{"gene":"WFIKKN2","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2008,"finding":"WFIKKN2 binds mature GDF8/myostatin, myostatin propeptide, and GDF11 with high affinity. Structure-function studies using WFIKKN1 (the paralog) revealed that the follistatin domain is primarily responsible for binding the mature growth factor, while the NTR domain contributes most significantly to interaction with myostatin propeptide.","method":"Binding assays (SPR/affinity), domain deletion/structure-function analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — SPR binding assays with domain mapping across two paralogs, replicated across multiple studies","pmids":["18596030"],"is_preprint":false},{"year":2010,"finding":"WFIKKN2 binds TGFβ1, BMP2, and BMP4 with relatively high affinity (Kd ~10⁻⁶ M) as measured by SPR, but does not inhibit their signaling activity in reporter assays even at micromolar concentrations. WFIKKN2 inhibits GDF8 and GDF11 biological activity in the nanomolar range, confirming it is a selective antagonist of GDF8/GDF11.","method":"Surface plasmon resonance (SPR) binding assays; reporter assays for signaling activity","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — two orthogonal methods (SPR binding + reporter assay) in a single study with clear quantitative results","pmids":["21054789"],"is_preprint":false},{"year":2013,"finding":"WFIKKN2 blocks myostatin receptor interaction with semilatent myostatin, but is less efficient than WFIKKN1 because WFIKKN2 lacks affinity for the propeptide domain. WFIKKN1's additional interaction with the myostatin propeptide increases its potency in suppressing semilatent myostatin receptor binding.","method":"Reporter assays for myostatin receptor binding; comparative binding studies between WFIKKN1 and WFIKKN2","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional reporter assays with mechanistic comparison, single lab but multiple assays","pmids":["23829672"],"is_preprint":false},{"year":2019,"finding":"The crystal structure of the murine WFIKKN2 follistatin domain (FSD) was solved to 1.39 Å resolution. The FSD interacts with GDF8 and GDF11 and blocks their interaction with the type II receptor ActRIIB. Alanine substitution of surface-exposed FSD residues reduced GDF8 antagonism in full-length WFIKKN2. Structural comparison revealed the WFIKKN2 FSD uses different binding interactions than follistatin or FSTL3 FSDs to block the type II receptor.","method":"X-ray crystallography (1.39 Å); native gel shift; surface plasmon resonance; alanine-scanning mutagenesis; reporter assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with mutagenesis and functional SPR/reporter assays in a single rigorous study","pmids":["30814254"],"is_preprint":false},{"year":2023,"finding":"WFIKKN2 functions as a bifunctional axon guidance cue: it repels mouse peripheral sensory axons through the DCC-family receptor Nope, and attracts motor axons through a distinct (non-Nope) DCC family receptor. WFIKKN2 was identified as a secreted ligand for divergent DCC family members Punc, Nope, and Protogenin.","method":"Ligand-receptor binding identification; in vivo axon guidance assays in mouse; receptor-specific functional tests","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — novel mechanistic finding with functional in vivo assays, but preprint (not yet peer-reviewed) and single lab","pmids":["37398498"],"is_preprint":true}],"current_model":"WFIKKN2 is a secreted multidomain extracellular protein that acts primarily as a potent antagonist of GDF8 (myostatin) and GDF11 by using its follistatin domain to bind the mature growth factors and block type II receptor (ActRIIB) interaction, while also binding TGFβ1, BMP2, and BMP4 without inhibiting their signaling; additionally, WFIKKN2 functions as a bifunctional axon guidance cue that repels sensory axons via the DCC-family receptor Nope and attracts motor axons via a separate mechanism."},"narrative":{"mechanistic_narrative":"WFIKKN2 is a secreted multidomain extracellular protein that acts as a selective, high-potency antagonist of the TGF-β superfamily ligands GDF8 (myostatin) and GDF11 [PMID:18596030, PMID:21054789]. It binds the mature growth factors with high affinity and neutralizes their biological activity in the nanomolar range, while binding TGFβ1, BMP2, and BMP4 with weaker affinity without inhibiting their signaling — establishing its functional specificity toward GDF8/GDF11 [PMID:21054789]. Mechanistically, the follistatin domain (FSD) is the principal growth-factor-binding module and blocks engagement of the type II receptor ActRIIB; a 1.39 Å crystal structure of the murine FSD together with alanine-scanning mutagenesis showed that surface-exposed FSD residues are required for GDF8 antagonism and that the WFIKKN2 FSD achieves receptor blockade through binding interactions distinct from those of follistatin or FSTL3 [PMID:30814254]. Relative to its paralog WFIKKN1, WFIKKN2 lacks appreciable affinity for the myostatin propeptide, rendering it a less efficient suppressor of semilatent myostatin receptor binding [PMID:18596030, PMID:23829672].","teleology":[{"year":2008,"claim":"Established that WFIKKN2 engages GDF8/myostatin and GDF11 directly and mapped which domains mediate binding, defining the protein as a ligand-trapping antagonist with a domain-divided binding logic.","evidence":"SPR/affinity binding assays with domain deletion and structure-function analysis across WFIKKN2 and its paralog WFIKKN1","pmids":["18596030"],"confidence":"High","gaps":["Did not resolve the structural basis of receptor blockade","Functional consequence on downstream signaling not directly measured in this study"]},{"year":2010,"claim":"Resolved whether WFIKKN2 is a broad or selective TGF-β superfamily antagonist by separating binding from functional inhibition, showing it neutralizes GDF8/GDF11 but merely binds TGFβ1/BMP2/BMP4 without blocking their signaling.","evidence":"SPR binding assays combined with cell-based signaling reporter assays","pmids":["21054789"],"confidence":"High","gaps":["Biological significance of non-inhibitory BMP/TGFβ binding unexplained","In vivo relevance of the selectivity not tested"]},{"year":2013,"claim":"Defined the mechanistic basis for the potency difference between paralogs by showing WFIKKN2's lack of propeptide affinity makes it less efficient than WFIKKN1 at suppressing semilatent myostatin receptor binding.","evidence":"Comparative reporter assays for myostatin receptor binding between WFIKKN1 and WFIKKN2","pmids":["23829672"],"confidence":"Medium","gaps":["Single-lab functional comparison without structural confirmation of the propeptide interface","Physiological consequence of reduced potency not assessed"]},{"year":2019,"claim":"Provided atomic-resolution mechanism for antagonism by showing the follistatin domain blocks ActRIIB engagement of GDF8/GDF11 through binding interactions distinct from those of follistatin or FSTL3.","evidence":"1.39 Å X-ray crystallography of the murine FSD with native gel shift, SPR, alanine-scanning mutagenesis, and reporter assays","pmids":["30814254"],"confidence":"High","gaps":["Structure limited to the isolated FSD, not full-length WFIKKN2 in complex with ligand","Contribution of other WFIKKN2 domains to the full receptor-blocking mechanism not crystallographically resolved"]},{"year":2023,"claim":"Extended WFIKKN2's role beyond growth-factor antagonism by identifying it as a bifunctional axon guidance cue acting through DCC-family receptors.","evidence":"Ligand-receptor binding identification and in vivo mouse axon guidance assays with receptor-specific tests (preprint)","pmids":["37398498"],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed and from a single lab","The non-Nope receptor mediating motor axon attraction is not identified","Relationship between the guidance function and the GDF8/GDF11 antagonist function is unestablished"]},{"year":null,"claim":"How WFIKKN2's multiple domains and its dual roles in growth-factor antagonism and axon guidance are integrated in vivo remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No full-length structure in complex with ligand or receptor","Physiological tissue contexts of GDF8/GDF11 antagonism versus axon guidance not reconciled","Functional meaning of non-inhibitory TGFβ1/BMP2/BMP4 binding unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,3]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[1,4]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,3]}],"complexes":[],"partners":["GDF8","GDF11","ACTRIIB","TGFB1","BMP2","BMP4","NEO1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8TEU8","full_name":"WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing protein 2","aliases":["Growth and differentiation factor-associated serum protein 1","GASP-1","hGASP-1","WAP, follistatin, immunoglobulin, Kunitz and NTR domain-containing-related protein","WFIKKN-related protein"],"length_aa":576,"mass_kda":63.9,"function":"Protease-inhibitor that contains multiple distinct protease inhibitor domains. Probably has serine protease- and metalloprotease-inhibitor activity. Inhibits the biological activity of mature myostatin, but not activin (By similarity)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q8TEU8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/WFIKKN2","classification":"Not Classified","n_dependent_lines":11,"n_total_lines":1208,"dependency_fraction":0.009105960264900662},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/WFIKKN2","total_profiled":1310},"omim":[{"mim_id":"616480","title":"KIAA1328 GENE; KIAA1328","url":"https://www.omim.org/entry/616480"},{"mim_id":"610895","title":"WAP, FOLLISTATIN, IMMUNOGLOBULIN, KUNITZ, AND NTR DOMAINS-CONTAINING PROTEIN 2; WFIKKN2","url":"https://www.omim.org/entry/610895"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"choroid plexus","ntpm":1103.3}],"url":"https://www.proteinatlas.org/search/WFIKKN2"},"hgnc":{"alias_symbol":["WFIKKNRP","WFDC20B"],"prev_symbol":[]},"alphafold":{"accession":"Q8TEU8","domains":[{"cath_id":"-","chopping":"48-91","consensus_level":"high","plddt":75.5084,"start":48,"end":91},{"cath_id":"3.30.60.30","chopping":"119-177","consensus_level":"medium","plddt":85.7983,"start":119,"end":177},{"cath_id":"2.60.40.10","chopping":"209-304","consensus_level":"medium","plddt":84.9473,"start":209,"end":304},{"cath_id":"4.10.410.10","chopping":"329-381","consensus_level":"medium","plddt":84.7009,"start":329,"end":381},{"cath_id":"4.10.410.10","chopping":"390-436","consensus_level":"high","plddt":84.3853,"start":390,"end":436},{"cath_id":"2.40.50.120","chopping":"455-574","consensus_level":"high","plddt":87.6457,"start":455,"end":574}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TEU8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TEU8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TEU8-F1-predicted_aligned_error_v6.png","plddt_mean":76.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=WFIKKN2","jax_strain_url":"https://www.jax.org/strain/search?query=WFIKKN2"},"sequence":{"accession":"Q8TEU8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8TEU8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8TEU8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TEU8"}},"corpus_meta":[{"pmid":"18596030","id":"PMC_18596030","title":"Both WFIKKN1 and WFIKKN2 have high affinity for growth and differentiation factors 8 and 11.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18596030","citation_count":67,"is_preprint":false},{"pmid":"21054789","id":"PMC_21054789","title":"WFIKKN1 and WFIKKN2 bind growth factors TGFβ1, BMP2 and BMP4 but do not inhibit their signalling activity.","date":"2010","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/21054789","citation_count":41,"is_preprint":false},{"pmid":"27325460","id":"PMC_27325460","title":"WFIKKN1 and WFIKKN2: \"Companion\" proteins regulating TGFB activity.","date":"2016","source":"Cytokine & growth factor reviews","url":"https://pubmed.ncbi.nlm.nih.gov/27325460","citation_count":22,"is_preprint":false},{"pmid":"21936825","id":"PMC_21936825","title":"Biological functions of the WAP domain-containing multidomain proteins WFIKKN1 and WFIKKN2.","date":"2011","source":"Biochemical Society transactions","url":"https://pubmed.ncbi.nlm.nih.gov/21936825","citation_count":18,"is_preprint":false},{"pmid":"23829672","id":"PMC_23829672","title":"Latent myostatin has significant activity and this activity is controlled more efficiently by WFIKKN1 than by WFIKKN2.","date":"2013","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/23829672","citation_count":17,"is_preprint":false},{"pmid":"30814254","id":"PMC_30814254","title":"Crystal structure of the WFIKKN2 follistatin domain reveals insight into how it inhibits growth differentiation factor 8 (GDF8) and GDF11.","date":"2019","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30814254","citation_count":16,"is_preprint":false},{"pmid":"26197924","id":"PMC_26197924","title":"Effect of variation in ovine WFIKKN2 on growth traits appears to be gender-dependent.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/26197924","citation_count":6,"is_preprint":false},{"pmid":"24704001","id":"PMC_24704001","title":"Variation in the ovine WFIKKN2 gene.","date":"2014","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/24704001","citation_count":3,"is_preprint":false},{"pmid":"37398498","id":"PMC_37398498","title":"WFIKKN2 is a bifunctional axon guidance cue that signals through divergent DCC family receptors.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/37398498","citation_count":1,"is_preprint":false},{"pmid":"41194281","id":"PMC_41194281","title":"WFIKKN2 is secreted and elevated in blood plasma of HER2-positive breast cancer patients - implications in cancer surveillance and recurrence monitoring.","date":"2025","source":"Biomarker research","url":"https://pubmed.ncbi.nlm.nih.gov/41194281","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6724,"output_tokens":1358,"usd":0.020271,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7998,"output_tokens":2093,"usd":0.046157,"stage2_stop_reason":"end_turn"},"total_usd":0.066428,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"WFIKKN2 binds mature GDF8/myostatin, myostatin propeptide, and GDF11 with high affinity. Structure-function studies using WFIKKN1 (the paralog) revealed that the follistatin domain is primarily responsible for binding the mature growth factor, while the NTR domain contributes most significantly to interaction with myostatin propeptide.\",\n      \"method\": \"Binding assays (SPR/affinity), domain deletion/structure-function analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — SPR binding assays with domain mapping across two paralogs, replicated across multiple studies\",\n      \"pmids\": [\"18596030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"WFIKKN2 binds TGFβ1, BMP2, and BMP4 with relatively high affinity (Kd ~10⁻⁶ M) as measured by SPR, but does not inhibit their signaling activity in reporter assays even at micromolar concentrations. WFIKKN2 inhibits GDF8 and GDF11 biological activity in the nanomolar range, confirming it is a selective antagonist of GDF8/GDF11.\",\n      \"method\": \"Surface plasmon resonance (SPR) binding assays; reporter assays for signaling activity\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — two orthogonal methods (SPR binding + reporter assay) in a single study with clear quantitative results\",\n      \"pmids\": [\"21054789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"WFIKKN2 blocks myostatin receptor interaction with semilatent myostatin, but is less efficient than WFIKKN1 because WFIKKN2 lacks affinity for the propeptide domain. WFIKKN1's additional interaction with the myostatin propeptide increases its potency in suppressing semilatent myostatin receptor binding.\",\n      \"method\": \"Reporter assays for myostatin receptor binding; comparative binding studies between WFIKKN1 and WFIKKN2\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional reporter assays with mechanistic comparison, single lab but multiple assays\",\n      \"pmids\": [\"23829672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The crystal structure of the murine WFIKKN2 follistatin domain (FSD) was solved to 1.39 Å resolution. The FSD interacts with GDF8 and GDF11 and blocks their interaction with the type II receptor ActRIIB. Alanine substitution of surface-exposed FSD residues reduced GDF8 antagonism in full-length WFIKKN2. Structural comparison revealed the WFIKKN2 FSD uses different binding interactions than follistatin or FSTL3 FSDs to block the type II receptor.\",\n      \"method\": \"X-ray crystallography (1.39 Å); native gel shift; surface plasmon resonance; alanine-scanning mutagenesis; reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with mutagenesis and functional SPR/reporter assays in a single rigorous study\",\n      \"pmids\": [\"30814254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"WFIKKN2 functions as a bifunctional axon guidance cue: it repels mouse peripheral sensory axons through the DCC-family receptor Nope, and attracts motor axons through a distinct (non-Nope) DCC family receptor. WFIKKN2 was identified as a secreted ligand for divergent DCC family members Punc, Nope, and Protogenin.\",\n      \"method\": \"Ligand-receptor binding identification; in vivo axon guidance assays in mouse; receptor-specific functional tests\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — novel mechanistic finding with functional in vivo assays, but preprint (not yet peer-reviewed) and single lab\",\n      \"pmids\": [\"37398498\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"WFIKKN2 is a secreted multidomain extracellular protein that acts primarily as a potent antagonist of GDF8 (myostatin) and GDF11 by using its follistatin domain to bind the mature growth factors and block type II receptor (ActRIIB) interaction, while also binding TGFβ1, BMP2, and BMP4 without inhibiting their signaling; additionally, WFIKKN2 functions as a bifunctional axon guidance cue that repels sensory axons via the DCC-family receptor Nope and attracts motor axons via a separate mechanism.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"WFIKKN2 is a secreted multidomain extracellular protein that acts as a selective, high-potency antagonist of the TGF-β superfamily ligands GDF8 (myostatin) and GDF11 [#0, #1]. It binds the mature growth factors with high affinity and neutralizes their biological activity in the nanomolar range, while binding TGFβ1, BMP2, and BMP4 with weaker affinity without inhibiting their signaling — establishing its functional specificity toward GDF8/GDF11 [#1]. Mechanistically, the follistatin domain (FSD) is the principal growth-factor-binding module and blocks engagement of the type II receptor ActRIIB; a 1.39 Å crystal structure of the murine FSD together with alanine-scanning mutagenesis showed that surface-exposed FSD residues are required for GDF8 antagonism and that the WFIKKN2 FSD achieves receptor blockade through binding interactions distinct from those of follistatin or FSTL3 [#3]. Relative to its paralog WFIKKN1, WFIKKN2 lacks appreciable affinity for the myostatin propeptide, rendering it a less efficient suppressor of semilatent myostatin receptor binding [#0, #2].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established that WFIKKN2 engages GDF8/myostatin and GDF11 directly and mapped which domains mediate binding, defining the protein as a ligand-trapping antagonist with a domain-divided binding logic.\",\n      \"evidence\": \"SPR/affinity binding assays with domain deletion and structure-function analysis across WFIKKN2 and its paralog WFIKKN1\",\n      \"pmids\": [\"18596030\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the structural basis of receptor blockade\", \"Functional consequence on downstream signaling not directly measured in this study\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Resolved whether WFIKKN2 is a broad or selective TGF-β superfamily antagonist by separating binding from functional inhibition, showing it neutralizes GDF8/GDF11 but merely binds TGFβ1/BMP2/BMP4 without blocking their signaling.\",\n      \"evidence\": \"SPR binding assays combined with cell-based signaling reporter assays\",\n      \"pmids\": [\"21054789\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biological significance of non-inhibitory BMP/TGFβ binding unexplained\", \"In vivo relevance of the selectivity not tested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined the mechanistic basis for the potency difference between paralogs by showing WFIKKN2's lack of propeptide affinity makes it less efficient than WFIKKN1 at suppressing semilatent myostatin receptor binding.\",\n      \"evidence\": \"Comparative reporter assays for myostatin receptor binding between WFIKKN1 and WFIKKN2\",\n      \"pmids\": [\"23829672\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab functional comparison without structural confirmation of the propeptide interface\", \"Physiological consequence of reduced potency not assessed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Provided atomic-resolution mechanism for antagonism by showing the follistatin domain blocks ActRIIB engagement of GDF8/GDF11 through binding interactions distinct from those of follistatin or FSTL3.\",\n      \"evidence\": \"1.39 Å X-ray crystallography of the murine FSD with native gel shift, SPR, alanine-scanning mutagenesis, and reporter assays\",\n      \"pmids\": [\"30814254\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure limited to the isolated FSD, not full-length WFIKKN2 in complex with ligand\", \"Contribution of other WFIKKN2 domains to the full receptor-blocking mechanism not crystallographically resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended WFIKKN2's role beyond growth-factor antagonism by identifying it as a bifunctional axon guidance cue acting through DCC-family receptors.\",\n      \"evidence\": \"Ligand-receptor binding identification and in vivo mouse axon guidance assays with receptor-specific tests (preprint)\",\n      \"pmids\": [\"37398498\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not yet peer-reviewed and from a single lab\", \"The non-Nope receptor mediating motor axon attraction is not identified\", \"Relationship between the guidance function and the GDF8/GDF11 antagonist function is unestablished\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How WFIKKN2's multiple domains and its dual roles in growth-factor antagonism and axon guidance are integrated in vivo remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No full-length structure in complex with ligand or receptor\", \"Physiological tissue contexts of GDF8/GDF11 antagonism versus axon guidance not reconciled\", \"Functional meaning of non-inhibitory TGFβ1/BMP2/BMP4 binding unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [1, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"GDF8\", \"GDF11\", \"ActRIIB\", \"TGFB1\", \"BMP2\", \"BMP4\", \"NEO1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}