{"gene":"WIPF2","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2002,"finding":"WIPF2 (WICH/WIRE) associates strongly with N-WASP (and weakly with WASP) via its C-terminal WASP-interacting (W) region, and ectopic expression of WICH induces actin-microspike formation cooperatively with N-WASP; expression of the W fragment alone suppresses N-WASP-induced microspike formation, indicating an essential role for WICH in N-WASP-mediated actin microspike formation.","method":"Co-immunoprecipitation, ectopic overexpression, dominant-negative fragment expression in cultured cells","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal binding assay and dominant-negative phenotype, single lab, two orthogonal approaches (binding + functional overexpression)","pmids":["11829459"],"is_preprint":false},{"year":2002,"finding":"WIRE (WIPF2) binds to the WH1 domain of WASP and N-WASP, localizes to actin filaments, relocalizes WASP to actin filaments (requiring direct WIRE-WASP interaction), binds the PDGF receptor substrate Nckβ, and promotes PDGF-induced peripheral filopodia/lamellipodia formation and WASP translocation to the cell margin downstream of PDGFRβ.","method":"Co-immunoprecipitation, ectopic overexpression in PAE/PDGFRβ cells, fluorescence microscopy, PDGF stimulation assay","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus live-cell imaging and functional overexpression, single lab, multiple orthogonal methods","pmids":["12213210"],"is_preprint":false},{"year":2004,"finding":"The WASP-binding domain of WIRE (WIPF2) maps to a core motif at amino acid residues 408–412 plus an adjacent stretch of aromatic residues; substitution mutations in either motif abolished WASP binding. Notably, WIRE mutants unable to bind WASP still reorganized the actin filament system, demonstrating that the WASP-independent pathway also regulates actin dynamics. In contrast, inhibition of PDGF receptor endocytosis by WIRE required an intact WASP-binding domain, indicating that WIRE controls receptor endocytosis and actin dynamics through distinct mechanisms.","method":"Site-directed mutagenesis, co-immunoprecipitation, ectopic overexpression with phenotypic readouts (actin reorganization, receptor endocytosis assay)","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — mutagenesis defining binding domain combined with functional rescue/loss-of-function assays, single lab, multiple orthogonal readouts","pmids":["15265696"],"is_preprint":false},{"year":2005,"finding":"WICH (WIPF2) cross-links actin filaments in vitro and induces thick bundled actin fibers upon overexpression in cultured fibroblasts; this actin cross-linking/bundling activity is suppressed by direct association with N-WASP.","method":"In vitro co-sedimentation assay, fluorescence microscopy, electron microscopy, overexpression in fibroblasts","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical reconstitution (co-sedimentation) plus cell-based overexpression, single lab but multiple orthogonal methods including EM","pmids":["15707985"],"is_preprint":false},{"year":2010,"finding":"WIRE (WIPF2) interacts with IRSp53 via the Verprolin (V)-domain of WIRE and the SH3 domain of IRSp53, and this interaction is regulated by Cdc42; co-expression of WIRE and IRSp53 in N-WASP−/− mouse fibroblasts induces filopodia independently of N-WASP. Cdc42 also regulates the plasma membrane localization of the WIRE-IRSp53 complex.","method":"Yeast two-hybrid screen, pull-down assay, overexpression in N-WASP−/− fibroblasts, site-directed mutagenesis of IRSp53 SH3 domain and WIRE V-domain, fluorescence microscopy","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal pull-down plus mutagenesis and KO cell rescue, single lab, multiple orthogonal methods","pmids":["20678498"],"is_preprint":false},{"year":2016,"finding":"WICH/WIRE (WIPF2) plays a non-redundant role from WIP in cancer cell invasion: WIP is essential for invadopodium assembly while WICH/WIRE specifically regulates N-WASP activation to control invadopodium maturation and degradative activity. Nck interaction with both WIP and WICH/WIRE modulates invadopodium maturation, and changes in their levels differentially redistribute Nck. WIP can replace WICH/WIRE functions at elevated levels.","method":"RNAi knockdown, biochemical co-immunoprecipitation, super-resolution fluorescence microscopy (STORM/dSTORM), invasion/degradation assays in breast cancer cells","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function RNAi with specific cellular phenotype (invadopodium maturation/degradation), confirmed by biochemical and advanced imaging approaches, multiple orthogonal methods","pmids":["27009365"],"is_preprint":false},{"year":2019,"finding":"WIPF2 mediates phagocytosis (internalization) of Aspergillus fumigatus conidia by human bronchial epithelial cells; RNAi-mediated knockdown of WIPF2 significantly reduces conidia internalization, and super-resolution fluorescence microscopy shows WIPF2 is transiently localized to the site of bound conidia. The Arp2/3 complex acts in the same pathway, as its small-molecule inhibition phenocopies WIPF2 knockdown.","method":"RNAi knockdown, small-molecule inhibition of Arp2/3, super-resolution fluorescence microscopy, quantitative internalization assay","journal":"Frontiers in cellular and infection microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi loss-of-function with specific phagocytosis phenotype plus direct localization imaging, single lab, two orthogonal methods","pmids":["30792969"],"is_preprint":false}],"current_model":"WIPF2 (WICH/WIRE) is a verprolin-family actin regulatory scaffold protein that binds N-WASP (strongly) and WASP (weakly) via a defined C-terminal WH1-interaction motif (core residues 408–412 plus flanking aromatic residues), directly cross-links and bundles actin filaments in vitro (an activity suppressed by N-WASP), promotes actin microspike and filopodium formation both N-WASP-dependently and, through an IRSp53/Cdc42 axis, N-WASP-independently; it acts downstream of PDGFRβ to regulate actin dynamics and receptor endocytosis through mechanistically separable pathways, controls invadopodium maturation and degradative activity in invasive cancer cells, and mediates Arp2/3-dependent phagocytosis of fungal conidia by airway epithelial cells."},"narrative":{"mechanistic_narrative":"WIPF2 (WICH/WIRE) is a verprolin-family actin regulatory scaffold that couples membrane receptor signaling to Arp2/3-dependent actin remodeling [PMID:11829459, PMID:12213210]. It binds the WH1 domain of N-WASP strongly and WASP weakly through a defined C-terminal WASP-interacting region, with binding determinants mapping to a core motif at residues 408–412 plus adjacent aromatic residues whose mutation abolishes WASP binding [PMID:11829459, PMID:15265696]. Functionally, WIPF2 localizes to actin filaments, relocalizes WASP to filaments and the cell margin, and cooperates with N-WASP to drive actin microspike formation; it also directly cross-links and bundles actin filaments in vitro, an activity that is suppressed upon association with N-WASP [PMID:11829459, PMID:12213210, PMID:15707985]. WIPF2 operates downstream of PDGFRβ, where it binds the receptor substrate Nckβ and promotes PDGF-induced filopodia and lamellipodia, and it controls actin dynamics and receptor endocytosis through mechanistically separable pathways: endocytosis inhibition requires an intact WASP-binding domain, whereas WASP-binding-deficient mutants still reorganize the actin system via an N-WASP-independent route [PMID:12213210, PMID:15265696]. This independent pathway runs through IRSp53, which binds the WIRE verprolin domain via its SH3 domain under Cdc42 control to generate filopodia even in N-WASP-null cells [PMID:20678498]. In invasive breast cancer cells WIPF2 plays a non-redundant role distinct from WIP, specifically regulating N-WASP activation to control invadopodium maturation and matrix-degradative activity, with Nck interactions tuning this output [PMID:27009365], and in airway epithelial cells it mediates Arp2/3-dependent phagocytosis of Aspergillus fumigatus conidia [PMID:30792969].","teleology":[{"year":2002,"claim":"Established WIPF2 as a dedicated N-WASP/WASP partner required for actin microspike formation rather than a passive cofactor, defining its place in the actin nucleation machinery.","evidence":"Co-immunoprecipitation, ectopic overexpression, and dominant-negative W-fragment expression in cultured cells; parallel work in PDGFRβ-expressing cells with PDGF stimulation and imaging","pmids":["11829459","12213210"],"confidence":"Medium","gaps":["Direct versus indirect nature of the actin-filament localization not biochemically resolved","Whether N-WASP binding is necessary for all microspike outputs untested at this stage"]},{"year":2004,"claim":"Mapped the WASP-binding determinant to residues 408–412 plus flanking aromatics and used binding-dead mutants to separate two outputs, showing actin reorganization is WASP-independent while receptor endocytosis requires WASP binding.","evidence":"Site-directed mutagenesis with co-IP and phenotypic readouts (actin reorganization, PDGFR endocytosis) in overexpressing cells","pmids":["15265696"],"confidence":"Medium","gaps":["Identity of the WASP-independent effector not yet defined here","Endocytosis assay based on overexpression, not endogenous loss-of-function"]},{"year":2005,"claim":"Demonstrated an intrinsic actin cross-linking/bundling activity of WIPF2 and that N-WASP association suppresses it, revealing a switch between filament bundling and nucleation-promoting roles.","evidence":"In vitro co-sedimentation, fluorescence and electron microscopy, plus fibroblast overexpression","pmids":["15707985"],"confidence":"High","gaps":["Structural basis of bundling and its suppression by N-WASP unresolved","Physiological relevance of bundling in cells not directly tested"]},{"year":2010,"claim":"Identified IRSp53 as the partner mediating the N-WASP-independent pathway, showing a Cdc42-regulated WIRE–IRSp53 complex drives filopodia even without N-WASP.","evidence":"Yeast two-hybrid, reciprocal pull-downs, domain mutagenesis, and rescue in N-WASP−/− fibroblasts with imaging","pmids":["20678498"],"confidence":"Medium","gaps":["How Cdc42 regulates complex assembly versus localization not mechanistically separated","Quantitative contribution relative to the N-WASP route in normal cells unknown"]},{"year":2016,"claim":"Distinguished WIPF2 from the paralog WIP functionally, assigning WIPF2 a non-redundant role in N-WASP-dependent invadopodium maturation and matrix degradation in cancer cells.","evidence":"RNAi knockdown, co-IP, super-resolution STORM imaging, and invasion/degradation assays in breast cancer cells","pmids":["27009365"],"confidence":"High","gaps":["WIP can substitute at elevated levels, so the basis of specificity is concentration-dependent and unresolved","In vivo relevance to metastasis not established"]},{"year":2019,"claim":"Extended WIPF2 function to innate defense, showing it drives Arp2/3-dependent phagocytic uptake of fungal conidia by airway epithelium.","evidence":"RNAi knockdown, Arp2/3 small-molecule inhibition, super-resolution imaging, and quantitative internalization assays in human bronchial epithelial cells","pmids":["30792969"],"confidence":"Medium","gaps":["Upstream receptor and signaling input to WIPF2 in this context not identified","Whether N-WASP or IRSp53 routes mediate conidial uptake untested"]},{"year":null,"claim":"How the bundling, N-WASP-dependent, and IRSp53/Cdc42-dependent activities are integrated and selectively deployed across distinct cellular processes remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the WIPF2–N-WASP or WIPF2–IRSp53 interfaces","No loss-of-function genetics linking WIPF2 to an organismal phenotype or disease","Regulatory inputs controlling the switch between bundling and nucleation-promoting modes unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,3,4]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,5]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[1,3]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,4,6]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,2]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6]}],"complexes":[],"partners":["WASL","WAS","IRSP53","NCK1","NCK2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8TF74","full_name":"WAS/WASL-interacting protein family member 2","aliases":["WASP-interacting protein-related protein","WIP- and CR16-homologous protein","WIP-related protein"],"length_aa":440,"mass_kda":46.3,"function":"Plays an active role in the formation of cell surface protrusions downstream of activated PDGFB receptors. Plays an important role in actin-microspike formation through cooperation with WASL. May cooperate with WASP and WASL to induce mobilization and reorganization of the actin filament system","subcellular_location":"Cytoplasm, cytoskeleton","url":"https://www.uniprot.org/uniprotkb/Q8TF74/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/WIPF2","classification":"Not Classified","n_dependent_lines":25,"n_total_lines":1208,"dependency_fraction":0.020695364238410598},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000171475","cell_line_id":"CID000551","localizations":[{"compartment":"cell_contact","grade":3},{"compartment":"membrane","grade":3},{"compartment":"cytoplasmic","grade":2}],"interactors":[{"gene":"WASL","stoichiometry":10.0},{"gene":"ACTG1","stoichiometry":0.2},{"gene":"FGA","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000551","total_profiled":1310},"omim":[{"mim_id":"611282","title":"DYNAMIN-BINDING PROTEIN; DNMBP","url":"https://www.omim.org/entry/611282"},{"mim_id":"609692","title":"WAS/WASL-INTERACTING PROTEIN FAMILY, MEMBER 2; WIPF2","url":"https://www.omim.org/entry/609692"},{"mim_id":"605056","title":"WASP-LIKE ACTIN NUCLEATION-PROMOTING FACTOR; WASL","url":"https://www.omim.org/entry/605056"}],"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/WIPF2"},"hgnc":{"alias_symbol":["WICH","WIRE"],"prev_symbol":[]},"alphafold":{"accession":"Q8TF74","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TF74","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TF74-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TF74-F1-predicted_aligned_error_v6.png","plddt_mean":59.66},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=WIPF2","jax_strain_url":"https://www.jax.org/strain/search?query=WIPF2"},"sequence":{"accession":"Q8TF74","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8TF74.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8TF74/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TF74"}},"corpus_meta":[{"pmid":"9486645","id":"PMC_9486645","title":"DNA-templated assembly and electrode attachment of a conducting silver 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Notably, WIRE mutants unable to bind WASP still reorganized the actin filament system, demonstrating that the WASP-independent pathway also regulates actin dynamics. In contrast, inhibition of PDGF receptor endocytosis by WIRE required an intact WASP-binding domain, indicating that WIRE controls receptor endocytosis and actin dynamics through distinct mechanisms.\",\n      \"method\": \"Site-directed mutagenesis, co-immunoprecipitation, ectopic overexpression with phenotypic readouts (actin reorganization, receptor endocytosis assay)\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — mutagenesis defining binding domain combined with functional rescue/loss-of-function assays, single lab, multiple orthogonal readouts\",\n      \"pmids\": [\"15265696\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"WICH (WIPF2) cross-links actin filaments in vitro and induces thick bundled actin fibers upon overexpression in cultured fibroblasts; this actin cross-linking/bundling activity is suppressed by direct association with N-WASP.\",\n      \"method\": \"In vitro co-sedimentation assay, fluorescence microscopy, electron microscopy, overexpression in fibroblasts\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical reconstitution (co-sedimentation) plus cell-based overexpression, single lab but multiple orthogonal methods including EM\",\n      \"pmids\": [\"15707985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"WIRE (WIPF2) interacts with IRSp53 via the Verprolin (V)-domain of WIRE and the SH3 domain of IRSp53, and this interaction is regulated by Cdc42; co-expression of WIRE and IRSp53 in N-WASP−/− mouse fibroblasts induces filopodia independently of N-WASP. Cdc42 also regulates the plasma membrane localization of the WIRE-IRSp53 complex.\",\n      \"method\": \"Yeast two-hybrid screen, pull-down assay, overexpression in N-WASP−/− fibroblasts, site-directed mutagenesis of IRSp53 SH3 domain and WIRE V-domain, fluorescence microscopy\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal pull-down plus mutagenesis and KO cell rescue, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"20678498\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"WICH/WIRE (WIPF2) plays a non-redundant role from WIP in cancer cell invasion: WIP is essential for invadopodium assembly while WICH/WIRE specifically regulates N-WASP activation to control invadopodium maturation and degradative activity. Nck interaction with both WIP and WICH/WIRE modulates invadopodium maturation, and changes in their levels differentially redistribute Nck. WIP can replace WICH/WIRE functions at elevated levels.\",\n      \"method\": \"RNAi knockdown, biochemical co-immunoprecipitation, super-resolution fluorescence microscopy (STORM/dSTORM), invasion/degradation assays in breast cancer cells\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function RNAi with specific cellular phenotype (invadopodium maturation/degradation), confirmed by biochemical and advanced imaging approaches, multiple orthogonal methods\",\n      \"pmids\": [\"27009365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"WIPF2 mediates phagocytosis (internalization) of Aspergillus fumigatus conidia by human bronchial epithelial cells; RNAi-mediated knockdown of WIPF2 significantly reduces conidia internalization, and super-resolution fluorescence microscopy shows WIPF2 is transiently localized to the site of bound conidia. The Arp2/3 complex acts in the same pathway, as its small-molecule inhibition phenocopies WIPF2 knockdown.\",\n      \"method\": \"RNAi knockdown, small-molecule inhibition of Arp2/3, super-resolution fluorescence microscopy, quantitative internalization assay\",\n      \"journal\": \"Frontiers in cellular and infection microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi loss-of-function with specific phagocytosis phenotype plus direct localization imaging, single lab, two orthogonal methods\",\n      \"pmids\": [\"30792969\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"WIPF2 (WICH/WIRE) is a verprolin-family actin regulatory scaffold protein that binds N-WASP (strongly) and WASP (weakly) via a defined C-terminal WH1-interaction motif (core residues 408–412 plus flanking aromatic residues), directly cross-links and bundles actin filaments in vitro (an activity suppressed by N-WASP), promotes actin microspike and filopodium formation both N-WASP-dependently and, through an IRSp53/Cdc42 axis, N-WASP-independently; it acts downstream of PDGFRβ to regulate actin dynamics and receptor endocytosis through mechanistically separable pathways, controls invadopodium maturation and degradative activity in invasive cancer cells, and mediates Arp2/3-dependent phagocytosis of fungal conidia by airway epithelial cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"WIPF2 (WICH/WIRE) is a verprolin-family actin regulatory scaffold that couples membrane receptor signaling to Arp2/3-dependent actin remodeling [#0, #1]. It binds the WH1 domain of N-WASP strongly and WASP weakly through a defined C-terminal WASP-interacting region, with binding determinants mapping to a core motif at residues 408–412 plus adjacent aromatic residues whose mutation abolishes WASP binding [#0, #2]. Functionally, WIPF2 localizes to actin filaments, relocalizes WASP to filaments and the cell margin, and cooperates with N-WASP to drive actin microspike formation; it also directly cross-links and bundles actin filaments in vitro, an activity that is suppressed upon association with N-WASP [#0, #1, #3]. WIPF2 operates downstream of PDGFRβ, where it binds the receptor substrate Nckβ and promotes PDGF-induced filopodia and lamellipodia, and it controls actin dynamics and receptor endocytosis through mechanistically separable pathways: endocytosis inhibition requires an intact WASP-binding domain, whereas WASP-binding-deficient mutants still reorganize the actin system via an N-WASP-independent route [#1, #2]. This independent pathway runs through IRSp53, which binds the WIRE verprolin domain via its SH3 domain under Cdc42 control to generate filopodia even in N-WASP-null cells [#4]. In invasive breast cancer cells WIPF2 plays a non-redundant role distinct from WIP, specifically regulating N-WASP activation to control invadopodium maturation and matrix-degradative activity, with Nck interactions tuning this output [#5], and in airway epithelial cells it mediates Arp2/3-dependent phagocytosis of Aspergillus fumigatus conidia [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established WIPF2 as a dedicated N-WASP/WASP partner required for actin microspike formation rather than a passive cofactor, defining its place in the actin nucleation machinery.\",\n      \"evidence\": \"Co-immunoprecipitation, ectopic overexpression, and dominant-negative W-fragment expression in cultured cells; parallel work in PDGFRβ-expressing cells with PDGF stimulation and imaging\",\n      \"pmids\": [\"11829459\", \"12213210\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct versus indirect nature of the actin-filament localization not biochemically resolved\",\n        \"Whether N-WASP binding is necessary for all microspike outputs untested at this stage\"\n      ]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Mapped the WASP-binding determinant to residues 408–412 plus flanking aromatics and used binding-dead mutants to separate two outputs, showing actin reorganization is WASP-independent while receptor endocytosis requires WASP binding.\",\n      \"evidence\": \"Site-directed mutagenesis with co-IP and phenotypic readouts (actin reorganization, PDGFR endocytosis) in overexpressing cells\",\n      \"pmids\": [\"15265696\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Identity of the WASP-independent effector not yet defined here\",\n        \"Endocytosis assay based on overexpression, not endogenous loss-of-function\"\n      ]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrated an intrinsic actin cross-linking/bundling activity of WIPF2 and that N-WASP association suppresses it, revealing a switch between filament bundling and nucleation-promoting roles.\",\n      \"evidence\": \"In vitro co-sedimentation, fluorescence and electron microscopy, plus fibroblast overexpression\",\n      \"pmids\": [\"15707985\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of bundling and its suppression by N-WASP unresolved\",\n        \"Physiological relevance of bundling in cells not directly tested\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified IRSp53 as the partner mediating the N-WASP-independent pathway, showing a Cdc42-regulated WIRE–IRSp53 complex drives filopodia even without N-WASP.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal pull-downs, domain mutagenesis, and rescue in N-WASP−/− fibroblasts with imaging\",\n      \"pmids\": [\"20678498\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"How Cdc42 regulates complex assembly versus localization not mechanistically separated\",\n        \"Quantitative contribution relative to the N-WASP route in normal cells unknown\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Distinguished WIPF2 from the paralog WIP functionally, assigning WIPF2 a non-redundant role in N-WASP-dependent invadopodium maturation and matrix degradation in cancer cells.\",\n      \"evidence\": \"RNAi knockdown, co-IP, super-resolution STORM imaging, and invasion/degradation assays in breast cancer cells\",\n      \"pmids\": [\"27009365\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"WIP can substitute at elevated levels, so the basis of specificity is concentration-dependent and unresolved\",\n        \"In vivo relevance to metastasis not established\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended WIPF2 function to innate defense, showing it drives Arp2/3-dependent phagocytic uptake of fungal conidia by airway epithelium.\",\n      \"evidence\": \"RNAi knockdown, Arp2/3 small-molecule inhibition, super-resolution imaging, and quantitative internalization assays in human bronchial epithelial cells\",\n      \"pmids\": [\"30792969\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Upstream receptor and signaling input to WIPF2 in this context not identified\",\n        \"Whether N-WASP or IRSp53 routes mediate conidial uptake untested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the bundling, N-WASP-dependent, and IRSp53/Cdc42-dependent activities are integrated and selectively deployed across distinct cellular processes remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structural model of the WIPF2–N-WASP or WIPF2–IRSp53 interfaces\",\n        \"No loss-of-function genetics linking WIPF2 to an organismal phenotype or disease\",\n        \"Regulatory inputs controlling the switch between bundling and nucleation-promoting modes unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 3, 4]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 4, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"WASL\", \"WAS\", \"IRSp53\", \"NCK1\", \"NCK2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}