Affinage

DAAM2

Disheveled-associated activator of morphogenesis 2 · UniProt Q86T65

Length
1068 aa
Mass
123.5 kDa
Annotated
2026-06-09
23 papers in source corpus 14 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2003 Low

    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

    PMID:12632087

    Open questions at the time
    • computational only, no functional or biochemical validation
    • no cellular role assigned
  2. 2012 High

    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

    PMID:22227309

    Open questions at the time
    • molecular basis of complex stabilization not resolved
    • role of FH2/actin activity in scaffolding untested here
  3. 2013 Medium

    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

    PMID:24091014

    Open questions at the time
    • direct cytoskeletal mechanism at junctions not biochemically dissected
    • single-lab morphogenetic readout
  4. 2015 High

    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

    PMID:25754822

    Open questions at the time
    • how DAAM2 engages PIP5K mechanistically not fully resolved
    • in vivo selectivity of pharmacological inhibition unclear
  5. 2015 High

    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

    PMID:26526197

    Open questions at the time
    • DAAM2-specific (non-redundant) cardiac contribution not isolated
    • link between AKT activity reduction and actin defect mechanistic gap
  6. 2017 Medium

    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

    PMID:29053101

    Open questions at the time
    • whether DAAM2 acts as an adaptor or recruits a specific E3 not established here
    • single-lab biochemistry
  7. 2020 High

    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

    PMID:32792353

    Open questions at the time
    • directionality between DAAM2-driven VHL degradation and Nedd4-driven VHL stabilization in same cells unresolved
  8. 2020 Medium

    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

    PMID:32353019

    Open questions at the time
    • DAAM2-specific placental requirement not defined
    • molecular PCP mechanism not dissected
  9. 2021 High

    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

    PMID:33310913

    Open questions at the time
    • physical hierarchy of Rac1/PIP5K/DAAM2 binding not fully ordered
    • structural basis of signalosome clustering unknown
  10. 2021 Medium

    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

    PMID:34633730

    Open questions at the time
    • mechanism linking DAAM2-Slc4a4 to actin and morphology not resolved
    • single-lab co-IP
  11. 2022 High

    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

    PMID:35101966

    Open questions at the time
    • how DAAM2 recruits Nedd4 to Gelsolin not structurally defined
    • relationship between scaffolding and ubiquitination activities unclear
  12. 2023 High

    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

    PMID:37607236

    Open questions at the time
    • phosphosite-level consequences on actin/Wnt activity not mapped
    • kinase regulation in non-OL tissues untested
  13. 2024 Medium

    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

    PMID:38877839

    Open questions at the time
    • failure to detect canonical Wnt regulation conflicts with earlier systems and is context/method dependent
    • domain mapping not validated by structure
  14. 2025 Medium

    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

    PMID:40714829

    Open questions at the time
    • molecular mechanism linking DAAM2 to chemokine secretion not defined
    • whether actin/Wnt activity underlies this role unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 5 GO:0060090 molecular adaptor activity 3 GO:0140096 catalytic activity, acting on a protein 3
Localization
GO:0005829 cytosol 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 3 R-HSA-392499 Metabolism of proteins 3
Partners
AXIN2DAAM1DVL2DVL3NEDD4RAC1SLC4A4VHL

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 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. Bioinformatics/in silico sequence analysis and domain architecture characterization International journal of oncology Low 12632087
2012 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. Loss-of-function and gain-of-function studies in chick spinal cord, β-catenin rescue experiments, biochemical co-immunoprecipitation of Daam2/Dvl3/Axin2 complexes Developmental cell High 22227309
2013 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. Laser microdissection, targeted gene misexpression in chicken dorsal mesentery, gene expression analysis Developmental cell Medium 24091014
2015 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. Dorsal patterning assay in chick spinal cord, multifaceted discovery platform, functional studies in oligodendrocytes, pharmacological inhibition Neuron High 25754822
2015 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. Conditional knockout mice (Daam1 CKO), Daam1/2 double knockout (DKO), Daam1-floxed × Wnt5a null genetic crosses, cardiac phenotype assessment Developmental biology High 26526197
2017 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. Protein expression screening (in silico), functional tumorigenesis assays, biochemical co-immunoprecipitation and ubiquitination assays eLife Medium 29053101
2020 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. Proteomic analysis of Daam2-VHL complex, conditional genetic knockout mouse models (developmental myelination), mouse demyelination models, analysis of MS white matter lesions Genes & development High 32792353
2020 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). Gene targeting/knockout mouse models, Daam1/Daam2/Wnt5a compound mutant analysis, embryonic phenotype assessment PloS one Medium 32353019
2021 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. Gain- and loss-of-function studies in chick spinal cord and human/monkey cell lines, membrane localization assays, signalosome clustering assays Journal of cell science High 33310913
2021 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. Astrocyte-specific conditional knockout mice, proteomic profiling, co-immunoprecipitation, calcium imaging, electrophysiology EMBO reports Medium 34633730
2022 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. OL-specific Daam2 cKO mice, primary OL cultures (gain- and loss-of-function), in vitro ubiquitination assay, in vivo protein level analysis The Journal of neuroscience High 35101966
2023 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. Kinase phosphorylation assays (CK2α on Daam2), OL developmental stage analysis, neonatal hypoxia and adult demyelination mouse models Proceedings of the National Academy of Sciences of the United States of America High 37607236
2024 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. Co-immunoprecipitation (Daam2-Dvl2 interaction and domain mapping), subcellular localization studies, Xenopus morpholino knockdown, actin cytoskeleton imaging Developmental dynamics Medium 38877839
2025 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. Spatial analysis of bone microenvironment, osteoblast-CTL co-culture experiments, SIRT1/EZH2/DAAM2 mechanistic studies, in vivo osteoporosis models Advanced science Medium 40714829

Source papers

Stage 0 corpus · 23 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Identification and characterization of human DAAM2 gene in silico. International journal of oncology 103 12632087
2013 Integration of left-right Pitx2 transcription and Wnt signaling drives asymmetric gut morphogenesis via Daam2. Developmental cell 68 24091014
2015 Daam2-PIP5K is a regulatory pathway for Wnt signaling and therapeutic target for remyelination in the CNS. Neuron 67 25754822
2012 Daam2 is required for dorsal patterning via modulation of canonical Wnt signaling in the developing spinal cord. Developmental cell 52 22227309
2015 DAAM1 and DAAM2 are co-required for myocardial maturation and sarcomere assembly. Developmental biology 46 26526197
2020 The Daam2-VHL-Nedd4 axis governs developmental and regenerative oligodendrocyte differentiation. Genes & development 29 32792353
2004 Identification of chick and mouse Daam1 and Daam2 genes and their expression patterns in the central nervous system. Brain research. Developmental brain research 29 15464228
2017 Daam2 driven degradation of VHL promotes gliomagenesis. eLife 21 29053101
2022 Daam2 Regulates Myelin Structure and the Oligodendrocyte Actin Cytoskeleton through Rac1 and Gelsolin. The Journal of neuroscience : the official journal of the Society for Neuroscience 16 35101966
2020 Placental defects lead to embryonic lethality in mice lacking the Formin and PCP proteins Daam1 and Daam2. PloS one 14 32353019
2021 Regional heterogeneity of astrocyte morphogenesis dictated by the formin protein, Daam2, modifies circuit function. EMBO reports 12 34633730
2021 DAAM2 is elevated in the circulation and placenta in pregnancies complicated by fetal growth restriction and is regulated by hypoxia. Scientific reports 10 33692394
2023 Daam2 phosphorylation by CK2α negatively regulates Wnt activity during white matter development and injury. Proceedings of the National Academy of Sciences of the United States of America 9 37607236
2015 Correlation Between Daam2 Expression Changes and Demyelination in Guillain-Barre Syndrome. Cellular and molecular neurobiology 7 26293489
2021 Daam2 couples translocation and clustering of Wnt receptor signalosomes through Rac1. Journal of cell science 6 33310913
2024 The dishevelled associated activator of morphogenesis protein 2 (Daam2) regulates neural tube closure. Developmental dynamics : an official publication of the American Association of Anatomists 4 38877839
2019 Whole exome sequencing identifies a rare variant in DAAM2 as a potential candidate in idiopathic pulmonary ossification. Annals of translational medicine 4 31475197
2011 DAAM2 polymorphism is closely related to the clinical outcomes of allogeneic hematopoietic stem cell transplantation. Annals of hematology 4 21909696
2025 Osteoblast-CD4+ CTL Crosstalk Mediated by SIRT1/DAAM2 Axis Prevents Age-Related Bone Loss. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 2 40714829
2022 Dishevelled-Associated Activator of Morphogenesis 2 (DAAM2) Predicts the Immuno-Hot Phenotype in Pancreatic Adenocarcinoma. Frontiers in molecular biosciences 2 35281277
2025 PPIL1 Drives Hepatocellular Carcinoma Progression and Cancer Stem Cell Self-renewal Through DAAM2-mediated Wnt/β-Catenin Activation. Cancer genomics & proteomics 1 40883023
2024 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? Clinical genetics 1 38860410
2022 Placental DAAM2 is unaltered in preeclampsia, but upregulated by treatment with proton pump inhibitors. Pregnancy hypertension 1 35933758

Missed literature

Know a paper Affinage missed for DAAM2? Flag it for the maintainers and the community.

No submissions yet.