{"gene":"DAAM2","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":2003,"finding":"DAAM2 was identified as a formin-family protein containing FH1 and FH2 domains, with 68.9% amino acid identity to DAAM1, and classified as a member of the FDD (Formin-like, Diaphanous, Daam) subfamily along with FMNL1, FMNL2, DIAPH1, DIAPH2, and DAAM1.","method":"Bioinformatics/in silico sequence analysis and domain architecture characterization","journal":"International journal of oncology","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational prediction only, no experimental validation of function","pmids":["12632087"],"is_preprint":false},{"year":2012,"finding":"Daam2 functions in canonical Wnt signal transduction during spinal cord development: loss-of-function disrupts dorsal progenitor identities and Wnt signaling (rescued by β-catenin); Daam2 association with Dvl3 is required for Wnt activity; Daam2 stabilizes Dvl3/Axin2 binding and enhances intracellular assembly of Dvl3/Axin2 complexes; gain-of-function amplifies Wnt signaling by potentiating ligand activation.","method":"Loss-of-function and gain-of-function studies in chick spinal cord, β-catenin rescue experiments, biochemical co-immunoprecipitation of Daam2/Dvl3/Axin2 complexes","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal biochemical assays, genetic rescue, gain- and loss-of-function with defined pathway readout in a single rigorous study","pmids":["22227309"],"is_preprint":false},{"year":2013,"finding":"In the chicken dorsal mesentery, Pitx2 transcriptionally activates Daam2 as a downstream effector, and Daam2 links actin dynamics to cadherin-based junctions to generate asymmetric cell behaviors required for leftward gut tilt; Daam2 mediates Wnt signaling downstream of Pitx2.","method":"Laser microdissection, targeted gene misexpression in chicken dorsal mesentery, gene expression analysis","journal":"Developmental cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — targeted misexpression with defined morphogenetic readout, single lab","pmids":["24091014"],"is_preprint":false},{"year":2015,"finding":"Daam2 promotes Wnt signaling and receptor complex formation through a PIP5K-PIP2 axis in oligodendrocytes; Daam2 suppresses oligodendrocyte differentiation during development and after white matter injury; pharmacological inhibition of Daam2-PIP5K stimulates remyelination after white matter injury.","method":"Dorsal patterning assay in chick spinal cord, multifaceted discovery platform, functional studies in oligodendrocytes, pharmacological inhibition","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple systems (chick spinal cord, OL cultures, WMI models), pathway biochemistry, pharmacological intervention with defined functional readouts","pmids":["25754822"],"is_preprint":false},{"year":2015,"finding":"DAAM1 and DAAM2 have redundant functions in myocardial sarcomere assembly and cardiomyocyte polarity; double knockout (DKO) mice show severely disrupted sarcomere structure and reduced AKT activity; DAAM1 acts in a common pathway with Wnt5a (genetic interaction), but also has Wnt5a-independent cardiac roles; DAAM1/2 nucleate actin and mediate Wnt-induced cytoskeletal changes.","method":"Conditional knockout mice (Daam1 CKO), Daam1/2 double knockout (DKO), Daam1-floxed × Wnt5a null genetic crosses, cardiac phenotype assessment","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with multiple KO combinations, specific cardiac/sarcomere phenotypic readout, replicated across allele combinations","pmids":["26526197"],"is_preprint":false},{"year":2017,"finding":"Daam2 promotes glioma formation by associating with VHL and facilitating its ubiquitination and degradation, thereby suppressing VHL tumor suppressor function in tumors lacking VHL mutations.","method":"Protein expression screening (in silico), functional tumorigenesis assays, biochemical co-immunoprecipitation and ubiquitination assays","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical ubiquitination assay plus functional tumorigenesis studies, single lab","pmids":["29053101"],"is_preprint":false},{"year":2020,"finding":"The E3 ligase VHL interacts with Daam2 and their mutual antagonism regulates oligodendrocyte differentiation; the E3 ubiquitin ligase Nedd4 stabilizes VHL via K63-linked ubiquitination, and this Daam2-VHL-Nedd4 axis governs developmental myelination and remyelination after white matter injury.","method":"Proteomic analysis of Daam2-VHL complex, conditional genetic knockout mouse models (developmental myelination), mouse demyelination models, analysis of MS white matter lesions","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — proteomic complex identification, conditional KO models, mechanistic ubiquitin linkage typing, validated in disease tissue","pmids":["32792353"],"is_preprint":false},{"year":2020,"finding":"Daam1 and Daam2 are functionally redundant in placental development; Daam1 is required for fetal survival through labyrinthine layer function; Daam1 acts in the Wnt/PCP pathway in mammals (evidenced by Daam1;Wnt5a genetic interaction producing neural tube closure defects).","method":"Gene targeting/knockout mouse models, Daam1/Daam2/Wnt5a compound mutant analysis, embryonic phenotype assessment","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via compound mutants, defined placental and neural tube phenotypes, single lab","pmids":["32353019"],"is_preprint":false},{"year":2021,"finding":"Daam2 regulates canonical Wnt signaling through the PIP2-PIP5K axis via its association with Rac1; clustering of Daam2-mediated Wnt receptor complexes requires both Rac1 and PIP5K; PIP5K promotes membrane localization of these complexes in a Rac1-dependent manner; Daam2-mediated canonical Wnt signaling depends on actin polymerization.","method":"Gain- and loss-of-function studies in chick spinal cord and human/monkey cell lines, membrane localization assays, signalosome clustering assays","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (localization, clustering, signaling assays) across multiple systems (chick, human, monkey cell lines)","pmids":["33310913"],"is_preprint":false},{"year":2021,"finding":"Loss of Daam2 in astrocytes increases morphological complexity in cortex and olfactory bulb; Slc4a4 is a binding partner of Daam2 in the cortex (identified by proteomic profiling and immunoprecipitation); combined deletion of Daam2 and Slc4a4 restores morphological alterations seen in Daam2 mutants; Daam2 controls astrocyte morphology differentially across brain regions.","method":"Astrocyte-specific conditional knockout mice, proteomic profiling, co-immunoprecipitation, calcium imaging, electrophysiology","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and genetic rescue in astrocyte-specific KO, single lab with multiple methods","pmids":["34633730"],"is_preprint":false},{"year":2022,"finding":"Daam2 regulates myelin structure and oligodendrocyte (OL) cytoskeleton through Rac1 and Gelsolin; Rac1 and Gelsolin operate downstream of Daam2 in OL differentiation; Daam2 suppresses Gelsolin levels posttranslationally by inducing its ubiquitination and degradation (via Nedd4 E3 ligase recruitment); Daam2 cKO mice show myelin decompaction and motor coordination deficits.","method":"OL-specific Daam2 cKO mice, primary OL cultures (gain- and loss-of-function), in vitro ubiquitination assay, in vivo protein level analysis","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro ubiquitination assay, genetic epistasis in primary cultures and in vivo, multiple orthogonal methods","pmids":["35101966"],"is_preprint":false},{"year":2023,"finding":"CK2α phosphorylates Daam2, inhibiting its function and Wnt activity during oligodendrocyte development; Daam2 phosphorylation differentially impacts distinct stages of OL development (accelerating early differentiation, decelerating maturation/myelination); CK2α-mediated Daam2 phosphorylation is protective after neonatal hypoxia and promotes myelin repair after adult demyelination.","method":"Kinase phosphorylation assays (CK2α on Daam2), OL developmental stage analysis, neonatal hypoxia and adult demyelination mouse models","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — kinase-substrate relationship established biochemically, validated in multiple in vivo models (developmental, hypoxia, demyelination)","pmids":["37607236"],"is_preprint":false},{"year":2024,"finding":"Daam2 binds to Dvl2 via specific domains; this interaction is Wnt-regulated; Daam2 is cytoplasmic and regulates actin filament formation; knockdown of Daam2 in Xenopus produces neural tube closure defects indicative of non-canonical Wnt pathway involvement; Daam2 did not detectably regulate canonical Wnt signaling in mammalian culture cells or Xenopus embryo.","method":"Co-immunoprecipitation (Daam2-Dvl2 interaction and domain mapping), subcellular localization studies, Xenopus morpholino knockdown, actin cytoskeleton imaging","journal":"Developmental dynamics","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — co-IP with domain mapping, Xenopus knockdown phenotype, localization imaging; single lab","pmids":["38877839"],"is_preprint":false},{"year":2025,"finding":"SIRT1 upregulates DAAM2 through acetylation of EZH2 in osteoblasts; DAAM2 serves as a downstream effector for SIRT1 to promote secretion of chemokines (CCL3, CCL5, CXCL10) that recruit CD4+ CTLs to eliminate senescent osteoblasts; targeting DAAM2 increases CD4+ CTL responses and can treat osteoporosis.","method":"Spatial analysis of bone microenvironment, osteoblast-CTL co-culture experiments, SIRT1/EZH2/DAAM2 mechanistic studies, in vivo osteoporosis models","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway dissection with in vivo validation, single lab, published 2025","pmids":["40714829"],"is_preprint":false}],"current_model":"DAAM2 is a formin-family scaffolding protein that functions as a key regulator of both canonical and non-canonical Wnt signaling: it associates with Dvl/Axin complexes to promote canonical Wnt receptor signalosome formation (via a PIP5K-PIP2-Rac1 axis), nucleates actin and modulates the cytoskeleton in multiple cell types (oligodendrocytes, astrocytes, cardiomyocytes), promotes VHL ubiquitination and degradation in glioma, regulates oligodendrocyte differentiation and myelin compaction through Gelsolin ubiquitination (via Nedd4) and is itself negatively regulated by CK2α-mediated phosphorylation; additionally, DAAM2 acts downstream of SIRT1/EZH2 in osteoblasts to modulate immune-bone homeostasis."},"narrative":{"mechanistic_narrative":"DAAM2 is a formin-family scaffolding protein that couples Wnt signaling to actin cytoskeletal remodeling across developmental and disease contexts [PMID:22227309, PMID:25754822]. In canonical Wnt transduction, DAAM2 associates with Dishevelled (Dvl3/Dvl2) and stabilizes Dvl/Axin complexes to potentiate ligand-driven receptor signalosome assembly [PMID:22227309, PMID:38877839], a clustering step that requires actin polymerization and proceeds through a PIP5K–PIP2–Rac1 axis that drives membrane localization of Wnt receptor complexes [PMID:25754822, PMID:33310913]. Beyond signal scaffolding, DAAM2 nucleates actin and shapes the cytoskeleton in multiple cell types, controlling myocardial sarcomere assembly redundantly with DAAM1 [PMID:26526197], astrocyte morphology via its partner Slc4a4 [PMID:34633730], and oligodendrocyte myelin compaction [PMID:35101966]. In oligodendrocytes DAAM2 suppresses differentiation while regulating the cytoskeleton through Rac1 and Gelsolin, promoting Gelsolin ubiquitination and degradation through recruitment of the E3 ligase Nedd4 [PMID:35101966]; this activity is held in check by CK2α-mediated phosphorylation, which differentially tunes early versus late stages of myelination and promotes repair after injury [PMID:37607236]. DAAM2 also operates as a regulator of protein stability in disease, binding VHL and facilitating its ubiquitination and degradation to drive glioma formation, with a reciprocal Nedd4-stabilized VHL axis governing myelination [PMID:29053101, PMID:32792353]. In osteoblasts, DAAM2 acts downstream of a SIRT1–EZH2 module to promote chemokine secretion that recruits CD4+ cytotoxic T lymphocytes to clear senescent cells [PMID:40714829].","teleology":[{"year":2003,"claim":"Established DAAM2 as a distinct formin-family member, defining the domain architecture (FH1/FH2) that would later rationalize its actin-nucleating activity.","evidence":"in silico sequence and domain analysis placing DAAM2 in the FDD subfamily","pmids":["12632087"],"confidence":"Low","gaps":["computational only, no functional or biochemical validation","no cellular role assigned"]},{"year":2012,"claim":"Answered whether DAAM2 has a defined signaling function by showing it scaffolds canonical Wnt transduction through Dvl3/Axin2 complex stabilization during spinal cord patterning.","evidence":"loss/gain-of-function in chick spinal cord, β-catenin rescue, and co-IP of Daam2/Dvl3/Axin2","pmids":["22227309"],"confidence":"High","gaps":["molecular basis of complex stabilization not resolved","role of FH2/actin activity in scaffolding untested here"]},{"year":2013,"claim":"Placed DAAM2 in a transcriptional and morphogenetic circuit, showing it is a Pitx2 target that links actin to cadherin junctions to drive left-right asymmetric gut morphogenesis.","evidence":"laser microdissection and targeted misexpression in chicken dorsal mesentery","pmids":["24091014"],"confidence":"Medium","gaps":["direct cytoskeletal mechanism at junctions not biochemically dissected","single-lab morphogenetic readout"]},{"year":2015,"claim":"Defined the membrane biochemistry of DAAM2-driven Wnt signaling and revealed its role suppressing oligodendrocyte differentiation, establishing a druggable Daam2-PIP5K node for remyelination.","evidence":"chick spinal cord patterning, oligodendrocyte cultures, white matter injury models, pharmacological PIP5K inhibition","pmids":["25754822"],"confidence":"High","gaps":["how DAAM2 engages PIP5K mechanistically not fully resolved","in vivo selectivity of pharmacological inhibition unclear"]},{"year":2015,"claim":"Demonstrated DAAM2 redundancy with DAAM1 in actin-based morphogenesis, showing the pair nucleates actin and mediates Wnt-induced cytoskeletal changes required for sarcomere assembly.","evidence":"Daam1 CKO, Daam1/2 DKO, and Daam1×Wnt5a genetic crosses with cardiac phenotyping","pmids":["26526197"],"confidence":"High","gaps":["DAAM2-specific (non-redundant) cardiac contribution not isolated","link between AKT activity reduction and actin defect mechanistic gap"]},{"year":2017,"claim":"Expanded DAAM2 function to protein-stability control in cancer by showing it associates with VHL and promotes its ubiquitination and degradation to drive glioma.","evidence":"tumorigenesis assays plus co-IP and ubiquitination assays","pmids":["29053101"],"confidence":"Medium","gaps":["whether DAAM2 acts as an adaptor or recruits a specific E3 not established here","single-lab biochemistry"]},{"year":2020,"claim":"Resolved the DAAM2-VHL axis in myelination, showing mutual antagonism with VHL and that Nedd4 stabilizes VHL via K63 ubiquitination to govern developmental and repair myelination.","evidence":"proteomics of Daam2-VHL complex, conditional KO mice, demyelination models, MS lesion analysis","pmids":["32792353"],"confidence":"High","gaps":["directionality between DAAM2-driven VHL degradation and Nedd4-driven VHL stabilization in same cells unresolved"]},{"year":2020,"claim":"Confirmed DAAM1/DAAM2 redundancy in mammalian development and Wnt/PCP function via placental and neural tube phenotypes.","evidence":"knockout and compound Daam1/Daam2/Wnt5a mutant mice","pmids":["32353019"],"confidence":"Medium","gaps":["DAAM2-specific placental requirement not defined","molecular PCP mechanism not dissected"]},{"year":2021,"claim":"Detailed the Rac1 dependence of DAAM2 Wnt signalosome clustering, integrating Rac1, PIP5K, PIP2, and actin polymerization into one membrane-clustering mechanism.","evidence":"gain/loss-of-function and localization/clustering assays in chick, human, and monkey cell lines","pmids":["33310913"],"confidence":"High","gaps":["physical hierarchy of Rac1/PIP5K/DAAM2 binding not fully ordered","structural basis of signalosome clustering unknown"]},{"year":2021,"claim":"Identified Slc4a4 as a DAAM2 partner controlling astrocyte morphology, extending DAAM2 cytoskeletal regulation to glia in a region-specific manner.","evidence":"astrocyte-specific cKO, proteomics, co-IP, genetic rescue, calcium imaging, electrophysiology","pmids":["34633730"],"confidence":"Medium","gaps":["mechanism linking DAAM2-Slc4a4 to actin and morphology not resolved","single-lab co-IP"]},{"year":2022,"claim":"Established the effector arm of DAAM2 in oligodendrocytes, showing it drives Gelsolin ubiquitination/degradation via Nedd4 and acts through Rac1 to control myelin compaction.","evidence":"OL-specific cKO, primary OL gain/loss-of-function, in vitro ubiquitination, in vivo protein analysis","pmids":["35101966"],"confidence":"High","gaps":["how DAAM2 recruits Nedd4 to Gelsolin not structurally defined","relationship between scaffolding and ubiquitination activities unclear"]},{"year":2023,"claim":"Identified an upstream regulatory switch by showing CK2α phosphorylates DAAM2 to inhibit it, with stage-specific effects on myelination and protective effects after injury.","evidence":"CK2α kinase assays on DAAM2, OL stage analysis, neonatal hypoxia and adult demyelination models","pmids":["37607236"],"confidence":"High","gaps":["phosphosite-level consequences on actin/Wnt activity not mapped","kinase regulation in non-OL tissues untested"]},{"year":2024,"claim":"Tested the canonical-versus-noncanonical question directly, mapping a Wnt-regulated Daam2-Dvl2 interaction and linking DAAM2 to non-canonical PCP-type neural tube closure via actin.","evidence":"co-IP domain mapping, localization, Xenopus morpholino knockdown, actin imaging","pmids":["38877839"],"confidence":"Medium","gaps":["failure to detect canonical Wnt regulation conflicts with earlier systems and is context/method dependent","domain mapping not validated by structure"]},{"year":2025,"claim":"Extended DAAM2 into immune-bone homeostasis as a SIRT1/EZH2 downstream effector driving chemokine-mediated recruitment of CD4+ CTLs to clear senescent osteoblasts.","evidence":"spatial bone microenvironment analysis, osteoblast-CTL co-culture, SIRT1/EZH2/DAAM2 dissection, osteoporosis models","pmids":["40714829"],"confidence":"Medium","gaps":["molecular mechanism linking DAAM2 to chemokine secretion not defined","whether actin/Wnt activity underlies this role unknown"]},{"year":null,"claim":"It remains unresolved how DAAM2 partitions between its canonical Wnt scaffolding, non-canonical PCP/actin, and E3-ligase-adaptor (VHL, Gelsolin) functions, and what determines context-specific selection among them.","evidence":"","pmids":[],"confidence":"Medium","gaps":["no unified structural model integrating FH2 actin activity with Dvl/Axin scaffolding","rules governing tissue-specific partner choice unknown","direct versus indirect contribution to ubiquitination unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[3,4,8,10,12]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,8,12]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[5,6,10]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[12]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[8]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,3,8]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,2,4,7]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[5,6,10]}],"complexes":[],"partners":["DVL3","DVL2","AXIN2","VHL","NEDD4","RAC1","SLC4A4","DAAM1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q86T65","full_name":"Disheveled-associated activator of morphogenesis 2","aliases":[],"length_aa":1068,"mass_kda":123.5,"function":"Key regulator of the Wnt signaling pathway, which is required for various processes during development, such as dorsal patterning, determination of left/right symmetry or myelination in the central nervous system. Acts downstream of Wnt ligands and upstream of beta-catenin (CTNNB1). Required for canonical Wnt signaling pathway during patterning in the dorsal spinal cord by promoting the aggregation of Disheveled (Dvl) complexes, thereby clustering and formation of Wnt receptor signalosomes and potentiating Wnt activity. During dorsal patterning of the spinal cord, inhibits oligodendrocytes differentiation via interaction with PIP5K1A. Also regulates non-canonical Wnt signaling pathway. Acts downstream of PITX2 in the developing gut and is required for left/right asymmetry within dorsal mesentery: affects mesenchymal condensation by lengthening cadherin-based junctions through WNT5A and non-canonical Wnt signaling, inducing polarized condensation in the left dorsal mesentery necessary to initiate gut rotation. Together with DAAM1, required for myocardial maturation and sarcomere assembly. Is a regulator of actin nucleation and elongation, filopodia formation and podocyte migration (PubMed:33232676)","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q86T65/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DAAM2","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/DAAM2","total_profiled":1310},"omim":[{"mim_id":"619263","title":"NEPHROTIC SYNDROME, TYPE 24; NPHS24","url":"https://www.omim.org/entry/619263"},{"mim_id":"616288","title":"FORMIN-LIKE 3; FMNL3","url":"https://www.omim.org/entry/616288"},{"mim_id":"608537","title":"VON HIPPEL-LINDAU TUMOR SUPPRESSOR; VHL","url":"https://www.omim.org/entry/608537"},{"mim_id":"606627","title":"DISHEVELLED-ASSOCIATED ACTIVATOR OF MORPHOGENESIS 2; DAAM2","url":"https://www.omim.org/entry/606627"},{"mim_id":"606626","title":"DISHEVELLED-ASSOCIATED ACTIVATOR OF MORPHOGENESIS 1; DAAM1","url":"https://www.omim.org/entry/606626"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Vesicles","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":145.9}],"url":"https://www.proteinatlas.org/search/DAAM2"},"hgnc":{"alias_symbol":["KIAA0381","NPHS24"],"prev_symbol":[]},"alphafold":{"accession":"Q86T65","domains":[{"cath_id":"-","chopping":"395-427","consensus_level":"medium","plddt":82.4442,"start":395,"end":427},{"cath_id":"1.20.58.630","chopping":"668-753","consensus_level":"high","plddt":91.2199,"start":668,"end":753},{"cath_id":"1.20.58.2220","chopping":"772-958","consensus_level":"medium","plddt":93.039,"start":772,"end":958},{"cath_id":"1.10.20","chopping":"46-90","consensus_level":"medium","plddt":79.3602,"start":46,"end":90},{"cath_id":"1.20.5","chopping":"428-502","consensus_level":"medium","plddt":82.0872,"start":428,"end":502}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86T65","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q86T65-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q86T65-F1-predicted_aligned_error_v6.png","plddt_mean":79.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DAAM2","jax_strain_url":"https://www.jax.org/strain/search?query=DAAM2"},"sequence":{"accession":"Q86T65","fasta_url":"https://rest.uniprot.org/uniprotkb/Q86T65.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q86T65/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86T65"}},"corpus_meta":[{"pmid":"12632087","id":"PMC_12632087","title":"Identification and characterization of human DAAM2 gene in silico.","date":"2003","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/12632087","citation_count":103,"is_preprint":false},{"pmid":"24091014","id":"PMC_24091014","title":"Integration of left-right Pitx2 transcription and Wnt signaling drives asymmetric gut morphogenesis via Daam2.","date":"2013","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/24091014","citation_count":68,"is_preprint":false},{"pmid":"25754822","id":"PMC_25754822","title":"Daam2-PIP5K is a regulatory pathway for Wnt signaling and therapeutic target for remyelination in the CNS.","date":"2015","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/25754822","citation_count":67,"is_preprint":false},{"pmid":"22227309","id":"PMC_22227309","title":"Daam2 is required for dorsal patterning via modulation of canonical Wnt signaling in the developing spinal cord.","date":"2012","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/22227309","citation_count":52,"is_preprint":false},{"pmid":"26526197","id":"PMC_26526197","title":"DAAM1 and DAAM2 are co-required for myocardial maturation and sarcomere assembly.","date":"2015","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/26526197","citation_count":46,"is_preprint":false},{"pmid":"32792353","id":"PMC_32792353","title":"The Daam2-VHL-Nedd4 axis governs developmental and regenerative oligodendrocyte differentiation.","date":"2020","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/32792353","citation_count":29,"is_preprint":false},{"pmid":"15464228","id":"PMC_15464228","title":"Identification of chick and mouse Daam1 and Daam2 genes and their expression patterns in the central nervous system.","date":"2004","source":"Brain research. 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Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/38877839","citation_count":4,"is_preprint":false},{"pmid":"21909696","id":"PMC_21909696","title":"DAAM2 polymorphism is closely related to the clinical outcomes of allogeneic hematopoietic stem cell transplantation.","date":"2011","source":"Annals of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/21909696","citation_count":4,"is_preprint":false},{"pmid":"31475197","id":"PMC_31475197","title":"Whole exome sequencing identifies a rare variant in DAAM2 as a potential candidate in idiopathic pulmonary ossification.","date":"2019","source":"Annals of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31475197","citation_count":4,"is_preprint":false},{"pmid":"40714829","id":"PMC_40714829","title":"Osteoblast-CD4+ CTL Crosstalk Mediated by SIRT1/DAAM2 Axis Prevents Age-Related Bone Loss.","date":"2025","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/40714829","citation_count":2,"is_preprint":false},{"pmid":"35281277","id":"PMC_35281277","title":"Dishevelled-Associated Activator of Morphogenesis 2 (DAAM2) Predicts the Immuno-Hot Phenotype in Pancreatic Adenocarcinoma.","date":"2022","source":"Frontiers in molecular biosciences","url":"https://pubmed.ncbi.nlm.nih.gov/35281277","citation_count":2,"is_preprint":false},{"pmid":"40883023","id":"PMC_40883023","title":"PPIL1 Drives Hepatocellular Carcinoma Progression and Cancer Stem Cell Self-renewal Through DAAM2-mediated Wnt/β-Catenin Activation.","date":"2025","source":"Cancer genomics & proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/40883023","citation_count":1,"is_preprint":false},{"pmid":"35933758","id":"PMC_35933758","title":"Placental DAAM2 is unaltered in preeclampsia, but upregulated by treatment with proton pump inhibitors.","date":"2022","source":"Pregnancy hypertension","url":"https://pubmed.ncbi.nlm.nih.gov/35933758","citation_count":1,"is_preprint":false},{"pmid":"38860410","id":"PMC_38860410","title":"Short stature and dysmorphic features in Asian Indian siblings with DAAM2-associated steroid-resistant nephrotic syndrome: Expansion of the phenotypic spectrum or a blended phenotype?","date":"2024","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/38860410","citation_count":1,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.05.18.25327658","title":"Minimalistic Transcriptomic Signatures Permit Accurate Early Prediction of COVID-19 Mortality","date":"2025-05-19","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.18.25327658","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13999,"output_tokens":3660,"usd":0.048448,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11282,"output_tokens":4367,"usd":0.082793,"stage2_stop_reason":"end_turn"},"total_usd":0.131241,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"DAAM2 was identified as a formin-family protein containing FH1 and FH2 domains, with 68.9% amino acid identity to DAAM1, and classified as a member of the FDD (Formin-like, Diaphanous, Daam) subfamily along with FMNL1, FMNL2, DIAPH1, DIAPH2, and DAAM1.\",\n      \"method\": \"Bioinformatics/in silico sequence analysis and domain architecture characterization\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational prediction only, no experimental validation of function\",\n      \"pmids\": [\"12632087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Daam2 functions in canonical Wnt signal transduction during spinal cord development: loss-of-function disrupts dorsal progenitor identities and Wnt signaling (rescued by β-catenin); Daam2 association with Dvl3 is required for Wnt activity; Daam2 stabilizes Dvl3/Axin2 binding and enhances intracellular assembly of Dvl3/Axin2 complexes; gain-of-function amplifies Wnt signaling by potentiating ligand activation.\",\n      \"method\": \"Loss-of-function and gain-of-function studies in chick spinal cord, β-catenin rescue experiments, biochemical co-immunoprecipitation of Daam2/Dvl3/Axin2 complexes\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal biochemical assays, genetic rescue, gain- and loss-of-function with defined pathway readout in a single rigorous study\",\n      \"pmids\": [\"22227309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In the chicken dorsal mesentery, Pitx2 transcriptionally activates Daam2 as a downstream effector, and Daam2 links actin dynamics to cadherin-based junctions to generate asymmetric cell behaviors required for leftward gut tilt; Daam2 mediates Wnt signaling downstream of Pitx2.\",\n      \"method\": \"Laser microdissection, targeted gene misexpression in chicken dorsal mesentery, gene expression analysis\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — targeted misexpression with defined morphogenetic readout, single lab\",\n      \"pmids\": [\"24091014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Daam2 promotes Wnt signaling and receptor complex formation through a PIP5K-PIP2 axis in oligodendrocytes; Daam2 suppresses oligodendrocyte differentiation during development and after white matter injury; pharmacological inhibition of Daam2-PIP5K stimulates remyelination after white matter injury.\",\n      \"method\": \"Dorsal patterning assay in chick spinal cord, multifaceted discovery platform, functional studies in oligodendrocytes, pharmacological inhibition\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple systems (chick spinal cord, OL cultures, WMI models), pathway biochemistry, pharmacological intervention with defined functional readouts\",\n      \"pmids\": [\"25754822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"DAAM1 and DAAM2 have redundant functions in myocardial sarcomere assembly and cardiomyocyte polarity; double knockout (DKO) mice show severely disrupted sarcomere structure and reduced AKT activity; DAAM1 acts in a common pathway with Wnt5a (genetic interaction), but also has Wnt5a-independent cardiac roles; DAAM1/2 nucleate actin and mediate Wnt-induced cytoskeletal changes.\",\n      \"method\": \"Conditional knockout mice (Daam1 CKO), Daam1/2 double knockout (DKO), Daam1-floxed × Wnt5a null genetic crosses, cardiac phenotype assessment\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with multiple KO combinations, specific cardiac/sarcomere phenotypic readout, replicated across allele combinations\",\n      \"pmids\": [\"26526197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Daam2 promotes glioma formation by associating with VHL and facilitating its ubiquitination and degradation, thereby suppressing VHL tumor suppressor function in tumors lacking VHL mutations.\",\n      \"method\": \"Protein expression screening (in silico), functional tumorigenesis assays, biochemical co-immunoprecipitation and ubiquitination assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical ubiquitination assay plus functional tumorigenesis studies, single lab\",\n      \"pmids\": [\"29053101\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The E3 ligase VHL interacts with Daam2 and their mutual antagonism regulates oligodendrocyte differentiation; the E3 ubiquitin ligase Nedd4 stabilizes VHL via K63-linked ubiquitination, and this Daam2-VHL-Nedd4 axis governs developmental myelination and remyelination after white matter injury.\",\n      \"method\": \"Proteomic analysis of Daam2-VHL complex, conditional genetic knockout mouse models (developmental myelination), mouse demyelination models, analysis of MS white matter lesions\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — proteomic complex identification, conditional KO models, mechanistic ubiquitin linkage typing, validated in disease tissue\",\n      \"pmids\": [\"32792353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Daam1 and Daam2 are functionally redundant in placental development; Daam1 is required for fetal survival through labyrinthine layer function; Daam1 acts in the Wnt/PCP pathway in mammals (evidenced by Daam1;Wnt5a genetic interaction producing neural tube closure defects).\",\n      \"method\": \"Gene targeting/knockout mouse models, Daam1/Daam2/Wnt5a compound mutant analysis, embryonic phenotype assessment\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via compound mutants, defined placental and neural tube phenotypes, single lab\",\n      \"pmids\": [\"32353019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Daam2 regulates canonical Wnt signaling through the PIP2-PIP5K axis via its association with Rac1; clustering of Daam2-mediated Wnt receptor complexes requires both Rac1 and PIP5K; PIP5K promotes membrane localization of these complexes in a Rac1-dependent manner; Daam2-mediated canonical Wnt signaling depends on actin polymerization.\",\n      \"method\": \"Gain- and loss-of-function studies in chick spinal cord and human/monkey cell lines, membrane localization assays, signalosome clustering assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (localization, clustering, signaling assays) across multiple systems (chick, human, monkey cell lines)\",\n      \"pmids\": [\"33310913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Loss of Daam2 in astrocytes increases morphological complexity in cortex and olfactory bulb; Slc4a4 is a binding partner of Daam2 in the cortex (identified by proteomic profiling and immunoprecipitation); combined deletion of Daam2 and Slc4a4 restores morphological alterations seen in Daam2 mutants; Daam2 controls astrocyte morphology differentially across brain regions.\",\n      \"method\": \"Astrocyte-specific conditional knockout mice, proteomic profiling, co-immunoprecipitation, calcium imaging, electrophysiology\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and genetic rescue in astrocyte-specific KO, single lab with multiple methods\",\n      \"pmids\": [\"34633730\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Daam2 regulates myelin structure and oligodendrocyte (OL) cytoskeleton through Rac1 and Gelsolin; Rac1 and Gelsolin operate downstream of Daam2 in OL differentiation; Daam2 suppresses Gelsolin levels posttranslationally by inducing its ubiquitination and degradation (via Nedd4 E3 ligase recruitment); Daam2 cKO mice show myelin decompaction and motor coordination deficits.\",\n      \"method\": \"OL-specific Daam2 cKO mice, primary OL cultures (gain- and loss-of-function), in vitro ubiquitination assay, in vivo protein level analysis\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro ubiquitination assay, genetic epistasis in primary cultures and in vivo, multiple orthogonal methods\",\n      \"pmids\": [\"35101966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CK2α phosphorylates Daam2, inhibiting its function and Wnt activity during oligodendrocyte development; Daam2 phosphorylation differentially impacts distinct stages of OL development (accelerating early differentiation, decelerating maturation/myelination); CK2α-mediated Daam2 phosphorylation is protective after neonatal hypoxia and promotes myelin repair after adult demyelination.\",\n      \"method\": \"Kinase phosphorylation assays (CK2α on Daam2), OL developmental stage analysis, neonatal hypoxia and adult demyelination mouse models\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — kinase-substrate relationship established biochemically, validated in multiple in vivo models (developmental, hypoxia, demyelination)\",\n      \"pmids\": [\"37607236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Daam2 binds to Dvl2 via specific domains; this interaction is Wnt-regulated; Daam2 is cytoplasmic and regulates actin filament formation; knockdown of Daam2 in Xenopus produces neural tube closure defects indicative of non-canonical Wnt pathway involvement; Daam2 did not detectably regulate canonical Wnt signaling in mammalian culture cells or Xenopus embryo.\",\n      \"method\": \"Co-immunoprecipitation (Daam2-Dvl2 interaction and domain mapping), subcellular localization studies, Xenopus morpholino knockdown, actin cytoskeleton imaging\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — co-IP with domain mapping, Xenopus knockdown phenotype, localization imaging; single lab\",\n      \"pmids\": [\"38877839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SIRT1 upregulates DAAM2 through acetylation of EZH2 in osteoblasts; DAAM2 serves as a downstream effector for SIRT1 to promote secretion of chemokines (CCL3, CCL5, CXCL10) that recruit CD4+ CTLs to eliminate senescent osteoblasts; targeting DAAM2 increases CD4+ CTL responses and can treat osteoporosis.\",\n      \"method\": \"Spatial analysis of bone microenvironment, osteoblast-CTL co-culture experiments, SIRT1/EZH2/DAAM2 mechanistic studies, in vivo osteoporosis models\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway dissection with in vivo validation, single lab, published 2025\",\n      \"pmids\": [\"40714829\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DAAM2 is a formin-family scaffolding protein that functions as a key regulator of both canonical and non-canonical Wnt signaling: it associates with Dvl/Axin complexes to promote canonical Wnt receptor signalosome formation (via a PIP5K-PIP2-Rac1 axis), nucleates actin and modulates the cytoskeleton in multiple cell types (oligodendrocytes, astrocytes, cardiomyocytes), promotes VHL ubiquitination and degradation in glioma, regulates oligodendrocyte differentiation and myelin compaction through Gelsolin ubiquitination (via Nedd4) and is itself negatively regulated by CK2α-mediated phosphorylation; additionally, DAAM2 acts downstream of SIRT1/EZH2 in osteoblasts to modulate immune-bone homeostasis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"DAAM2 is a formin-family scaffolding protein that couples Wnt signaling to actin cytoskeletal remodeling across developmental and disease contexts [#1, #3]. In canonical Wnt transduction, DAAM2 associates with Dishevelled (Dvl3/Dvl2) and stabilizes Dvl/Axin complexes to potentiate ligand-driven receptor signalosome assembly [#1, #12], a clustering step that requires actin polymerization and proceeds through a PIP5K–PIP2–Rac1 axis that drives membrane localization of Wnt receptor complexes [#3, #8]. Beyond signal scaffolding, DAAM2 nucleates actin and shapes the cytoskeleton in multiple cell types, controlling myocardial sarcomere assembly redundantly with DAAM1 [#4], astrocyte morphology via its partner Slc4a4 [#9], and oligodendrocyte myelin compaction [#10]. In oligodendrocytes DAAM2 suppresses differentiation while regulating the cytoskeleton through Rac1 and Gelsolin, promoting Gelsolin ubiquitination and degradation through recruitment of the E3 ligase Nedd4 [#10]; this activity is held in check by CK2\\u03b1-mediated phosphorylation, which differentially tunes early versus late stages of myelination and promotes repair after injury [#11]. DAAM2 also operates as a regulator of protein stability in disease, binding VHL and facilitating its ubiquitination and degradation to drive glioma formation, with a reciprocal Nedd4-stabilized VHL axis governing myelination [#5, #6]. In osteoblasts, DAAM2 acts downstream of a SIRT1\\u2013EZH2 module to promote chemokine secretion that recruits CD4+ cytotoxic T lymphocytes to clear senescent cells [#13].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established DAAM2 as a distinct formin-family member, defining the domain architecture (FH1/FH2) that would later rationalize its actin-nucleating activity.\",\n      \"evidence\": \"in silico sequence and domain analysis placing DAAM2 in the FDD subfamily\",\n      \"pmids\": [\"12632087\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"computational only, no functional or biochemical validation\", \"no cellular role assigned\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Answered whether DAAM2 has a defined signaling function by showing it scaffolds canonical Wnt transduction through Dvl3/Axin2 complex stabilization during spinal cord patterning.\",\n      \"evidence\": \"loss/gain-of-function in chick spinal cord, \\u03b2-catenin rescue, and co-IP of Daam2/Dvl3/Axin2\",\n      \"pmids\": [\"22227309\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"molecular basis of complex stabilization not resolved\", \"role of FH2/actin activity in scaffolding untested here\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Placed DAAM2 in a transcriptional and morphogenetic circuit, showing it is a Pitx2 target that links actin to cadherin junctions to drive left-right asymmetric gut morphogenesis.\",\n      \"evidence\": \"laser microdissection and targeted misexpression in chicken dorsal mesentery\",\n      \"pmids\": [\"24091014\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"direct cytoskeletal mechanism at junctions not biochemically dissected\", \"single-lab morphogenetic readout\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined the membrane biochemistry of DAAM2-driven Wnt signaling and revealed its role suppressing oligodendrocyte differentiation, establishing a druggable Daam2-PIP5K node for remyelination.\",\n      \"evidence\": \"chick spinal cord patterning, oligodendrocyte cultures, white matter injury models, pharmacological PIP5K inhibition\",\n      \"pmids\": [\"25754822\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"how DAAM2 engages PIP5K mechanistically not fully resolved\", \"in vivo selectivity of pharmacological inhibition unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated DAAM2 redundancy with DAAM1 in actin-based morphogenesis, showing the pair nucleates actin and mediates Wnt-induced cytoskeletal changes required for sarcomere assembly.\",\n      \"evidence\": \"Daam1 CKO, Daam1/2 DKO, and Daam1\\u00d7Wnt5a genetic crosses with cardiac phenotyping\",\n      \"pmids\": [\"26526197\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"DAAM2-specific (non-redundant) cardiac contribution not isolated\", \"link between AKT activity reduction and actin defect mechanistic gap\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Expanded DAAM2 function to protein-stability control in cancer by showing it associates with VHL and promotes its ubiquitination and degradation to drive glioma.\",\n      \"evidence\": \"tumorigenesis assays plus co-IP and ubiquitination assays\",\n      \"pmids\": [\"29053101\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"whether DAAM2 acts as an adaptor or recruits a specific E3 not established here\", \"single-lab biochemistry\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Resolved the DAAM2-VHL axis in myelination, showing mutual antagonism with VHL and that Nedd4 stabilizes VHL via K63 ubiquitination to govern developmental and repair myelination.\",\n      \"evidence\": \"proteomics of Daam2-VHL complex, conditional KO mice, demyelination models, MS lesion analysis\",\n      \"pmids\": [\"32792353\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"directionality between DAAM2-driven VHL degradation and Nedd4-driven VHL stabilization in same cells unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Confirmed DAAM1/DAAM2 redundancy in mammalian development and Wnt/PCP function via placental and neural tube phenotypes.\",\n      \"evidence\": \"knockout and compound Daam1/Daam2/Wnt5a mutant mice\",\n      \"pmids\": [\"32353019\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"DAAM2-specific placental requirement not defined\", \"molecular PCP mechanism not dissected\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Detailed the Rac1 dependence of DAAM2 Wnt signalosome clustering, integrating Rac1, PIP5K, PIP2, and actin polymerization into one membrane-clustering mechanism.\",\n      \"evidence\": \"gain/loss-of-function and localization/clustering assays in chick, human, and monkey cell lines\",\n      \"pmids\": [\"33310913\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"physical hierarchy of Rac1/PIP5K/DAAM2 binding not fully ordered\", \"structural basis of signalosome clustering unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified Slc4a4 as a DAAM2 partner controlling astrocyte morphology, extending DAAM2 cytoskeletal regulation to glia in a region-specific manner.\",\n      \"evidence\": \"astrocyte-specific cKO, proteomics, co-IP, genetic rescue, calcium imaging, electrophysiology\",\n      \"pmids\": [\"34633730\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"mechanism linking DAAM2-Slc4a4 to actin and morphology not resolved\", \"single-lab co-IP\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established the effector arm of DAAM2 in oligodendrocytes, showing it drives Gelsolin ubiquitination/degradation via Nedd4 and acts through Rac1 to control myelin compaction.\",\n      \"evidence\": \"OL-specific cKO, primary OL gain/loss-of-function, in vitro ubiquitination, in vivo protein analysis\",\n      \"pmids\": [\"35101966\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"how DAAM2 recruits Nedd4 to Gelsolin not structurally defined\", \"relationship between scaffolding and ubiquitination activities unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified an upstream regulatory switch by showing CK2\\u03b1 phosphorylates DAAM2 to inhibit it, with stage-specific effects on myelination and protective effects after injury.\",\n      \"evidence\": \"CK2\\u03b1 kinase assays on DAAM2, OL stage analysis, neonatal hypoxia and adult demyelination models\",\n      \"pmids\": [\"37607236\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"phosphosite-level consequences on actin/Wnt activity not mapped\", \"kinase regulation in non-OL tissues untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Tested the canonical-versus-noncanonical question directly, mapping a Wnt-regulated Daam2-Dvl2 interaction and linking DAAM2 to non-canonical PCP-type neural tube closure via actin.\",\n      \"evidence\": \"co-IP domain mapping, localization, Xenopus morpholino knockdown, actin imaging\",\n      \"pmids\": [\"38877839\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"failure to detect canonical Wnt regulation conflicts with earlier systems and is context/method dependent\", \"domain mapping not validated by structure\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended DAAM2 into immune-bone homeostasis as a SIRT1/EZH2 downstream effector driving chemokine-mediated recruitment of CD4+ CTLs to clear senescent osteoblasts.\",\n      \"evidence\": \"spatial bone microenvironment analysis, osteoblast-CTL co-culture, SIRT1/EZH2/DAAM2 dissection, osteoporosis models\",\n      \"pmids\": [\"40714829\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"molecular mechanism linking DAAM2 to chemokine secretion not defined\", \"whether actin/Wnt activity underlies this role unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how DAAM2 partitions between its canonical Wnt scaffolding, non-canonical PCP/actin, and E3-ligase-adaptor (VHL, Gelsolin) functions, and what determines context-specific selection among them.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"no unified structural model integrating FH2 actin activity with Dvl/Axin scaffolding\", \"rules governing tissue-specific partner choice unknown\", \"direct versus indirect contribution to ubiquitination unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [3, 4, 8, 10, 12]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 8, 12]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [5, 6, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 3, 8]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 2, 4, 7]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [5, 6, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"DVL3\", \"DVL2\", \"AXIN2\", \"VHL\", \"NEDD4\", \"RAC1\", \"SLC4A4\", \"DAAM1\"],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}