming a role for CYRI proteins in macropinocytosis.\",\n      \"method\": \"Image-based dextran uptake assay in CYRI-depleted cultured cells, fluorescence microscopy quantification\",\n      \"journal\": \"Bio-protocol\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean KO/depletion with defined cellular phenotype (dextran uptake), single lab, single method; corroborates earlier finding\",\n      \"pmids\": [\"35530513\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CYRI-A is a RAC1-interacting protein that is transiently recruited to nascent macropinosomes in a PI3K- and RAC1-dependent manner, where it acts as a local inhibitor of actin polymerization by competing with the Scar/WAVE complex for active RAC1; together with its paralog CYRI-B, it regulates macropinocytosis, integrin (α5β1) internalization, and thereby limits cell migration and invasion, with an additional regulatory layer provided by the ability of CYRI-A and CYRI-B to form autoinhibited hetero- or homodimers.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CYRI-A is a RAC1-interacting protein that negatively regulates actin dynamics to control macropinocytosis and integrin trafficking [#0, #3]. It is transiently recruited to nascent macropinosomes in a PI3K- and RAC1-dependent manner, arriving after RAC1 and actin signaling but before RAB5A, consistent with a role as a local inhibitor of actin polymerization at these sites [#0]. Mechanistically, CYRI-family proteins bind active GTP-bound RAC1 through an N-terminal RAC1-binding subdomain and compete with the Scar/WAVE complex for this interaction, establishing a negative feedback loop on RAC1-driven actin assembly [#2, #3]. CYRI-A and its paralog CYRI-B can additionally form autoinhibited homo- and heterodimers, adding a further regulatory layer to RAC1 signaling [#2]. Functionally, loss of CYRI proteins reduces internalization of high-molecular-weight dextran, confirming their requirement for macropinocytosis [#4], while co-depletion of CYRI-A and CYRI-B elevates surface \\u03b15\\u03b21 integrin via reduced internalization and enhances cell migration, invasion, and anchorage-independent growth [#1].\",\n  \"teleology\": [\n    {\n      \"year\": 2020,\n      \"claim\": \"Establishing how CYRI proteins act on RAC1 was needed to explain their effect on actin; the structure showed CYRI-B binds active RAC1 and competes with Scar/WAVE, defining a negative-feedback mechanism on actin dynamics.\",\n      \"evidence\": \"Crystal structure of CYRI-B:RAC1Q61L complex with competitive binding assays\",\n      \"pmids\": [\"33217330\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"CYRI-A itself was characterized largely as a family member by dimerization behavior, not by an independent CYRI-A:RAC1 structure\",\n        \"the cellular consequence of dimerization on RAC1 binding was not functionally dissected\",\n        \"stoichiometry and dynamics of CYRI vs Scar/WAVE competition in cells not resolved\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Beyond a single inhibitory mode, it was unknown how CYRI activity is itself regulated; demonstrating that CYRI-A and CYRI-B form autoinhibited homo- and heterodimers added an additional regulatory layer to RAC1 signaling.\",\n      \"evidence\": \"Biochemical analysis of CYRI-A/B dimerization alongside crystallographic domain architecture analysis\",\n      \"pmids\": [\"33217330\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"trigger and kinetics of dimer assembly/disassembly in cells unknown\",\n        \"relative abundance and biological role of homodimers vs heterodimers not defined\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Where and when CYRI-A acts in the cell was unknown; live imaging placed it transiently at nascent macropinosomes downstream of PI3K/RAC1/actin and before RAB5A, localizing its inhibitory function to an early macropinosome stage.\",\n      \"evidence\": \"Live-cell imaging, subcellular localization, PI3K/RAC1 pharmacological inhibition, and depletion in cultured cells\",\n      \"pmids\": [\"34165494\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"molecular signal driving the transient recruitment and departure not identified\",\n        \"whether RAB5A timing is a direct consequence of CYRI-A action untested\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The downstream physiological output of CYRI loss was unclear; co-depletion of CYRI-A and CYRI-B raised surface \\u03b15\\u03b21 integrin via reduced internalization and increased migration, invasion, and 3D growth, linking CYRI to integrin trafficking and invasive behavior.\",\n      \"evidence\": \"siRNA knockdown, surface integrin flow cytometry, Transwell migration/invasion and 3D growth assays\",\n      \"pmids\": [\"34165494\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"CYRI-A-specific contribution not separated from CYRI-B in the co-depletion phenotype\",\n        \"direct mechanistic link between actin/macropinosome regulation and integrin internalization not established\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"A dedicated functional readout was needed to confirm the macropinocytosis role; CYRI-depleted cells internalized less high-molecular-weight dextran, directly confirming a requirement for CYRI proteins in macropinocytosis.\",\n      \"evidence\": \"Image-based dextran uptake assay with fluorescence quantification in CYRI-depleted cells\",\n      \"pmids\": [\"35530513\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"single-method assay from one lab\",\n        \"does not separate CYRI-A from CYRI-B contributions to dextran uptake\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how CYRI-A and CYRI-B activities are individually apportioned across macropinocytosis, integrin trafficking, and migration, and how dimerization-based autoinhibition is dynamically controlled in living cells.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"no CYRI-A-specific loss-of-function dissection separating it from CYRI-B\",\n        \"no characterization of the upstream signal that toggles dimer autoinhibition\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RAC1\", \"CYRIB\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}