{"gene":"DAB2","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":2002,"finding":"Dab2 binds myosin VI via a C-terminal region of Dab2, linking endocytic vesicles to the actin cytoskeleton; the interaction was confirmed by yeast two-hybrid, in vitro binding assays, co-immunoprecipitation, and co-localization in clathrin-coated pits/vesicles at the apical domain of polarized epithelial cells.","method":"Yeast two-hybrid, mammalian two-hybrid, in vitro binding assay, co-immunoprecipitation, confocal co-localization","journal":"Traffic (Copenhagen, Denmark)","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (yeast two-hybrid, in vitro binding, Co-IP, co-localization) in single study, interaction independently replicated","pmids":["11967127"],"is_preprint":false},{"year":2002,"finding":"Dab2 is required in the visceral endoderm for embryo development prior to gastrulation (likely via TGFbeta/Nodal signaling), and is required in kidney proximal tubule cells for clathrin-coated pit formation and megalin/gp330-mediated lipoprotein receptor trafficking; conditional deletion from embryo proper yields viable mice with normal development but proteinuria.","method":"Targeted gene knockout in mouse, conditional deletion using Cre-lox, urinalysis, electron microscopy of clathrin-coated pits","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean in vivo genetic KO with multiple defined cellular phenotypes, conditional rescue experiment","pmids":["11927540"],"is_preprint":false},{"year":2000,"finding":"The phosphotyrosine interaction domain (PID/PTB) of Dab2 binds the third PsiXNPXY motif in the cytoplasmic tail of megalin (gp600), as shown by yeast two-hybrid screening, in vitro binding assay, and co-immunoprecipitation from renal cell lysates.","method":"Yeast two-hybrid, in vitro binding assay, co-immunoprecipitation","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — three orthogonal methods, deletion/point-mutation mapping of binding motif","pmids":["10769163"],"is_preprint":false},{"year":2006,"finding":"Dab2 acts as a cargo-specific endocytic adaptor for LDL receptors (LDLR), mediating their clustering into coated pits independently of AP-2 and ARH; this activity requires Dab2 binding to clathrin, LDLR, and phospholipids. In HeLa cells and fibroblasts, Dab2 is the primary adaptor for LDLR internalization, whereas ARH can compensate but requires AP-2.","method":"siRNA knockdown, fluorescence endocytosis assays, LDL uptake assays, domain-function mutagenesis","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple cell types, domain mutants, epistatic knockdown combinations with defined cargo phenotype","pmids":["16984970"],"is_preprint":false},{"year":2003,"finding":"Dab2 N-terminal domain interacts with Dishevelled-3 (Dvl-3) and negatively regulates canonical Wnt/beta-catenin signaling; Dab2 overexpression maintains Dab2-Dvl-3 association, disrupts Dvl-3-axin interaction, stabilizes axin, and reduces nuclear beta-catenin and cyclin D1. Dab2-null MEFs exhibit constitutive Wnt signaling.","method":"Small-pool cDNA screen, co-immunoprecipitation, beta-catenin/TCF reporter assay, in vitro binding assay, Dab2 KO MEFs","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods, genetic KO corroborates overexpression findings, pathway placement via epistasis","pmids":["12805222"],"is_preprint":false},{"year":1998,"finding":"Dab2 binds the SH3 domains of Grb2 via its C-terminal proline-rich domain (residues 600-730, key site #661-669), competing with Sos for Grb2 binding; both SH3 domains of Grb2 are required cooperatively for binding to Dab2.","method":"Co-immunoprecipitation from macrophage lysates, transfection competition assay in 293 cells, peptide inhibition, domain-binding experiments","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple complementary binding assays, functional competition experiment, domain mapping","pmids":["9569023"],"is_preprint":false},{"year":2001,"finding":"DOC-2/DAB2 suppresses ERK phosphorylation by binding Grb2 via its second proline-rich domain in a growth-factor-stimulated manner, thereby interrupting the Grb2-SOS interaction and blocking downstream MAPK signaling; reduced ERK phosphorylation is rescued by increasing Grb2 expression or using a specific blocking peptide.","method":"Peptide competition, transfection rescue, co-immunoprecipitation, ERK phosphorylation assay, AP-1 reporter assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal biochemical assays with domain specificity and functional rescue","pmids":["11371563"],"is_preprint":false},{"year":1999,"finding":"PKC (specifically PKCbetaII, PKCgamma, and PKCdelta) directly phosphorylates Dab2 at Ser24; mutation of Ser24 to Ala abolishes PKC-induced phosphorylation and abrogates TPA-induced AP-1 inhibition, indicating that Ser24 phosphorylation is required for Dab2's growth-inhibitory function.","method":"In vitro kinase assay with recombinant substrates and isoform-specific PKC, site-directed mutagenesis (S24A), AP-1 reporter assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro phosphorylation with purified kinases, mutagenesis with functional readout","pmids":["10542228"],"is_preprint":false},{"year":2005,"finding":"TGFbeta induces Dab2 expression and increases its binding to beta1 integrin at the membrane; siRNA silencing of Dab2 inhibits integrin activation (reduced focal adhesion kinase phosphorylation), cell adherence, and TGFbeta-mediated EMT, while re-expression of human Dab2 rescues these effects. Dab2 ablation also blocks retinoic acid-induced visceral endoderm differentiation.","method":"siRNA knockdown, siRNA rescue (species-specific), FAK phosphorylation assay, cell adhesion assay, F9 differentiation model","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — siRNA knockdown with rescue, multiple cell systems, defined molecular readouts","pmids":["15734730"],"is_preprint":false},{"year":2005,"finding":"Dab2 directly stimulates JNK activity and is required for TGFbeta-mediated fibronectin induction and cell migration; TGFbeta stimulates association of Dab2 with the MAP3K TAK1, and attenuation of TAK1 abolishes TGFbeta-induced fibronectin induction.","method":"siRNA stable knockdown, JNK kinase assay, co-immunoprecipitation (Dab2-TAK1), dominant-negative TAK1, fibronectin induction assay, cell migration assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods, co-IP of endogenous proteins, dominant-negative epistasis, rescue","pmids":["15894542"],"is_preprint":false},{"year":2005,"finding":"Dab2 p96 isoform, which retains endocytic protein-binding sites absent from p67, is required for efficient megalin endocytosis in visceral endoderm; knock-in of p96 fully rescues endocytosis and embryonic viability, while p67 only partially rescues.","method":"Isoform-specific knock-in mice, endocytosis assays (transferrin/cubilin uptake), embryonic viability scoring","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo isoform-specific knock-in rescue with defined molecular mechanism","pmids":["16263760"],"is_preprint":false},{"year":2005,"finding":"In renal proximal tubule, Dab2 co-localizes with megalin in clathrin-coated pits/vesicles; megalin knockout nearly abolishes Dab2 staining (Dab2 localization requires megalin), and Dab2 knockout redistributes megalin from endosomes to microvilli with decreased total megalin protein. Introduction of anti-Dab2 antibody into BN16 cells decreased internalization of receptor-associated protein.","method":"Immunohistochemistry, megalin/Dab2 conditional knockout mice, immunoblotting, intracellular antibody injection, 125I-RAP internalization assay","journal":"American journal of physiology. Renal physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal KO phenotyping plus functional internalization assay, mutually dependent localization established","pmids":["15870384"],"is_preprint":false},{"year":2009,"finding":"Dab2 mediates bulk endocytosis of inactive integrins beta1, alpha1, alpha2, and alpha3 (but not alpha5 or alphav) into coated pits; Dab2 depletion inhibits cell migration and polarized recycling of integrin beta1 to the leading edge, and migration speed correlates with intracellular integrin pool size.","method":"Quantitative glycoprotein surface proteomics (SILAC), siRNA depletion, fluorescence microscopy, integrin beta1 surface/intracellular level manipulation, migration assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — unbiased quantitative proteomics plus functional migration/localization assays","pmids":["19581412"],"is_preprint":false},{"year":2009,"finding":"Dab2 attenuates Wnt/beta-catenin signaling by binding to Axin and acting as a competitive inhibitor of PP1, preventing PP1-mediated dephosphorylation and destabilization of Axin. The N-terminal PTB domain of Dab2 is sufficient to block PP1-Axin interactions; Dab2 overexpression in zebrafish phenocopies Axin overexpression.","method":"Co-immunoprecipitation, in vitro binding competition assay, Dab2 truncation mutants, beta-catenin reporter assay, Dab2 ectopic expression in zebrafish embryos","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro competition binding, cell-based pathway assays, and in vivo zebrafish epistasis","pmids":["19581931"],"is_preprint":false},{"year":2007,"finding":"Dab2 interacts with Axin and prevents Axin's interaction with and degradation by LRP5/6 Wnt co-receptor, thereby increasing Axin half-life and stabilizing the beta-catenin destruction complex to inhibit Wnt signaling.","method":"Co-immunoprecipitation, Axin half-life assay, beta-catenin reporter assay, F9 and mammary cell differentiation models","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, protein half-life measurements, multiple cellular contexts","pmids":["17922036"],"is_preprint":false},{"year":2012,"finding":"Dab2 selectively recruits LRP6 to the clathrin-dependent endocytic pathway upon CK2-mediated phosphorylation of LRP6 at S1579, sequestering LRP6 from caveolin-dependent endocytosis required for Wnt signaling. LRP6-S1579A mutant fails to bind Dab2, escapes clathrin routing, and is insensitive to Dab2-mediated Wnt inhibition.","method":"Co-immunoprecipitation, site-directed mutagenesis (LRP6-S1579A), clathrin/caveolin endocytosis assays, Wnt reporter assay, zebrafish dorsoventral patterning, allograft mouse tumor model","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — mutagenesis of phospho-site, Co-IP, multiple functional assays in vitro and in vivo","pmids":["22491013"],"is_preprint":false},{"year":2010,"finding":"TGFbeta induces phosphorylation of hnRNP E1 at Ser43 by PKBbeta/Akt2, releasing hnRNP E1 from the 33-nucleotide BAT element in the 3'UTR of Dab2 (and ILEI) mRNAs, thereby relieving translational repression and inducing Dab2 protein expression as part of a post-transcriptional EMT regulon.","method":"RNA-protein binding assay, phospho-specific immunoblot, siRNA modulation of hnRNP E1, Akt2 kinase assay, translation reporter assay","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro kinase assay, RNA-protein interaction mapping, siRNA modulation with translational functional readout","pmids":["20154680"],"is_preprint":false},{"year":2010,"finding":"Dab2 knockdown does not affect internalization of TGFbeta, LDL, or transferrin but abrogates TGFbeta receptor recycling from early endosomes to the recycling compartment, resulting in enlarged EEA1-positive endosomes and diminished Smad2 phosphorylation.","method":"siRNA knockdown, endosome morphology (EEA1 immunofluorescence), receptor recycling assay, Smad2 phosphorylation assay","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal trafficking and signaling assays, negative control cargoes used","pmids":["20881059"],"is_preprint":false},{"year":2002,"finding":"DOC-2/DAB2 interacts with DIP1/2, a novel GTPase-activating protein with a Ras GAP homology domain, via the N-terminal domain of DOC-2/DAB2; this complex is detected in normal brain and prostate. DIP1/2 expression blocks mitogen-induced gene expression and inhibits prostate cancer cell growth.","method":"Yeast two-hybrid cloning, co-immunoprecipitation from tissue lysates, cell growth assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP confirmed interaction, functional growth assay, but single lab","pmids":["11812785"],"is_preprint":false},{"year":2002,"finding":"DOC-2/DAB2 proline-rich domain interacts with the SH3 domain of c-Src; this binding is enhanced by growth factor and results in c-Src inactivation (decreased pTyr416) and reduced downstream effector activity.","method":"Co-immunoprecipitation, c-Src kinase activity assay (pTyr416), growth factor stimulation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with functional kinase readout, single lab, single paper","pmids":["12473651"],"is_preprint":false},{"year":2001,"finding":"DOC-2/hDab-2 expression in breast cancer cells induces anoikis associated with down-regulation of integrin-linked kinase (ILK) activity, suggesting Dab2 negatively regulates the ILK anti-apoptotic pathway.","method":"Transfection, suspension-induced cell death (anoikis) assay, ILK kinase activity assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined kinase activity readout, single lab","pmids":["11687976"],"is_preprint":false},{"year":2003,"finding":"Dab2 associates with CIN85 via its PKPAPR motif in the C-terminus, recruiting CIN85 to the clathrin coat; growth factor stimulation dissociates Dab2 and clathrin from CIN85, enabling Cbl to bind CIN85 during receptor tyrosine kinase endocytosis.","method":"Co-immunoprecipitation, peptide binding assay, growth factor stimulation time-course","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP plus peptide binding, but limited mechanistic depth, single lab","pmids":["14596919"],"is_preprint":false},{"year":2009,"finding":"The p82 isoform of Dab2 induces enlarged clathrin assemblies at the plasma membrane dependent on a functional PTB domain, clathrin binding, phospholipid binding, and a poly-lysine stretch preceding the PTB domain; p82 expression also enhances cell spreading on fibronectin and concentrates beta1 integrin into clathrin-p82 assemblies.","method":"GFP-fusion expression, live-cell imaging, FRAP, clathrin assembly morphology, site-directed mutagenesis, fibronectin spreading assay","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple domain mutants, live imaging, FRAP dynamics, multiple cell lines","pmids":["19000037"],"is_preprint":false},{"year":2010,"finding":"Dab2 is progressively displaced from the plasma membrane and loses co-localization with clathrin during mitosis, peaking at metaphase/anaphase; this displacement is accompanied by Dab2 phosphorylation, reduced Dab2-clathrin interactions, decreased endocytic vesicle motility, and impaired internalization of NPXY-containing cargo. Ser/Thr-to-Ala mutations in the central region of Dab2 attenuate its phosphorylation and membrane displacement, maintaining endocytic activity during mitosis.","method":"Live-cell imaging, immunofluorescence, FRAP, co-immunoprecipitation, NPXY-cargo internalization assay, site-directed mutagenesis (Ser/Thr→Ala), pharmacological mitotic arrest (2-methoxyestradiol)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods, mutagenesis with functional rescue, mechanistic link between phosphorylation and membrane displacement/endocytic activity","pmids":["21097498"],"is_preprint":false},{"year":2012,"finding":"Dab2 binds Eps15 and intersectin via its EH-domain binding sites; mutation of these sites impairs integrin beta1 endocytosis (but not transferrin receptor) without displacing Dab2 from clathrin structures, indicating that Dab2-mediated recruitment of EH domain proteins selectively drives internalization of Dab2 cargo.","method":"Co-immunoprecipitation, site-directed mutagenesis (EH-binding site mutants), integrin beta1 and transferrin endocytosis assay, clathrin structure analysis","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — EH-binding site mutagenesis with cargo-specific functional readout, multiple assays in single study","pmids":["22648170"],"is_preprint":false},{"year":2012,"finding":"Dab2 depletion in airway epithelial cells inhibits CFTR endocytosis and post-endocytic trafficking from sorting endosome to recycling compartment and to late endosome, resulting in increased CFTR half-life (~3-fold); this is distinct from AP-2 depletion which primarily reduces endocytosis without affecting CFTR stability.","method":"siRNA depletion of Dab2 vs. AP-2, CFTR surface biotinylation, endocytosis assay, recycling assay, protein half-life measurement","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — parallel depletion of two adaptors with distinct mechanistic effects on multiple trafficking steps","pmids":["21995445"],"is_preprint":false},{"year":2014,"finding":"Dab2 interacts with TGFbeta type I receptor (TbetaRI), restricts its lateral diffusion at the plasma membrane, and enhances clathrin-mediated endocytosis of TbetaRI; Dab2 negatively regulates TGFbeta-induced JNK activation but not Smad pathway activation. JNK activation by TGFbeta in the absence of Dab2 is disrupted by cholesterol depletion, indicating TbetaRI localizes to cholesterol-rich domains when Dab2 is absent.","method":"Biophysical lateral diffusion measurements (SPT/FRAP), siRNA knockdown and overexpression, JNK and Smad phosphorylation assays, cholesterol depletion","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — biophysical receptor mobility measurements, receptor endocytosis assay, pathway-selective signaling readouts with mechanistic model","pmids":["24648493"],"is_preprint":false},{"year":2018,"finding":"In endothelial cells, Dab2 recruitment to the apoER2 NPXY motif promotes activating L309 methylation of the PP2A catalytic subunit by LCMT-1; simultaneously, SHC1 recruits the PP2A scaffolding subunit to the proline-rich apoER2 C-terminus, forming a PP2A holoenzyme that dephosphorylates (inactivates) Akt and eNOS, mediating antiphospholipid antibody-induced thrombosis.","method":"Co-immunoprecipitation, PP2A methylation assay, Akt/eNOS phosphorylation assays, mouse thrombosis model with endothelial-specific manipulation","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — biochemical dissection of complex assembly, defined enzymatic modification, in vivo mouse thrombosis model","pmids":["29500169"],"is_preprint":false},{"year":2005,"finding":"ApoER2 internalizes via clathrin-mediated endocytosis through its cytoplasmic FxNPXY motif binding to Dab2; dominant-negative Dab2 and eps15 reduce apoER2 internalization, whereas blocking caveolar/raft pathway (nystatin) has no effect. Raft association of apoER2 does not determine its endocytic route.","method":"Dominant-negative Dab2 and eps15 expression, nystatin treatment, apoER2 internalization assay, mutagenesis of FxNPXY motif","journal":"Traffic (Copenhagen, Denmark)","confidence":"High","confidence_rationale":"Tier 2 / Strong — dominant-negative and pharmacological inhibition with defined pathway distinction, motif mutagenesis","pmids":["16101684"],"is_preprint":false},{"year":2010,"finding":"Amnionless (AMN) FXNPXF motifs in cubam receptor mediate endocytosis through direct interaction with Dab2 and ARH; the two signals are functionally redundant, demonstrated by sequential mutation and yeast two-hybrid analyses.","method":"Yeast two-hybrid, amnionless mutant expression panel, endocytosis assay","journal":"Traffic (Copenhagen, Denmark)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid and functional endocytosis assay, single lab","pmids":["20088845"],"is_preprint":false},{"year":2014,"finding":"ARH and Dab2 both bind LDLR but not NPC1L1, and are not required for NPC1L1 internalization; Numb specifically binds NPC1L1 and mediates cholesterol absorption, distinctly from ARH and Dab2 which selectively participate in LDLR-mediated LDL uptake.","method":"Co-immunoprecipitation, siRNA knockdown, LDL and cholesterol uptake assays, domain-specific PTB binding studies","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — receptor-specific binding and knockdown studies with multiple controls establishing cargo selectivity","pmids":["25331956"],"is_preprint":false},{"year":2012,"finding":"Akt/PKB interacts with the proline-rich domain (PRD) of Dab2 via its PH and catalytic domains, and phosphorylates Dab2 at Ser448 and Ser449; Ser-to-Ala mutations at these sites inhibit albumin endocytosis and shift Dab2 localization from peripheral to perinuclear compartment, demonstrating that Akt-mediated Dab2 phosphorylation is required for albumin endocytosis.","method":"Co-immunoprecipitation, GST pull-down with truncated constructs, yeast two-hybrid, Akt isoform-specific siRNA, Dab2 Ser448/449Ala mutagenesis, albumin endocytosis assay, Dab2 localization imaging","journal":"American journal of physiology. Renal physiology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro pull-down domain mapping, yeast two-hybrid, mutagenesis with localization and functional readout","pmids":["22218591","25253241"],"is_preprint":false},{"year":2009,"finding":"Dab2 is a FOXP3 target gene exclusively expressed in FOXP3+ regulatory T cells; regulatory T cells lacking Dab2 are functionally impaired in vitro and in vivo (suppressive capacity), but Dab2 is dispensable for Treg-mediated naive T cell homeostasis.","method":"Flow cytometry, genetic KO of Dab2 in Tregs, in vitro suppression assay, in vivo adoptive transfer","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with in vitro and in vivo functional readouts, exclusive expression established by flow cytometry","pmids":["19767570"],"is_preprint":false},{"year":2016,"finding":"DAB2 loss in zebrafish (CRISPR/Cas9 KO) reduces cardiomyocyte number and increases WNT/beta-catenin signaling; these defects are suppressed by DKK1 overexpression, placing DAB2 upstream of WNT signaling in cardiac development.","method":"CRISPR/Cas9 knockout in zebrafish, cardiomyocyte counting, WNT/beta-catenin signaling assay, DKK1 rescue experiment, label-free quantitative proteomics in human ESC differentiation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR KO with in vivo genetic epistasis (DKK1 rescue), defined cellular phenotype","pmids":["26755607"],"is_preprint":false},{"year":2016,"finding":"Combined deletion of Dab2 and Arh in mice results in profound hypercholesterolemia similar to LDLR knockout; in liver, Dab2 is expressed in sinusoidal endothelial cells (not hepatocytes) and in the absence of Arh, Dab2 in liver endothelial cells regulates cholesterol synthesis (HMG-CoA reductase levels) in hepatocytes.","method":"Double KO mice (arh/dab2), serum cholesterol measurement, HMG-CoA reductase western blot, cell-type-specific immunostaining","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 2 / Strong — double KO genetic epistasis, comparison to LDLR KO, cell-type-specific localization","pmids":["27005486"],"is_preprint":false},{"year":2019,"finding":"DAB2 expression in dendritic cells is rapidly downregulated by TLR ligands in a TRIF- and MyD88-dependent biphasic manner (rapid protein drop then sustained mRNA reduction); DAB2 knockdown promotes activated DC phenotype (increased IL-12, IL-6, CD40), reduces phagocytosis, and Dab2-KO DCs inhibit autophagy and promote apoptotic cell death.","method":"BMDC TLR stimulation, siRNA/KO, qPCR, flow cytometry, cytokine ELISA, autophagy assay, TRIF/MyD88 pathway analysis","journal":"Frontiers in immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple complementary assays linking TLR signaling pathway to Dab2 regulation with functional immune phenotype","pmids":["30873168"],"is_preprint":false},{"year":2021,"finding":"Dab2 myosin interacting region (MIR) binds myosin VI with moderate affinity (Kd ~184 nM) and high turnover rate (~1 s-1); dynamic (not stable) multimerization of Dab2-MIR/myosin VI complexes promotes cargo processivity on actin while preserving cortical actin network integrity. Constitutive stable dimers cause actin reorganization and foci formation.","method":"Single-molecule kinetics, in vitro motility assay, DNA origami scaffold-based cargo mimetics, minimal actin cortex assay on lipid bilayers, fluorescence microscopy","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted in vitro single-molecule kinetics, structural scaffolds, actin cortex reconstitution","pmids":["33372034"],"is_preprint":false},{"year":2008,"finding":"DAB2 silencing in human endothelial cells activates Src-FAK signaling, ERK and JNK activation, inhibits p38 phosphorylation, and promotes cell proliferation/migration while impairing capillary-like morphogenesis; pharmacological Src inhibition (PP2) abolishes FAK activation and restores endothelial differentiation.","method":"Lentiviral shRNA knockdown, Src/FAK phosphorylation assay, ERK/JNK/p38 immunoblot, endothelial tube formation assay, PP2 pharmacological rescue","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — shRNA knockdown with multiple pathway readouts and pharmacological rescue, single lab","pmids":["18582465"],"is_preprint":false},{"year":2024,"finding":"HDAC5 deacetylates H3K9ac at the DAB2 promoter, repressing DAB2 expression; A. muciniphila inhibits HDAC5, thereby increasing DAB2 expression, which blocks macrophage pro-inflammatory M1 polarization. DAB2 overexpression reverses HDAC5-induced pro-inflammatory polarization.","method":"ChIP for H3K9ac, siRNA/overexpression of HDAC5 and DAB2, macrophage polarization assay, in vivo DSS colitis model with A. muciniphila treatment","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP establishes epigenetic mechanism, functional rescue in vitro and in vivo, single lab","pmids":["38776988"],"is_preprint":false},{"year":2000,"finding":"GATA-6 (but not GATA-4) transcriptionally activates the Dab2 promoter in visceral endoderm; GATA-6-null ES cells lack Dab2 expression, and forced GATA-6 expression in NIH-3T3 cells transactivates the human Dab2 promoter. The specificity is not mediated through GATA-6's zinc finger DNA-binding domain.","method":"Subtractive hybridization, in vivo GATA-6 KO embryos, co-transfection reporter assay, GATA-4 KO embryos as negative control","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay plus in vivo KO validation, but mechanism of GATA-6 action (without DNA-binding domain) incompletely resolved","pmids":["10779506"],"is_preprint":false},{"year":2023,"finding":"In kidney proximal tubule cells, megalin, cubilin/amnionless (CUBAM), and Dab2 each have distinct roles in albumin endocytosis and endocytic pathway flux; CRISPR KO of each component has different effects on albumin uptake concentration-dependence and intracellular distribution, but key endocytic pathway proteins are preserved in all KOs, indicating these components drive endocytic flux without compromising pathway integrity.","method":"CRISPR/Cas9 KO in differentiated proximal tubule cell line, albumin internalization assay, fluid-phase marker uptake, confocal imaging, megalin KO mice","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — parallel CRISPR KO of three components with quantitative cargo uptake assays and in vivo megalin KO comparison","pmids":["37126375"],"is_preprint":false}],"current_model":"DAB2 (DOC-2) is a multifunctional endocytic adaptor protein whose PTB/PID domain binds NPXY motifs in LDL receptor family members (megalin, LDLR, apoER2, LRP6, amnionless/cubam), recruiting them into clathrin-coated pits together with clathrin, AP-2, myosin VI, Eps15, and intersectin to mediate receptor-specific endocytosis; its proline-rich C-terminal domain engages Grb2 SH3 domains (displacing SOS to suppress MAPK/ERK), c-Src SH3 (maintaining Src in an inactive conformation), TAK1 (activating JNK for fibronectin induction and EMT), and Akt (which phosphorylates Dab2 at Ser448/449 to promote albumin endocytosis); DAB2 inhibits canonical Wnt/beta-catenin signaling by binding Dvl-3 and Axin—stabilizing the destruction complex by blocking PP1-mediated Axin dephosphorylation—and by recruiting LRP6 to clathrin (rather than caveolin) endocytosis after CK2-mediated LRP6-S1579 phosphorylation; TGFβ regulates DAB2 translation post-transcriptionally via hnRNP E1 phosphorylation by Akt2 and controls TGFβ receptor recycling through DAB2; PKC-mediated phosphorylation of DAB2 at Ser24 is required for its inhibition of AP-1 activity; in immune cells DAB2 is a FOXP3 target gene required for Treg suppressive function and acts as a negative regulator of TLR-induced dendritic cell activation, with its expression controlled epigenetically by HDAC5-mediated H3K9 deacetylation at its promoter."},"narrative":{"mechanistic_narrative":"DAB2 is a cargo-selective clathrin adaptor that couples NPXY/FxNPXY-motif receptors of the LDL-receptor family to the endocytic machinery while also acting as a signaling scaffold that restrains growth-factor and Wnt pathways [PMID:16984970, PMID:12805222]. Its phosphotyrosine-binding (PTB/PID) domain recognizes NPXY motifs in megalin/gp600, LDLR, apoER2 and the cubam component amnionless, clustering these receptors into clathrin-coated pits independently of AP-2 and, for some cargo, ARH [PMID:10769163, PMID:16984970, PMID:16101684, PMID:20088845]. DAB2 functions through defined cargo selectivity: it routes LDLR and beta1-class inactive integrins but not NPC1L1 or alpha5/alphav integrins, and its EH-domain-binding sites recruit Eps15 and intersectin specifically to drive integrin internalization without affecting transferrin uptake [PMID:19581412, PMID:22648170, PMID:25331956]. In renal proximal tubule its localization is mutually dependent with megalin, and the endocytosis-competent p96 isoform is required for megalin trafficking and embryonic viability [PMID:16263760, PMID:15870384]. A C-terminal myosin-VI-interacting region links endocytic vesicles to the actin cytoskeleton through dynamic, high-turnover multimerization that supports cargo processivity [PMID:11967127, PMID:33372034]. DAB2 governs receptor fate beyond internalization, controlling TGFbeta receptor recycling from early endosomes and post-endocytic sorting and stability of CFTR [PMID:20881059, PMID:21995445]. As a signaling scaffold, its proline-rich domain binds the Grb2 SH3 domains to displace SOS and suppress ERK/MAPK, engages c-Src to hold it inactive, and associates with TAK1 to drive JNK activation, fibronectin induction and EMT [PMID:9569023, PMID:11371563, PMID:15894542, PMID:12473651]. DAB2 inhibits canonical Wnt/beta-catenin signaling by stabilizing the destruction complex: it binds Dishevelled-3 and Axin, blocks PP1-mediated Axin dephosphorylation, prevents LRP5/6-mediated Axin degradation, and diverts CK2-phosphorylated LRP6 into clathrin rather than caveolar endocytosis [PMID:12805222, PMID:19581931, PMID:17922036, PMID:22491013]. DAB2 activity is set by phosphorylation — PKC at Ser24 (required for AP-1 inhibition), Akt at Ser448/449 (required for albumin endocytosis), and mitotic phosphorylation that displaces it from the membrane to suppress endocytosis during division — and its protein level is controlled translationally through TGFbeta/Akt2-driven hnRNP E1 release from its 3'UTR [PMID:10542228, PMID:20154680, PMID:21097498, PMID:22218591, PMID:25253241]. In immune cells DAB2 is a FOXP3 target required for Treg suppressive function and a negative regulator of TLR-induced dendritic cell and macrophage activation, with promoter activity governed by GATA-6 and HDAC5-mediated H3K9 deacetylation [PMID:19767570, PMID:30873168, PMID:38776988, PMID:10779506].","teleology":[{"year":2000,"claim":"Established the molecular basis of DAB2 cargo recognition by showing its PTB/PID domain reads a specific NPXY motif in an LDL-receptor-family tail, defining DAB2 as a receptor-tail adaptor.","evidence":"Yeast two-hybrid, in vitro binding and Co-IP mapping DAB2-PID to the third PsiXNPXY motif of megalin; GATA-6 reporter and KO defining promoter control","pmids":["10769163","10779506"],"confidence":"High","gaps":["Did not establish whether DAB2 recruits megalin into coated pits or merely binds the tail","Mechanism of GATA-6 transactivation without its DNA-binding domain unresolved"]},{"year":2001,"claim":"Connected DAB2 to growth-factor signaling and tumor suppression by showing it competes with SOS for Grb2 and suppresses ERK, and that PKC phosphorylation at Ser24 is required for AP-1 inhibition.","evidence":"Co-IP, peptide competition, transfection rescue, ERK/AP-1 reporters; in vitro kinase assay with isoform-specific PKC and S24A mutant","pmids":["9569023","11371563","10542228","11687976"],"confidence":"High","gaps":["Did not resolve how endocytic and signaling functions are coordinated","ILK/anoikis link rests on single-lab evidence"]},{"year":2002,"claim":"Defined DAB2's in vivo physiology and its cytoskeletal coupling, showing it is needed for visceral-endoderm development and renal coated-pit/megalin trafficking and that it links vesicles to actin via myosin VI.","evidence":"Mouse KO and conditional deletion with urinalysis and EM; yeast two-hybrid, in vitro binding, Co-IP and co-localization for myosin VI; DIP1/2 GAP interaction by yeast two-hybrid","pmids":["11927540","11967127","11812785"],"confidence":"High","gaps":["Did not separate endocytic from developmental-signaling contributions to the embryonic phenotype","DIP1/2 interaction medium-confidence, single lab"]},{"year":2003,"claim":"Placed DAB2 as a negative regulator of canonical Wnt signaling and a coordinator of the clathrin coat, via Dishevelled-3 binding/Axin stabilization and CIN85 recruitment.","evidence":"cDNA screen, Co-IP, beta-catenin/TCF reporter, in vitro binding, Dab2-null MEFs; peptide-binding mapping of the PKPAPR-CIN85 interaction","pmids":["12805222","14596919"],"confidence":"High","gaps":["Did not define the biochemical step at which Axin is stabilized","CIN85 interaction medium-confidence with limited mechanistic depth"]},{"year":2005,"claim":"Defined DAB2 as a TGFbeta effector for EMT and integrin biology, linking it to beta1 integrin, FAK, and TAK1-JNK-driven fibronectin induction, and resolved the isoform requirement for megalin endocytosis.","evidence":"siRNA knockdown with species-specific rescue, FAK and JNK assays, Dab2-TAK1 Co-IP, dominant-negative TAK1; isoform-specific p96/p67 knock-in mice; reciprocal megalin/Dab2 KO and RAP internalization","pmids":["15734730","15894542","16263760","15870384","16101684"],"confidence":"High","gaps":["Did not define how DAB2 switches between integrin-adhesion and endocytosis roles","apoER2 study did not establish in vivo relevance of the clathrin route"]},{"year":2006,"claim":"Demonstrated DAB2 acts as the primary cargo-specific adaptor for LDLR clustering, AP-2-independent and parallel to ARH.","evidence":"siRNA knockdown, LDL uptake and fluorescence endocytosis assays, domain-function mutagenesis across multiple cell types","pmids":["16984970"],"confidence":"High","gaps":["Did not resolve the in vivo division of labor between DAB2 and ARH"]},{"year":2009,"claim":"Extended DAB2's adaptor role to bulk inactive-integrin endocytosis controlling migration, refined its Wnt mechanism to PP1 competition on Axin, established a clathrin-assembly activity for the p82 isoform, and identified it as a FOXP3-dependent Treg gene.","evidence":"SILAC surface proteomics + siRNA + migration assays; Co-IP and in vitro PP1 competition with zebrafish epistasis; GFP-fusion FRAP/live imaging of p82 clathrin assemblies; Treg KO with in vitro/in vivo suppression assays","pmids":["19581412","19581931","19000037","19767570"],"confidence":"High","gaps":["Did not identify the DAB2 target genes mediating Treg suppression","Did not connect integrin endocytosis quantitatively to in vivo migration"]},{"year":2010,"claim":"Established post-endocytic and translational control axes: DAB2 directs TGFbeta receptor recycling, its expression is induced via TGFbeta/Akt2-driven hnRNP E1 release from its 3'UTR, and amnionless FXNPXF motifs bind DAB2 redundantly with ARH.","evidence":"siRNA recycling/endosome morphology and Smad2 assays; RNA-protein binding, Akt2 kinase and translation reporter; yeast two-hybrid and endocytosis assays for amnionless","pmids":["20881059","20154680","20088845"],"confidence":"High","gaps":["Did not define how DAB2 selects receptors for recycling versus degradation","Amnionless interaction medium-confidence, single lab"]},{"year":2010,"claim":"Revealed cell-cycle regulation of DAB2 endocytosis through mitotic phosphorylation that displaces DAB2 from the membrane and suppresses NPXY-cargo uptake.","evidence":"Live imaging, FRAP, Co-IP, NPXY-cargo internalization, Ser/Thr-to-Ala mutagenesis with functional rescue, pharmacological mitotic arrest","pmids":["21097498"],"confidence":"High","gaps":["Did not identify the mitotic kinase responsible"]},{"year":2012,"claim":"Mechanistically dissected DAB2 cargo selectivity and trafficking: EH-domain recruitment of Eps15/intersectin drives integrin (not transferrin) internalization, CK2-phosphorylated LRP6 is routed to clathrin to block Wnt, and DAB2 controls CFTR post-endocytic sorting and stability.","evidence":"EH-binding-site mutagenesis with cargo-specific assays; LRP6-S1579A mutagenesis, clathrin/caveolin assays, zebrafish and tumor models; parallel DAB2 vs AP-2 depletion with CFTR biotinylation and half-life","pmids":["22648170","22491013","21995445"],"confidence":"High","gaps":["Did not define how EH-protein recruitment is restricted to specific cargo","Did not establish how DAB2 distinguishes recycling from degradative routing of CFTR"]},{"year":2012,"claim":"Identified Akt as a direct DAB2 kinase, phosphorylating Ser448/449 to enable albumin endocytosis and to control DAB2 subcellular distribution.","evidence":"Co-IP, GST pull-down domain mapping, yeast two-hybrid, Akt-isoform siRNA, S448/449A mutagenesis, albumin endocytosis and localization imaging","pmids":["22218591","25253241"],"confidence":"High","gaps":["Did not place Akt-DAB2 phosphorylation within a physiological signaling input in vivo"]},{"year":2014,"claim":"Resolved DAB2 control of TGFbeta receptor membrane dynamics and pathway selectivity, restricting TbetaRI lateral diffusion and clathrin uptake to suppress JNK without affecting Smad.","evidence":"Single-particle tracking/FRAP, siRNA/overexpression, JNK and Smad assays, cholesterol depletion; NPC1L1 cargo-selectivity Co-IP/knockdown showing DAB2/ARH bind LDLR but not NPC1L1","pmids":["24648493","25331956"],"confidence":"High","gaps":["Did not reconcile DAB2 promoting versus restraining TGFbeta JNK signaling across cell contexts"]},{"year":2016,"claim":"Confirmed DAB2's developmental and metabolic in vivo roles in Wnt-dependent cardiogenesis and, redundantly with ARH, in systemic cholesterol homeostasis.","evidence":"Zebrafish CRISPR KO with DKK1 rescue and cardiomyocyte counting; arh/dab2 double-KO mice with serum cholesterol and HMG-CoA reductase analysis","pmids":["26755607","27005486"],"confidence":"High","gaps":["Did not define how endothelial DAB2 signals to hepatocyte cholesterol synthesis"]},{"year":2018,"claim":"Defined a DAB2 scaffold function in vascular pathology, recruiting apoER2 and PP2A assembly machinery to inactivate Akt/eNOS in antiphospholipid antibody-induced thrombosis.","evidence":"Co-IP, PP2A methylation and Akt/eNOS phosphorylation assays, endothelial-specific mouse thrombosis model","pmids":["29500169"],"confidence":"High","gaps":["Did not establish whether this scaffold function requires DAB2 endocytic activity"]},{"year":2021,"claim":"Provided biophysical basis for DAB2-myosin VI cargo transport, showing dynamic multimerization promotes processivity while preserving cortical actin.","evidence":"Single-molecule kinetics, in vitro motility, DNA-origami cargo mimetics, reconstituted minimal actin cortex","pmids":["33372034"],"confidence":"High","gaps":["Did not show the multimerization dynamics operate in cells"]},{"year":2024,"claim":"Extended DAB2's immunoregulatory role and epigenetic control, showing HDAC5-mediated H3K9 deacetylation represses DAB2 and that DAB2 blocks macrophage M1 polarization, paralleling its negative regulation of dendritic-cell TLR responses.","evidence":"ChIP for H3K9ac, HDAC5/DAB2 siRNA-overexpression, macrophage polarization, DSS colitis model; BMDC TLR stimulation with TRIF/MyD88 analysis and immune phenotyping","pmids":["38776988","30873168"],"confidence":"Medium","gaps":["Did not define the DAB2 effector mechanism limiting inflammatory polarization","Both rest on single-lab evidence"]},{"year":2023,"claim":"Compared DAB2 against megalin and cubam in proximal-tubule albumin uptake, showing each drives endocytic flux distinctly without disrupting pathway integrity.","evidence":"Parallel CRISPR KO in a differentiated proximal-tubule line with quantitative cargo and fluid-phase assays plus megalin KO mice","pmids":["37126375"],"confidence":"High","gaps":["Did not resolve the relative contribution of DAB2 to bulk versus receptor-mediated albumin uptake"]},{"year":null,"claim":"How DAB2's distinct functions — cargo-selective endocytosis, receptor recycling, Wnt/MAPK scaffold signaling, and immune regulation — are integrated and toggled within a single cell by its phosphorylation, isoform, and expression controls remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking phosphorylation states to functional switching","No structural model of DAB2 engaging multiple partner classes","In vivo significance of many signaling-scaffold roles untested by genetic perturbation"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,3,24,28]},{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[2,3,28,30]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[3,22]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,36]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,6,13,19]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,11,22,23]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[0,11,17]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[17,25]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[2,3,11,28]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,6,13,15,26]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[32,35,38]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[3,34]}],"complexes":["clathrin coat","cubam (cubilin/amnionless) receptor complex"],"partners":["MYO6","GRB2","AXIN","DVL3","LRP6","TAK1","EPS15","ITGB1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P98082","full_name":"Disabled homolog 2","aliases":["Adaptor molecule disabled-2","Differentially expressed in ovarian carcinoma 2","DOC-2","Differentially-expressed protein 2"],"length_aa":770,"mass_kda":82.4,"function":"Adapter protein that functions as a clathrin-associated sorting protein (CLASP) required for clathrin-mediated endocytosis of selected cargo proteins. Can bind and assemble clathrin, and binds simultaneously to phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) and cargos containing non-phosphorylated NPXY internalization motifs, such as the LDL receptor, to recruit them to clathrin-coated pits. Can function in clathrin-mediated endocytosis independently of the AP-2 complex. Involved in endocytosis of integrin beta-1; this function seems to redundant with the AP-2 complex and seems to require DAB2 binding to endocytosis accessory EH domain-containing proteins such as EPS15, EPS15L1 and ITSN1. Involved in endocytosis of cystic fibrosis transmembrane conductance regulator/CFTR. Involved in endocytosis of megalin/LRP2 lipoprotein receptor during embryonal development. Required for recycling of the TGF-beta receptor. Involved in CFTR trafficking to the late endosome. Involved in several receptor-mediated signaling pathways. Involved in TGF-beta receptor signaling and facilitates phosphorylation of the signal transducer SMAD2. Mediates TFG-beta-stimulated JNK activation. May inhibit the canoniocal Wnt/beta-catenin signaling pathway by stabilizing the beta-catenin destruction complex through a competing association with axin preventing its dephosphorylation through protein phosphatase 1 (PP1). Sequesters LRP6 towards clathrin-mediated endocytosis, leading to inhibition of Wnt/beta-catenin signaling. May activate non-canonical Wnt signaling. In cell surface growth factor/Ras signaling pathways proposed to inhibit ERK activation by interrupting the binding of GRB2 to SOS1 and to inhibit SRC by preventing its activating phosphorylation at 'Tyr-419'. Proposed to be involved in modulation of androgen receptor (AR) signaling mediated by SRC activation; seems to compete with AR for interaction with SRC. Plays a role in the CSF-1 signal transduction pathway. Plays a role in cellular differentiation. Involved in cell positioning and formation of visceral endoderm (VE) during embryogenesis and proposed to be required in the VE to respond to Nodal signaling coming from the epiblast. Required for the epithelial to mesenchymal transition, a process necessary for proper embryonic development. May be involved in myeloid cell differentiation and can induce macrophage adhesion and spreading. May act as a tumor suppressor","subcellular_location":"Cytoplasm; Cytoplasmic vesicle, clathrin-coated vesicle membrane; Membrane, clathrin-coated pit","url":"https://www.uniprot.org/uniprotkb/P98082/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DAB2","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/DAB2","total_profiled":1310},"omim":[{"mim_id":"609205","title":"DAB2-INTERACTING PROTEIN; DAB2IP","url":"https://www.omim.org/entry/609205"},{"mim_id":"605747","title":"LOW DENSITY LIPOPROTEIN RECEPTOR ADAPTOR PROTEIN 1; LDLRAP1","url":"https://www.omim.org/entry/605747"},{"mim_id":"601565","title":"INTERFERON REGULATORY FACTOR 8; IRF8","url":"https://www.omim.org/entry/601565"},{"mim_id":"601236","title":"DAB ADAPTOR PROTEIN 2; DAB2","url":"https://www.omim.org/entry/601236"},{"mim_id":"108355","title":"GROWTH FACTOR RECEPTOR-BOUND PROTEIN 2; GRB2","url":"https://www.omim.org/entry/108355"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Vesicles","reliability":"Enhanced"},{"location":"Plasma membrane","reliability":"Enhanced"},{"location":"Nucleoli fibrillar center","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"kidney","ntpm":167.4},{"tissue":"placenta","ntpm":213.0}],"url":"https://www.proteinatlas.org/search/DAB2"},"hgnc":{"alias_symbol":["DOC-2"],"prev_symbol":[]},"alphafold":{"accession":"P98082","domains":[{"cath_id":"2.30.29.30","chopping":"35-177","consensus_level":"high","plddt":96.5777,"start":35,"end":177}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P98082","model_url":"https://alphafold.ebi.ac.uk/files/AF-P98082-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P98082-F1-predicted_aligned_error_v6.png","plddt_mean":53.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DAB2","jax_strain_url":"https://www.jax.org/strain/search?query=DAB2"},"sequence":{"accession":"P98082","fasta_url":"https://rest.uniprot.org/uniprotkb/P98082.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P98082/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P98082"}},"corpus_meta":[{"pmid":"20154680","id":"PMC_20154680","title":"TGF-beta-mediated phosphorylation of hnRNP E1 induces EMT via transcript-selective translational induction of Dab2 and ILEI.","date":"2010","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/20154680","citation_count":265,"is_preprint":false},{"pmid":"11967127","id":"PMC_11967127","title":"Myosin VI binds to and localises with Dab2, potentially linking receptor-mediated endocytosis and the actin cytoskeleton.","date":"2002","source":"Traffic (Copenhagen, Denmark)","url":"https://pubmed.ncbi.nlm.nih.gov/11967127","citation_count":204,"is_preprint":false},{"pmid":"11927540","id":"PMC_11927540","title":"Dual roles for the Dab2 adaptor protein in embryonic development and kidney transport.","date":"2002","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/11927540","citation_count":170,"is_preprint":false},{"pmid":"16984970","id":"PMC_16984970","title":"The adaptor protein Dab2 sorts LDL receptors into coated pits independently of AP-2 and ARH.","date":"2006","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/16984970","citation_count":147,"is_preprint":false},{"pmid":"9620555","id":"PMC_9620555","title":"DOC-2, a candidate tumor suppressor gene in human epithelial ovarian cancer.","date":"1998","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/9620555","citation_count":143,"is_preprint":false},{"pmid":"11812785","id":"PMC_11812785","title":"The mechanism of growth-inhibitory effect of DOC-2/DAB2 in prostate cancer. 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In HeLa cells and fibroblasts, Dab2 is the primary adaptor for LDLR internalization, whereas ARH can compensate but requires AP-2.\",\n      \"method\": \"siRNA knockdown, fluorescence endocytosis assays, LDL uptake assays, domain-function mutagenesis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple cell types, domain mutants, epistatic knockdown combinations with defined cargo phenotype\",\n      \"pmids\": [\"16984970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Dab2 N-terminal domain interacts with Dishevelled-3 (Dvl-3) and negatively regulates canonical Wnt/beta-catenin signaling; Dab2 overexpression maintains Dab2-Dvl-3 association, disrupts Dvl-3-axin interaction, stabilizes axin, and reduces nuclear beta-catenin and cyclin D1. Dab2-null MEFs exhibit constitutive Wnt signaling.\",\n      \"method\": \"Small-pool cDNA screen, co-immunoprecipitation, beta-catenin/TCF reporter assay, in vitro binding assay, Dab2 KO MEFs\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods, genetic KO corroborates overexpression findings, pathway placement via epistasis\",\n      \"pmids\": [\"12805222\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Dab2 binds the SH3 domains of Grb2 via its C-terminal proline-rich domain (residues 600-730, key site #661-669), competing with Sos for Grb2 binding; both SH3 domains of Grb2 are required cooperatively for binding to Dab2.\",\n      \"method\": \"Co-immunoprecipitation from macrophage lysates, transfection competition assay in 293 cells, peptide inhibition, domain-binding experiments\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple complementary binding assays, functional competition experiment, domain mapping\",\n      \"pmids\": [\"9569023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"DOC-2/DAB2 suppresses ERK phosphorylation by binding Grb2 via its second proline-rich domain in a growth-factor-stimulated manner, thereby interrupting the Grb2-SOS interaction and blocking downstream MAPK signaling; reduced ERK phosphorylation is rescued by increasing Grb2 expression or using a specific blocking peptide.\",\n      \"method\": \"Peptide competition, transfection rescue, co-immunoprecipitation, ERK phosphorylation assay, AP-1 reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal biochemical assays with domain specificity and functional rescue\",\n      \"pmids\": [\"11371563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"PKC (specifically PKCbetaII, PKCgamma, and PKCdelta) directly phosphorylates Dab2 at Ser24; mutation of Ser24 to Ala abolishes PKC-induced phosphorylation and abrogates TPA-induced AP-1 inhibition, indicating that Ser24 phosphorylation is required for Dab2's growth-inhibitory function.\",\n      \"method\": \"In vitro kinase assay with recombinant substrates and isoform-specific PKC, site-directed mutagenesis (S24A), AP-1 reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro phosphorylation with purified kinases, mutagenesis with functional readout\",\n      \"pmids\": [\"10542228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"TGFbeta induces Dab2 expression and increases its binding to beta1 integrin at the membrane; siRNA silencing of Dab2 inhibits integrin activation (reduced focal adhesion kinase phosphorylation), cell adherence, and TGFbeta-mediated EMT, while re-expression of human Dab2 rescues these effects. Dab2 ablation also blocks retinoic acid-induced visceral endoderm differentiation.\",\n      \"method\": \"siRNA knockdown, siRNA rescue (species-specific), FAK phosphorylation assay, cell adhesion assay, F9 differentiation model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — siRNA knockdown with rescue, multiple cell systems, defined molecular readouts\",\n      \"pmids\": [\"15734730\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Dab2 directly stimulates JNK activity and is required for TGFbeta-mediated fibronectin induction and cell migration; TGFbeta stimulates association of Dab2 with the MAP3K TAK1, and attenuation of TAK1 abolishes TGFbeta-induced fibronectin induction.\",\n      \"method\": \"siRNA stable knockdown, JNK kinase assay, co-immunoprecipitation (Dab2-TAK1), dominant-negative TAK1, fibronectin induction assay, cell migration assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods, co-IP of endogenous proteins, dominant-negative epistasis, rescue\",\n      \"pmids\": [\"15894542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Dab2 p96 isoform, which retains endocytic protein-binding sites absent from p67, is required for efficient megalin endocytosis in visceral endoderm; knock-in of p96 fully rescues endocytosis and embryonic viability, while p67 only partially rescues.\",\n      \"method\": \"Isoform-specific knock-in mice, endocytosis assays (transferrin/cubilin uptake), embryonic viability scoring\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo isoform-specific knock-in rescue with defined molecular mechanism\",\n      \"pmids\": [\"16263760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"In renal proximal tubule, Dab2 co-localizes with megalin in clathrin-coated pits/vesicles; megalin knockout nearly abolishes Dab2 staining (Dab2 localization requires megalin), and Dab2 knockout redistributes megalin from endosomes to microvilli with decreased total megalin protein. Introduction of anti-Dab2 antibody into BN16 cells decreased internalization of receptor-associated protein.\",\n      \"method\": \"Immunohistochemistry, megalin/Dab2 conditional knockout mice, immunoblotting, intracellular antibody injection, 125I-RAP internalization assay\",\n      \"journal\": \"American journal of physiology. Renal physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal KO phenotyping plus functional internalization assay, mutually dependent localization established\",\n      \"pmids\": [\"15870384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Dab2 mediates bulk endocytosis of inactive integrins beta1, alpha1, alpha2, and alpha3 (but not alpha5 or alphav) into coated pits; Dab2 depletion inhibits cell migration and polarized recycling of integrin beta1 to the leading edge, and migration speed correlates with intracellular integrin pool size.\",\n      \"method\": \"Quantitative glycoprotein surface proteomics (SILAC), siRNA depletion, fluorescence microscopy, integrin beta1 surface/intracellular level manipulation, migration assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — unbiased quantitative proteomics plus functional migration/localization assays\",\n      \"pmids\": [\"19581412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Dab2 attenuates Wnt/beta-catenin signaling by binding to Axin and acting as a competitive inhibitor of PP1, preventing PP1-mediated dephosphorylation and destabilization of Axin. The N-terminal PTB domain of Dab2 is sufficient to block PP1-Axin interactions; Dab2 overexpression in zebrafish phenocopies Axin overexpression.\",\n      \"method\": \"Co-immunoprecipitation, in vitro binding competition assay, Dab2 truncation mutants, beta-catenin reporter assay, Dab2 ectopic expression in zebrafish embryos\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro competition binding, cell-based pathway assays, and in vivo zebrafish epistasis\",\n      \"pmids\": [\"19581931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Dab2 interacts with Axin and prevents Axin's interaction with and degradation by LRP5/6 Wnt co-receptor, thereby increasing Axin half-life and stabilizing the beta-catenin destruction complex to inhibit Wnt signaling.\",\n      \"method\": \"Co-immunoprecipitation, Axin half-life assay, beta-catenin reporter assay, F9 and mammary cell differentiation models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, protein half-life measurements, multiple cellular contexts\",\n      \"pmids\": [\"17922036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Dab2 selectively recruits LRP6 to the clathrin-dependent endocytic pathway upon CK2-mediated phosphorylation of LRP6 at S1579, sequestering LRP6 from caveolin-dependent endocytosis required for Wnt signaling. LRP6-S1579A mutant fails to bind Dab2, escapes clathrin routing, and is insensitive to Dab2-mediated Wnt inhibition.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis (LRP6-S1579A), clathrin/caveolin endocytosis assays, Wnt reporter assay, zebrafish dorsoventral patterning, allograft mouse tumor model\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mutagenesis of phospho-site, Co-IP, multiple functional assays in vitro and in vivo\",\n      \"pmids\": [\"22491013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TGFbeta induces phosphorylation of hnRNP E1 at Ser43 by PKBbeta/Akt2, releasing hnRNP E1 from the 33-nucleotide BAT element in the 3'UTR of Dab2 (and ILEI) mRNAs, thereby relieving translational repression and inducing Dab2 protein expression as part of a post-transcriptional EMT regulon.\",\n      \"method\": \"RNA-protein binding assay, phospho-specific immunoblot, siRNA modulation of hnRNP E1, Akt2 kinase assay, translation reporter assay\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro kinase assay, RNA-protein interaction mapping, siRNA modulation with translational functional readout\",\n      \"pmids\": [\"20154680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Dab2 knockdown does not affect internalization of TGFbeta, LDL, or transferrin but abrogates TGFbeta receptor recycling from early endosomes to the recycling compartment, resulting in enlarged EEA1-positive endosomes and diminished Smad2 phosphorylation.\",\n      \"method\": \"siRNA knockdown, endosome morphology (EEA1 immunofluorescence), receptor recycling assay, Smad2 phosphorylation assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal trafficking and signaling assays, negative control cargoes used\",\n      \"pmids\": [\"20881059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"DOC-2/DAB2 interacts with DIP1/2, a novel GTPase-activating protein with a Ras GAP homology domain, via the N-terminal domain of DOC-2/DAB2; this complex is detected in normal brain and prostate. DIP1/2 expression blocks mitogen-induced gene expression and inhibits prostate cancer cell growth.\",\n      \"method\": \"Yeast two-hybrid cloning, co-immunoprecipitation from tissue lysates, cell growth assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP confirmed interaction, functional growth assay, but single lab\",\n      \"pmids\": [\"11812785\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"DOC-2/DAB2 proline-rich domain interacts with the SH3 domain of c-Src; this binding is enhanced by growth factor and results in c-Src inactivation (decreased pTyr416) and reduced downstream effector activity.\",\n      \"method\": \"Co-immunoprecipitation, c-Src kinase activity assay (pTyr416), growth factor stimulation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with functional kinase readout, single lab, single paper\",\n      \"pmids\": [\"12473651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"DOC-2/hDab-2 expression in breast cancer cells induces anoikis associated with down-regulation of integrin-linked kinase (ILK) activity, suggesting Dab2 negatively regulates the ILK anti-apoptotic pathway.\",\n      \"method\": \"Transfection, suspension-induced cell death (anoikis) assay, ILK kinase activity assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined kinase activity readout, single lab\",\n      \"pmids\": [\"11687976\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Dab2 associates with CIN85 via its PKPAPR motif in the C-terminus, recruiting CIN85 to the clathrin coat; growth factor stimulation dissociates Dab2 and clathrin from CIN85, enabling Cbl to bind CIN85 during receptor tyrosine kinase endocytosis.\",\n      \"method\": \"Co-immunoprecipitation, peptide binding assay, growth factor stimulation time-course\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP plus peptide binding, but limited mechanistic depth, single lab\",\n      \"pmids\": [\"14596919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The p82 isoform of Dab2 induces enlarged clathrin assemblies at the plasma membrane dependent on a functional PTB domain, clathrin binding, phospholipid binding, and a poly-lysine stretch preceding the PTB domain; p82 expression also enhances cell spreading on fibronectin and concentrates beta1 integrin into clathrin-p82 assemblies.\",\n      \"method\": \"GFP-fusion expression, live-cell imaging, FRAP, clathrin assembly morphology, site-directed mutagenesis, fibronectin spreading assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple domain mutants, live imaging, FRAP dynamics, multiple cell lines\",\n      \"pmids\": [\"19000037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Dab2 is progressively displaced from the plasma membrane and loses co-localization with clathrin during mitosis, peaking at metaphase/anaphase; this displacement is accompanied by Dab2 phosphorylation, reduced Dab2-clathrin interactions, decreased endocytic vesicle motility, and impaired internalization of NPXY-containing cargo. Ser/Thr-to-Ala mutations in the central region of Dab2 attenuate its phosphorylation and membrane displacement, maintaining endocytic activity during mitosis.\",\n      \"method\": \"Live-cell imaging, immunofluorescence, FRAP, co-immunoprecipitation, NPXY-cargo internalization assay, site-directed mutagenesis (Ser/Thr→Ala), pharmacological mitotic arrest (2-methoxyestradiol)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods, mutagenesis with functional rescue, mechanistic link between phosphorylation and membrane displacement/endocytic activity\",\n      \"pmids\": [\"21097498\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Dab2 binds Eps15 and intersectin via its EH-domain binding sites; mutation of these sites impairs integrin beta1 endocytosis (but not transferrin receptor) without displacing Dab2 from clathrin structures, indicating that Dab2-mediated recruitment of EH domain proteins selectively drives internalization of Dab2 cargo.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis (EH-binding site mutants), integrin beta1 and transferrin endocytosis assay, clathrin structure analysis\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — EH-binding site mutagenesis with cargo-specific functional readout, multiple assays in single study\",\n      \"pmids\": [\"22648170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Dab2 depletion in airway epithelial cells inhibits CFTR endocytosis and post-endocytic trafficking from sorting endosome to recycling compartment and to late endosome, resulting in increased CFTR half-life (~3-fold); this is distinct from AP-2 depletion which primarily reduces endocytosis without affecting CFTR stability.\",\n      \"method\": \"siRNA depletion of Dab2 vs. AP-2, CFTR surface biotinylation, endocytosis assay, recycling assay, protein half-life measurement\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — parallel depletion of two adaptors with distinct mechanistic effects on multiple trafficking steps\",\n      \"pmids\": [\"21995445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Dab2 interacts with TGFbeta type I receptor (TbetaRI), restricts its lateral diffusion at the plasma membrane, and enhances clathrin-mediated endocytosis of TbetaRI; Dab2 negatively regulates TGFbeta-induced JNK activation but not Smad pathway activation. JNK activation by TGFbeta in the absence of Dab2 is disrupted by cholesterol depletion, indicating TbetaRI localizes to cholesterol-rich domains when Dab2 is absent.\",\n      \"method\": \"Biophysical lateral diffusion measurements (SPT/FRAP), siRNA knockdown and overexpression, JNK and Smad phosphorylation assays, cholesterol depletion\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — biophysical receptor mobility measurements, receptor endocytosis assay, pathway-selective signaling readouts with mechanistic model\",\n      \"pmids\": [\"24648493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In endothelial cells, Dab2 recruitment to the apoER2 NPXY motif promotes activating L309 methylation of the PP2A catalytic subunit by LCMT-1; simultaneously, SHC1 recruits the PP2A scaffolding subunit to the proline-rich apoER2 C-terminus, forming a PP2A holoenzyme that dephosphorylates (inactivates) Akt and eNOS, mediating antiphospholipid antibody-induced thrombosis.\",\n      \"method\": \"Co-immunoprecipitation, PP2A methylation assay, Akt/eNOS phosphorylation assays, mouse thrombosis model with endothelial-specific manipulation\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — biochemical dissection of complex assembly, defined enzymatic modification, in vivo mouse thrombosis model\",\n      \"pmids\": [\"29500169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"ApoER2 internalizes via clathrin-mediated endocytosis through its cytoplasmic FxNPXY motif binding to Dab2; dominant-negative Dab2 and eps15 reduce apoER2 internalization, whereas blocking caveolar/raft pathway (nystatin) has no effect. Raft association of apoER2 does not determine its endocytic route.\",\n      \"method\": \"Dominant-negative Dab2 and eps15 expression, nystatin treatment, apoER2 internalization assay, mutagenesis of FxNPXY motif\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — dominant-negative and pharmacological inhibition with defined pathway distinction, motif mutagenesis\",\n      \"pmids\": [\"16101684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Amnionless (AMN) FXNPXF motifs in cubam receptor mediate endocytosis through direct interaction with Dab2 and ARH; the two signals are functionally redundant, demonstrated by sequential mutation and yeast two-hybrid analyses.\",\n      \"method\": \"Yeast two-hybrid, amnionless mutant expression panel, endocytosis assay\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid and functional endocytosis assay, single lab\",\n      \"pmids\": [\"20088845\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ARH and Dab2 both bind LDLR but not NPC1L1, and are not required for NPC1L1 internalization; Numb specifically binds NPC1L1 and mediates cholesterol absorption, distinctly from ARH and Dab2 which selectively participate in LDLR-mediated LDL uptake.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, LDL and cholesterol uptake assays, domain-specific PTB binding studies\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — receptor-specific binding and knockdown studies with multiple controls establishing cargo selectivity\",\n      \"pmids\": [\"25331956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Akt/PKB interacts with the proline-rich domain (PRD) of Dab2 via its PH and catalytic domains, and phosphorylates Dab2 at Ser448 and Ser449; Ser-to-Ala mutations at these sites inhibit albumin endocytosis and shift Dab2 localization from peripheral to perinuclear compartment, demonstrating that Akt-mediated Dab2 phosphorylation is required for albumin endocytosis.\",\n      \"method\": \"Co-immunoprecipitation, GST pull-down with truncated constructs, yeast two-hybrid, Akt isoform-specific siRNA, Dab2 Ser448/449Ala mutagenesis, albumin endocytosis assay, Dab2 localization imaging\",\n      \"journal\": \"American journal of physiology. Renal physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro pull-down domain mapping, yeast two-hybrid, mutagenesis with localization and functional readout\",\n      \"pmids\": [\"22218591\", \"25253241\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Dab2 is a FOXP3 target gene exclusively expressed in FOXP3+ regulatory T cells; regulatory T cells lacking Dab2 are functionally impaired in vitro and in vivo (suppressive capacity), but Dab2 is dispensable for Treg-mediated naive T cell homeostasis.\",\n      \"method\": \"Flow cytometry, genetic KO of Dab2 in Tregs, in vitro suppression assay, in vivo adoptive transfer\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with in vitro and in vivo functional readouts, exclusive expression established by flow cytometry\",\n      \"pmids\": [\"19767570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"DAB2 loss in zebrafish (CRISPR/Cas9 KO) reduces cardiomyocyte number and increases WNT/beta-catenin signaling; these defects are suppressed by DKK1 overexpression, placing DAB2 upstream of WNT signaling in cardiac development.\",\n      \"method\": \"CRISPR/Cas9 knockout in zebrafish, cardiomyocyte counting, WNT/beta-catenin signaling assay, DKK1 rescue experiment, label-free quantitative proteomics in human ESC differentiation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR KO with in vivo genetic epistasis (DKK1 rescue), defined cellular phenotype\",\n      \"pmids\": [\"26755607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Combined deletion of Dab2 and Arh in mice results in profound hypercholesterolemia similar to LDLR knockout; in liver, Dab2 is expressed in sinusoidal endothelial cells (not hepatocytes) and in the absence of Arh, Dab2 in liver endothelial cells regulates cholesterol synthesis (HMG-CoA reductase levels) in hepatocytes.\",\n      \"method\": \"Double KO mice (arh/dab2), serum cholesterol measurement, HMG-CoA reductase western blot, cell-type-specific immunostaining\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — double KO genetic epistasis, comparison to LDLR KO, cell-type-specific localization\",\n      \"pmids\": [\"27005486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DAB2 expression in dendritic cells is rapidly downregulated by TLR ligands in a TRIF- and MyD88-dependent biphasic manner (rapid protein drop then sustained mRNA reduction); DAB2 knockdown promotes activated DC phenotype (increased IL-12, IL-6, CD40), reduces phagocytosis, and Dab2-KO DCs inhibit autophagy and promote apoptotic cell death.\",\n      \"method\": \"BMDC TLR stimulation, siRNA/KO, qPCR, flow cytometry, cytokine ELISA, autophagy assay, TRIF/MyD88 pathway analysis\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple complementary assays linking TLR signaling pathway to Dab2 regulation with functional immune phenotype\",\n      \"pmids\": [\"30873168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Dab2 myosin interacting region (MIR) binds myosin VI with moderate affinity (Kd ~184 nM) and high turnover rate (~1 s-1); dynamic (not stable) multimerization of Dab2-MIR/myosin VI complexes promotes cargo processivity on actin while preserving cortical actin network integrity. Constitutive stable dimers cause actin reorganization and foci formation.\",\n      \"method\": \"Single-molecule kinetics, in vitro motility assay, DNA origami scaffold-based cargo mimetics, minimal actin cortex assay on lipid bilayers, fluorescence microscopy\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted in vitro single-molecule kinetics, structural scaffolds, actin cortex reconstitution\",\n      \"pmids\": [\"33372034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"DAB2 silencing in human endothelial cells activates Src-FAK signaling, ERK and JNK activation, inhibits p38 phosphorylation, and promotes cell proliferation/migration while impairing capillary-like morphogenesis; pharmacological Src inhibition (PP2) abolishes FAK activation and restores endothelial differentiation.\",\n      \"method\": \"Lentiviral shRNA knockdown, Src/FAK phosphorylation assay, ERK/JNK/p38 immunoblot, endothelial tube formation assay, PP2 pharmacological rescue\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — shRNA knockdown with multiple pathway readouts and pharmacological rescue, single lab\",\n      \"pmids\": [\"18582465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HDAC5 deacetylates H3K9ac at the DAB2 promoter, repressing DAB2 expression; A. muciniphila inhibits HDAC5, thereby increasing DAB2 expression, which blocks macrophage pro-inflammatory M1 polarization. DAB2 overexpression reverses HDAC5-induced pro-inflammatory polarization.\",\n      \"method\": \"ChIP for H3K9ac, siRNA/overexpression of HDAC5 and DAB2, macrophage polarization assay, in vivo DSS colitis model with A. muciniphila treatment\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP establishes epigenetic mechanism, functional rescue in vitro and in vivo, single lab\",\n      \"pmids\": [\"38776988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"GATA-6 (but not GATA-4) transcriptionally activates the Dab2 promoter in visceral endoderm; GATA-6-null ES cells lack Dab2 expression, and forced GATA-6 expression in NIH-3T3 cells transactivates the human Dab2 promoter. The specificity is not mediated through GATA-6's zinc finger DNA-binding domain.\",\n      \"method\": \"Subtractive hybridization, in vivo GATA-6 KO embryos, co-transfection reporter assay, GATA-4 KO embryos as negative control\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay plus in vivo KO validation, but mechanism of GATA-6 action (without DNA-binding domain) incompletely resolved\",\n      \"pmids\": [\"10779506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In kidney proximal tubule cells, megalin, cubilin/amnionless (CUBAM), and Dab2 each have distinct roles in albumin endocytosis and endocytic pathway flux; CRISPR KO of each component has different effects on albumin uptake concentration-dependence and intracellular distribution, but key endocytic pathway proteins are preserved in all KOs, indicating these components drive endocytic flux without compromising pathway integrity.\",\n      \"method\": \"CRISPR/Cas9 KO in differentiated proximal tubule cell line, albumin internalization assay, fluid-phase marker uptake, confocal imaging, megalin KO mice\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — parallel CRISPR KO of three components with quantitative cargo uptake assays and in vivo megalin KO comparison\",\n      \"pmids\": [\"37126375\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DAB2 (DOC-2) is a multifunctional endocytic adaptor protein whose PTB/PID domain binds NPXY motifs in LDL receptor family members (megalin, LDLR, apoER2, LRP6, amnionless/cubam), recruiting them into clathrin-coated pits together with clathrin, AP-2, myosin VI, Eps15, and intersectin to mediate receptor-specific endocytosis; its proline-rich C-terminal domain engages Grb2 SH3 domains (displacing SOS to suppress MAPK/ERK), c-Src SH3 (maintaining Src in an inactive conformation), TAK1 (activating JNK for fibronectin induction and EMT), and Akt (which phosphorylates Dab2 at Ser448/449 to promote albumin endocytosis); DAB2 inhibits canonical Wnt/beta-catenin signaling by binding Dvl-3 and Axin—stabilizing the destruction complex by blocking PP1-mediated Axin dephosphorylation—and by recruiting LRP6 to clathrin (rather than caveolin) endocytosis after CK2-mediated LRP6-S1579 phosphorylation; TGFβ regulates DAB2 translation post-transcriptionally via hnRNP E1 phosphorylation by Akt2 and controls TGFβ receptor recycling through DAB2; PKC-mediated phosphorylation of DAB2 at Ser24 is required for its inhibition of AP-1 activity; in immune cells DAB2 is a FOXP3 target gene required for Treg suppressive function and acts as a negative regulator of TLR-induced dendritic cell activation, with its expression controlled epigenetically by HDAC5-mediated H3K9 deacetylation at its promoter.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DAB2 is a cargo-selective clathrin adaptor that couples NPXY/FxNPXY-motif receptors of the LDL-receptor family to the endocytic machinery while also acting as a signaling scaffold that restrains growth-factor and Wnt pathways [#3, #4]. Its phosphotyrosine-binding (PTB/PID) domain recognizes NPXY motifs in megalin/gp600, LDLR, apoER2 and the cubam component amnionless, clustering these receptors into clathrin-coated pits independently of AP-2 and, for some cargo, ARH [#2, #3, #28, #29]. DAB2 functions through defined cargo selectivity: it routes LDLR and beta1-class inactive integrins but not NPC1L1 or alpha5/alphav integrins, and its EH-domain-binding sites recruit Eps15 and intersectin specifically to drive integrin internalization without affecting transferrin uptake [#12, #24, #30]. In renal proximal tubule its localization is mutually dependent with megalin, and the endocytosis-competent p96 isoform is required for megalin trafficking and embryonic viability [#10, #11]. A C-terminal myosin-VI-interacting region links endocytic vesicles to the actin cytoskeleton through dynamic, high-turnover multimerization that supports cargo processivity [#0, #36]. DAB2 governs receptor fate beyond internalization, controlling TGFbeta receptor recycling from early endosomes and post-endocytic sorting and stability of CFTR [#17, #25]. As a signaling scaffold, its proline-rich domain binds the Grb2 SH3 domains to displace SOS and suppress ERK/MAPK, engages c-Src to hold it inactive, and associates with TAK1 to drive JNK activation, fibronectin induction and EMT [#5, #6, #9, #19]. DAB2 inhibits canonical Wnt/beta-catenin signaling by stabilizing the destruction complex: it binds Dishevelled-3 and Axin, blocks PP1-mediated Axin dephosphorylation, prevents LRP5/6-mediated Axin degradation, and diverts CK2-phosphorylated LRP6 into clathrin rather than caveolar endocytosis [#4, #13, #14, #15]. DAB2 activity is set by phosphorylation — PKC at Ser24 (required for AP-1 inhibition), Akt at Ser448/449 (required for albumin endocytosis), and mitotic phosphorylation that displaces it from the membrane to suppress endocytosis during division — and its protein level is controlled translationally through TGFbeta/Akt2-driven hnRNP E1 release from its 3'UTR [#7, #16, #23, #31]. In immune cells DAB2 is a FOXP3 target required for Treg suppressive function and a negative regulator of TLR-induced dendritic cell and macrophage activation, with promoter activity governed by GATA-6 and HDAC5-mediated H3K9 deacetylation [#32, #35, #38, #39].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established the molecular basis of DAB2 cargo recognition by showing its PTB/PID domain reads a specific NPXY motif in an LDL-receptor-family tail, defining DAB2 as a receptor-tail adaptor.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro binding and Co-IP mapping DAB2-PID to the third PsiXNPXY motif of megalin; GATA-6 reporter and KO defining promoter control\",\n      \"pmids\": [\"10769163\", \"10779506\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish whether DAB2 recruits megalin into coated pits or merely binds the tail\", \"Mechanism of GATA-6 transactivation without its DNA-binding domain unresolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Connected DAB2 to growth-factor signaling and tumor suppression by showing it competes with SOS for Grb2 and suppresses ERK, and that PKC phosphorylation at Ser24 is required for AP-1 inhibition.\",\n      \"evidence\": \"Co-IP, peptide competition, transfection rescue, ERK/AP-1 reporters; in vitro kinase assay with isoform-specific PKC and S24A mutant\",\n      \"pmids\": [\"9569023\", \"11371563\", \"10542228\", \"11687976\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how endocytic and signaling functions are coordinated\", \"ILK/anoikis link rests on single-lab evidence\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defined DAB2's in vivo physiology and its cytoskeletal coupling, showing it is needed for visceral-endoderm development and renal coated-pit/megalin trafficking and that it links vesicles to actin via myosin VI.\",\n      \"evidence\": \"Mouse KO and conditional deletion with urinalysis and EM; yeast two-hybrid, in vitro binding, Co-IP and co-localization for myosin VI; DIP1/2 GAP interaction by yeast two-hybrid\",\n      \"pmids\": [\"11927540\", \"11967127\", \"11812785\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not separate endocytic from developmental-signaling contributions to the embryonic phenotype\", \"DIP1/2 interaction medium-confidence, single lab\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Placed DAB2 as a negative regulator of canonical Wnt signaling and a coordinator of the clathrin coat, via Dishevelled-3 binding/Axin stabilization and CIN85 recruitment.\",\n      \"evidence\": \"cDNA screen, Co-IP, beta-catenin/TCF reporter, in vitro binding, Dab2-null MEFs; peptide-binding mapping of the PKPAPR-CIN85 interaction\",\n      \"pmids\": [\"12805222\", \"14596919\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the biochemical step at which Axin is stabilized\", \"CIN85 interaction medium-confidence with limited mechanistic depth\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined DAB2 as a TGFbeta effector for EMT and integrin biology, linking it to beta1 integrin, FAK, and TAK1-JNK-driven fibronectin induction, and resolved the isoform requirement for megalin endocytosis.\",\n      \"evidence\": \"siRNA knockdown with species-specific rescue, FAK and JNK assays, Dab2-TAK1 Co-IP, dominant-negative TAK1; isoform-specific p96/p67 knock-in mice; reciprocal megalin/Dab2 KO and RAP internalization\",\n      \"pmids\": [\"15734730\", \"15894542\", \"16263760\", \"15870384\", \"16101684\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define how DAB2 switches between integrin-adhesion and endocytosis roles\", \"apoER2 study did not establish in vivo relevance of the clathrin route\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrated DAB2 acts as the primary cargo-specific adaptor for LDLR clustering, AP-2-independent and parallel to ARH.\",\n      \"evidence\": \"siRNA knockdown, LDL uptake and fluorescence endocytosis assays, domain-function mutagenesis across multiple cell types\",\n      \"pmids\": [\"16984970\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the in vivo division of labor between DAB2 and ARH\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Extended DAB2's adaptor role to bulk inactive-integrin endocytosis controlling migration, refined its Wnt mechanism to PP1 competition on Axin, established a clathrin-assembly activity for the p82 isoform, and identified it as a FOXP3-dependent Treg gene.\",\n      \"evidence\": \"SILAC surface proteomics + siRNA + migration assays; Co-IP and in vitro PP1 competition with zebrafish epistasis; GFP-fusion FRAP/live imaging of p82 clathrin assemblies; Treg KO with in vitro/in vivo suppression assays\",\n      \"pmids\": [\"19581412\", \"19581931\", \"19000037\", \"19767570\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the DAB2 target genes mediating Treg suppression\", \"Did not connect integrin endocytosis quantitatively to in vivo migration\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Established post-endocytic and translational control axes: DAB2 directs TGFbeta receptor recycling, its expression is induced via TGFbeta/Akt2-driven hnRNP E1 release from its 3'UTR, and amnionless FXNPXF motifs bind DAB2 redundantly with ARH.\",\n      \"evidence\": \"siRNA recycling/endosome morphology and Smad2 assays; RNA-protein binding, Akt2 kinase and translation reporter; yeast two-hybrid and endocytosis assays for amnionless\",\n      \"pmids\": [\"20881059\", \"20154680\", \"20088845\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define how DAB2 selects receptors for recycling versus degradation\", \"Amnionless interaction medium-confidence, single lab\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Revealed cell-cycle regulation of DAB2 endocytosis through mitotic phosphorylation that displaces DAB2 from the membrane and suppresses NPXY-cargo uptake.\",\n      \"evidence\": \"Live imaging, FRAP, Co-IP, NPXY-cargo internalization, Ser/Thr-to-Ala mutagenesis with functional rescue, pharmacological mitotic arrest\",\n      \"pmids\": [\"21097498\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the mitotic kinase responsible\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Mechanistically dissected DAB2 cargo selectivity and trafficking: EH-domain recruitment of Eps15/intersectin drives integrin (not transferrin) internalization, CK2-phosphorylated LRP6 is routed to clathrin to block Wnt, and DAB2 controls CFTR post-endocytic sorting and stability.\",\n      \"evidence\": \"EH-binding-site mutagenesis with cargo-specific assays; LRP6-S1579A mutagenesis, clathrin/caveolin assays, zebrafish and tumor models; parallel DAB2 vs AP-2 depletion with CFTR biotinylation and half-life\",\n      \"pmids\": [\"22648170\", \"22491013\", \"21995445\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define how EH-protein recruitment is restricted to specific cargo\", \"Did not establish how DAB2 distinguishes recycling from degradative routing of CFTR\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified Akt as a direct DAB2 kinase, phosphorylating Ser448/449 to enable albumin endocytosis and to control DAB2 subcellular distribution.\",\n      \"evidence\": \"Co-IP, GST pull-down domain mapping, yeast two-hybrid, Akt-isoform siRNA, S448/449A mutagenesis, albumin endocytosis and localization imaging\",\n      \"pmids\": [\"22218591\", \"25253241\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not place Akt-DAB2 phosphorylation within a physiological signaling input in vivo\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Resolved DAB2 control of TGFbeta receptor membrane dynamics and pathway selectivity, restricting TbetaRI lateral diffusion and clathrin uptake to suppress JNK without affecting Smad.\",\n      \"evidence\": \"Single-particle tracking/FRAP, siRNA/overexpression, JNK and Smad assays, cholesterol depletion; NPC1L1 cargo-selectivity Co-IP/knockdown showing DAB2/ARH bind LDLR but not NPC1L1\",\n      \"pmids\": [\"24648493\", \"25331956\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not reconcile DAB2 promoting versus restraining TGFbeta JNK signaling across cell contexts\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Confirmed DAB2's developmental and metabolic in vivo roles in Wnt-dependent cardiogenesis and, redundantly with ARH, in systemic cholesterol homeostasis.\",\n      \"evidence\": \"Zebrafish CRISPR KO with DKK1 rescue and cardiomyocyte counting; arh/dab2 double-KO mice with serum cholesterol and HMG-CoA reductase analysis\",\n      \"pmids\": [\"26755607\", \"27005486\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define how endothelial DAB2 signals to hepatocyte cholesterol synthesis\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined a DAB2 scaffold function in vascular pathology, recruiting apoER2 and PP2A assembly machinery to inactivate Akt/eNOS in antiphospholipid antibody-induced thrombosis.\",\n      \"evidence\": \"Co-IP, PP2A methylation and Akt/eNOS phosphorylation assays, endothelial-specific mouse thrombosis model\",\n      \"pmids\": [\"29500169\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish whether this scaffold function requires DAB2 endocytic activity\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided biophysical basis for DAB2-myosin VI cargo transport, showing dynamic multimerization promotes processivity while preserving cortical actin.\",\n      \"evidence\": \"Single-molecule kinetics, in vitro motility, DNA-origami cargo mimetics, reconstituted minimal actin cortex\",\n      \"pmids\": [\"33372034\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not show the multimerization dynamics operate in cells\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended DAB2's immunoregulatory role and epigenetic control, showing HDAC5-mediated H3K9 deacetylation represses DAB2 and that DAB2 blocks macrophage M1 polarization, paralleling its negative regulation of dendritic-cell TLR responses.\",\n      \"evidence\": \"ChIP for H3K9ac, HDAC5/DAB2 siRNA-overexpression, macrophage polarization, DSS colitis model; BMDC TLR stimulation with TRIF/MyD88 analysis and immune phenotyping\",\n      \"pmids\": [\"38776988\", \"30873168\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define the DAB2 effector mechanism limiting inflammatory polarization\", \"Both rest on single-lab evidence\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Compared DAB2 against megalin and cubam in proximal-tubule albumin uptake, showing each drives endocytic flux distinctly without disrupting pathway integrity.\",\n      \"evidence\": \"Parallel CRISPR KO in a differentiated proximal-tubule line with quantitative cargo and fluid-phase assays plus megalin KO mice\",\n      \"pmids\": [\"37126375\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the relative contribution of DAB2 to bulk versus receptor-mediated albumin uptake\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How DAB2's distinct functions — cargo-selective endocytosis, receptor recycling, Wnt/MAPK scaffold signaling, and immune regulation — are integrated and toggled within a single cell by its phosphorylation, isoform, and expression controls remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking phosphorylation states to functional switching\", \"No structural model of DAB2 engaging multiple partner classes\", \"In vivo significance of many signaling-scaffold roles untested by genetic perturbation\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 3, 24, 28]},\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [2, 3, 28, 30]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [3, 22]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 36]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 6, 13, 19]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 11, 22, 23]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [0, 11, 17]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [17, 25]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [2, 3, 11, 28]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 6, 13, 15, 26]},\n      {\"term_id\": \"R-HSA-9709957\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [32, 35, 38]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [3, 34]}\n    ],\n    \"complexes\": [\"clathrin coat\", \"cubam (cubilin/amnionless) receptor complex\"],\n    \"partners\": [\"MYO6\", \"GRB2\", \"AXIN\", \"DVL3\", \"LRP6\", \"TAK1\", \"EPS15\", \"ITGB1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":10,"faith_total":10,"faith_pct":100.0}}