{"gene":"DAB2IP","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":2002,"finding":"DAB2IP (then called DIP1/2) was cloned as a novel GTPase-activating protein (GAP) that interacts with the N-terminal domain of DOC-2/DAB2. It contains a Ras-GAP homology domain, 10 proline repeats, and a leucine zipper. Interaction between DOC-2/DAB2 and DIP1/2 is detected in normal brain and prostate tissues. The complex blocks mitogen-induced gene expression and inhibits prostate cancer growth.","method":"Yeast two-hybrid cloning, co-immunoprecipitation, structural domain characterization, functional growth assays","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, domain characterization, functional assays; foundational cloning paper with multiple orthogonal methods","pmids":["11812785"],"is_preprint":false},{"year":2002,"finding":"Human DAB2IP is a novel member of the Ras-GTPase-activating protein family that directly interacts with DAB2. The gene is located at 9q33.1-q33.3, spans ~96 kb with 15 exons, and its promoter lacks a TATA box. Transcriptional downregulation via epigenetic mechanisms (reduced promoter activity) is responsible for loss of DAB2IP expression in prostate cancer cells.","method":"Molecular cloning, promoter mapping and luciferase reporter assay, RT-PCR expression analysis","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter mapping with functional reporter assays, single lab, two orthogonal methods","pmids":["11944990"],"is_preprint":false},{"year":2003,"finding":"Mouse Dab2IP interacts with the intracellular adapter protein Disabled-1 (Dab1) in brain lysates; the interaction is mediated by the Dab1-PTB domain and an NPxY motif in Dab2IP. This positions Dab2IP as a potential downstream effector in the Reelin signaling pathway that influences Ras signaling during brain development.","method":"Yeast two-hybrid screen, co-immunoprecipitation from brain lysates, domain mapping, Northern blot, in situ hybridization, immunohistochemistry","journal":"Brain Research. Molecular Brain Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP from brain tissue, domain mapping confirmed by biochemical assay, single lab","pmids":["12877983"],"is_preprint":false},{"year":2004,"finding":"DAB2IP (AIP1) is localized on the plasma membrane of resting endothelial cells in a complex with TNFR1. TNF binding induces AIP1 release from TNFR1, cytoplasmic translocation, and formation of a signaling complex with TRADD, RIP1, TRAF2, and AIP1. A proline-rich region (aa 796–807) maintains AIP1 in a closed conformation associated with TNFR1; deletion of this region causes constitutive binding to TRAF2 and ASK1. A PERIOD-like domain (aa 591–719) binds the RING finger of TRAF2 and enhances TRAF2-induced ASK1 activation, while simultaneously inhibiting IKK-NF-κB signaling.","method":"Co-immunoprecipitation, subcellular fractionation, deletion mutant analysis, domain mapping, signaling reporter assays","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, domain mutagenesis, multiple orthogonal methods defining mechanism in a single rigorous study","pmids":["15310755"],"is_preprint":false},{"year":2009,"finding":"DAB2IP functions as a scaffold protein that simultaneously suppresses the PI3K-Akt survival pathway and enhances ASK1 activation leading to apoptosis. Structural-functional analyses indicate that the proline-rich (PR) and PERIOD-like (PER) domains regulate PI3K-Akt activity, while the C2 domain is critical for ASK1 activity. Loss of DAB2IP in mice results in glandular epithelial hyperplasia and apoptotic defects.","method":"Gain-of-function and loss-of-function experiments, domain deletion mutagenesis, Western blot signaling analysis, DAB2IP knockout mouse model, in vivo xenograft","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — domain mutagenesis, in vivo knockout model, multiple orthogonal assays in a single study","pmids":["19903888"],"is_preprint":false},{"year":2010,"finding":"Loss of DAB2IP initiates epithelial-to-mesenchymal transition (EMT) characterized by E-cadherin repression and vimentin upregulation in prostate epithelial and carcinoma cells. DAB2IP functions as a scaffold protein modulating EMT by regulating nuclear β-catenin/TCF transcriptional activity. Restoration of DAB2IP in metastatic PCa cells reversed EMT; knockdown in a xenograft model led to lymph node and distant organ metastases.","method":"Knockdown/overexpression in cell lines, DAB2IP knockout mouse model, human prostate xenograft-mouse model, reporter assays, clinical specimen IHC","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal models (KO mouse, xenograft, cell lines), replicated with gain- and loss-of-function","pmids":["20080667"],"is_preprint":false},{"year":2012,"finding":"DAB2IP is epigenetically silenced in medulloblastoma by EZH2-induced trimethylation of its promoter (H3K27me3). Ectopic DAB2IP expression enhances stress-induced apoptosis in medulloblastoma cells, and reduced DAB2IP confers resistance to irradiation-induced cell death.","method":"Gene expression meta-analysis, chromatin immunoprecipitation (EZH2/H3K27me3), ectopic expression functional assays, irradiation survival assays","journal":"Clinical Cancer Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP for epigenetic mechanism plus functional rescue assay, single lab","pmids":["22696229"],"is_preprint":false},{"year":2012,"finding":"DAB2IP is required for proper neuronal migration in the embryonic mouse neocortex. Knockdown disrupts the transition from multipolar to bipolar neuronal morphology in the intermediate zone and impairs neurite development, associated with reduced expression of neuronal microtubule-associated proteins (MAPs). Both PH and GRD (GAP-related) domains are required for neuronal migration.","method":"In utero electroporation (shRNA knockdown and overexpression), immunohistochemistry, domain deletion in vivo structure-function analysis, ex vivo neuronal culture","journal":"PLoS ONE","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo domain structure-function, bidirectional perturbation (KD and OE), multiple cellular phenotype readouts","pmids":["23056358"],"is_preprint":false},{"year":2012,"finding":"DAB2IP regulates autophagy in prostate cancer cells. Restoring DAB2IP expression decreases autophagy-associated proteins (LC3B, Beclin-1) and reduces phosphorylation of S6K and mTOR, shifting cells toward apoptosis in response to combined radiation and DNA-PKcs inhibition.","method":"DAB2IP knockdown/restoration in cell lines, Western blot for autophagy markers and mTOR signaling, apoptosis assays, colony formation, in vivo xenograft","journal":"Neoplasia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain/loss of function with mechanistic pathway readout, single lab","pmids":["23308052"],"is_preprint":false},{"year":2013,"finding":"DAB2IP inhibits androgen receptor (AR) signaling through two distinct mechanisms: (1) suppressing AR nuclear translocation/phosphorylation in the genomic pathway and (2) inactivating c-Src via a unique functional domain in the non-genomic pathway. DAB2IP also inhibits constitutively active AR splice variants. In DAB2IP-/- mice, prostate epithelia show hyperplasia with more active AR.","method":"Cell line gain/loss of function, AR nuclear translocation assays, c-Src kinase assays, domain-specific mutants, DAB2IP knockout mouse model, tissue microarray","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — two mechanistically distinct pathways defined with domain mutants, validated in KO mouse model and clinical specimens","pmids":["23604126"],"is_preprint":false},{"year":2013,"finding":"DAB2IP blocks cross-talk between Wnt/β-catenin and IGF-I signaling, suppressing Egr-1 expression which in turn controls Clusterin (an antiapoptotic factor). Loss of DAB2IP in chemoresistant prostate cancer cells leads to elevated Egr-1 and Clusterin via this pathway, conferring resistance to docetaxel and other chemotherapeutic drugs.","method":"Knockdown/overexpression in cell lines, luciferase reporter assay for Egr-1/Clusterin regulation, rescue experiments (Clusterin shRNA/OGX-011), Western blot signaling, DAB2IP KO mouse model, tissue microarray","journal":"Clinical Cancer Research","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic pathway defined by reporter assays, rescue experiments, and validated in KO mouse model","pmids":["23838317"],"is_preprint":false},{"year":2013,"finding":"Dab2IP deficiency in mouse cerebellum produces a delay in Purkinje cell dendrite development, a decrease in parallel fiber synaptic marker VGluT1, and an increase in climbing fiber synaptic marker VGluT2, demonstrating a role for Dab2IP in dendrite development and synapse number regulation.","method":"Retrovirus gene trap Dab2IP knockdown mouse model, immunohistochemistry for synaptic markers, morphological analysis of Purkinje cell dendrites","journal":"PLoS ONE","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KD mouse model with specific cellular phenotype readouts, single lab","pmids":["23326475"],"is_preprint":false},{"year":2014,"finding":"Mutant p53 (mutp53) binds and inhibits DAB2IP in the cytoplasm, thereby fueling NF-κB activation and dampening ASK1/JNK activation in response to TNFα. This leads to increased invasiveness of cancer cells responding to inflammatory cytokines. Interfering with the mutp53-DAB2IP interaction reduced cancer cell aggressiveness in xenografts.","method":"Co-immunoprecipitation (mutp53-DAB2IP interaction), cytoplasmic fractionation, NF-κB and ASK1/JNK signaling assays, xenograft mouse model, interference with interaction","journal":"Molecular Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP demonstrating direct interaction, multiple signaling readouts, validated in vivo with xenograft","pmids":["25454946"],"is_preprint":false},{"year":2014,"finding":"DAB2IP suppresses cancer stem cell (CSC) properties by (1) suppressing c-kit (CD117) gene expression through interaction with a silencer element in the c-kit gene, and (2) inhibiting c-kit–PI3K–Akt–mTOR signaling that increases c-Myc to activate ZEB1 gene expression. Loss of DAB2IP elevates ZEB1 and CD117, increasing CSC phenotypes.","method":"Gain/loss-of-function in cell lines, promoter-silencer reporter assay, signaling pathway analysis (Western blot), DAB2IP KO mouse model, clinical specimen correlation","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — silencer interaction defined by reporter assay, signaling cascade validated, confirmed in KO mouse","pmids":["25043300"],"is_preprint":false},{"year":2014,"finding":"Akt1 phosphorylates DAB2IP on S847, which regulates the interaction between DAB2IP and its effector molecules H-Ras and TRAF2. Additionally, DAB2IP is degraded through the ubiquitin-proteasome pathway by SCF(Fbw7), which recognizes two Fbw7 phospho-degron motifs in DAB2IP regulated by the kinase CK1δ.","method":"In vitro kinase assay (Akt1 phosphorylation of DAB2IP), co-immunoprecipitation (DAB2IP-H-Ras/TRAF2), proteasome inhibitor experiments, phospho-degron mutant analysis, CK1δ kinase assays","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro phosphorylation assay and Co-IP for interaction mapping, single lab","pmids":["24912918"],"is_preprint":false},{"year":2014,"finding":"DAB2IP interacts with and suppresses STAT3 via its proline-rich (PR) domain, inhibiting STAT3 phosphorylation, transactivation, and downstream survivin expression. Loss of DAB2IP stabilizes mitochondrial transmembrane potential and prevents cytochrome c/Omi/Smac release, conferring resistance to androgen deprivation-induced apoptosis.","method":"Co-immunoprecipitation (DAB2IP-STAT3), domain mapping (PR domain), Western blot for apoptotic mediators, mitochondrial membrane potential assay, DAB2IP KO mouse model, luciferase reporter","journal":"Cell Death & Disease","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain-specific Co-IP, multiple apoptosis pathway readouts, validated in KO mouse","pmids":["26512963"],"is_preprint":false},{"year":2014,"finding":"Skp2 (E3 ubiquitin ligase) mediates proteasome-dependent degradation of DAB2IP, with the ubiquitination site located in the N-terminal domain. Reciprocally, DAB2IP suppresses Skp2 protein expression through Akt signaling, forming a homeostatic feedback loop.","method":"Co-immunoprecipitation, ubiquitination assays, proteasome inhibitor experiments, domain mapping (N-terminal), Western blot with Akt pathway inhibitors, tissue microarray IHC","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assay with domain mapping, single lab","pmids":["25115390"],"is_preprint":false},{"year":2015,"finding":"DAB2IP regulates neuronal positioning in the developing cortex by modulating Rap1 and integrin signaling. Dab2IP knockdown results in elevated activated Rap1 and integrin levels in the developing cortex, linking Dab2IP to multipolar-to-bipolar transition of migrating neurons via these signaling intermediates.","method":"Dab2IP knockdown mouse model (retroviral gene trap), BrdU birth dating, layer-specific marker immunohistochemistry, Rap1 and integrin activation assays","journal":"Developmental Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KD mouse model with signaling readouts, single lab","pmids":["25721469"],"is_preprint":false},{"year":2016,"finding":"Smurf1 (E3 ubiquitin ligase) negatively regulates DAB2IP through ubiquitin-mediated degradation. Smurf1-mediated cell proliferation and migration are largely dependent on DAB2IP as a key effector. Akt1 and Akt2 phosphorylate Smurf1, increasing Smurf1 abundance and further reducing DAB2IP levels.","method":"Co-immunoprecipitation, ubiquitination assays, knockdown rescue experiments, Akt phosphorylation assays, cell proliferation and migration assays","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assays with functional rescue, single lab","pmids":["27036023"],"is_preprint":false},{"year":2016,"finding":"DAB2IP loss impairs kinetochore-microtubule (KT-MT) attachment, compromises the spindle assembly checkpoint (SAC), and causes aberrant chromosomal segregation. Mechanistically, DAB2IP directly interacts with Plk1 and its loss inhibits Plk1 kinase activity, impairing Plk1-mediated BubR1 phosphorylation and reducing BubR1 localization at kinetochores during mitosis. DAB2IP restoration enhances sensitivity to microtubule-stabilizing drugs and a Plk1 inhibitor.","method":"Co-immunoprecipitation (DAB2IP-Plk1), kinase activity assay, BubR1 phosphorylation assay, kinetochore localization by immunofluorescence, chromosomal segregation analysis, drug sensitivity assays","journal":"Nucleic Acids Research","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct Co-IP, kinase activity measurement, functional rescue, multiple orthogonal readouts in one study","pmids":["27568005"],"is_preprint":false},{"year":2016,"finding":"DAB2IP suppresses PROX1 transcription in prostate cancer cells. In DAB2IP-deficient cells, PROX1 overexpression stabilizes HIF1α protein by inhibiting the ubiquitin-proteasome pathway, leading to EMT (E-cadherin repression, vimentin upregulation, MMP induction) and enhanced cell migration.","method":"Cell line gain/loss-of-function, promoter reporter assays for PROX1, HIF1α ubiquitination and stability assays, Western blot, migration assay, DAB2IP KO mouse model","journal":"Cellular Signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination and reporter assays, validated in KO mouse, single lab","pmids":["27476001"],"is_preprint":false},{"year":2016,"finding":"Loss of DAB2IP in renal cell carcinoma activates ERK/RSK1 and PI3K/mTOR pathways, synergistically inducing HIF-2α expression. Elevated HIF-2α suppresses p21/WAF1, conferring resistance to mTOR inhibitors. Combined targeting of both pathways results in synergistic tumor inhibition.","method":"DAB2IP knockdown/overexpression in RCC cell lines, Western blot pathway analysis, HIF-2α knockdown rescue, drug sensitivity assays, in vivo xenograft","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain/loss-of-function with mechanistic pathway analysis and in vivo validation, single lab","pmids":["26876207"],"is_preprint":false},{"year":2017,"finding":"Mutant p53 (mutp53) augments insulin-induced AKT1 activation by binding and inhibiting DAB2IP in the cytoplasm, providing a specific gain-of-function for mutant p53 in response to insulin stimulation and increasing cancer cell proliferation and invasiveness.","method":"Co-immunoprecipitation (mutp53-DAB2IP in cytoplasmic fractions), AKT1 phosphorylation assays, gain/loss-of-function with cell proliferation and invasion readouts","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for direct interaction, signaling and phenotypic readouts, single lab","pmids":["28667123"],"is_preprint":false},{"year":2017,"finding":"DAB2IP acts as a GAP toward RAB40C GTPase, binding RAB40C mainly via its GAP domain to regulate lipid droplet (LD) homeostasis. Overexpression of DAB2IP or its GAP-defective mutant, and siRNA depletion of DAB2IP, confirm that DAB2IP negatively regulates RAB40C-mediated LD accumulation.","method":"Co-immunoprecipitation (DAB2IP-RAB40C), CRISPR-Cas9 RAB40C knockout, GAP-defective mutant overexpression, siRNA depletion, lipid droplet quantification by imaging","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mutant validation and multiple perturbation approaches, single lab","pmids":["29156729"],"is_preprint":false},{"year":2017,"finding":"Down-regulation of DAB2IP increases hnRNPK protein levels through the MAPK/ERK signaling pathway, causing translocation of hnRNPK into the nucleus where it enhances MMP2 transcription, thereby promoting invasion and metastasis of colorectal cancer cells.","method":"2D-DIGE proteomics to identify hnRNPK, cDNA microarray to identify MMP2, DAB2IP knockdown/overexpression, nuclear/cytoplasmic fractionation, MMP2 promoter reporter assay, invasion assays","journal":"International Journal of Cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics-based target identification, fractionation, and reporter assay, single lab","pmids":["28335083"],"is_preprint":false},{"year":2018,"finding":"miR-149-3p is a direct post-transcriptional negative regulator of DAB2IP. Downregulation of DAB2IP by miR-149-3p enhances cancer cell motility and invasiveness, activates NF-κB signaling, promotes expression of pro-inflammatory and pro-angiogenic factors. Notably, miR-149-3p secreted by prostate cancer cells induces DAB2IP downregulation in recipient vascular endothelial cells, stimulating their proliferation and motility.","method":"High-throughput miRNA mimic screen, luciferase reporter assay for direct targeting, NF-κB signaling assays, endothelial cell transfer/co-culture experiments, tumor growth assays with endogenous miR-149-3p inhibition","journal":"Cell Death and Differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — screen plus direct validation by reporter and functional rescue, cell-autonomous and non-autonomous mechanism, single lab","pmids":["29568059"],"is_preprint":false},{"year":2020,"finding":"In ovarian cancer stem cells (OCSCs), DAB2IP is silenced by EZH2-mediated H3K27 trimethylation of the DAB2IP promoter. CRISPR/Cas9 deletion of DAB2IP upregulates stemness genes and converts non-CSC to CSC. DAB2IP suppresses the CSC phenotype by inhibiting WNT5B expression, which reduces noncanonical WNT signaling via C-JUN activation downstream of RAC1.","method":"CRISPR/Cas9 deletion, ChIP for H3K27me3 at DAB2IP promoter, transcriptomic analysis, reverse phase protein array, RAC1 inhibition experiments, in vivo tumor growth assays","journal":"Cancer Research","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR KO, ChIP, transcriptomic plus protein array, in vivo validation; multiple orthogonal methods in one study","pmids":["32816909"],"is_preprint":false},{"year":2020,"finding":"RASSF1A binds to DAB2IP and upregulates DAB2IP protein levels in NSCLC cells. Suppression of RASSF1A leads to downregulation of DAB2IP and enhanced GTP loading onto RAS (increased RAS activation), thereby increasing RAS mitogenic signaling in both mutant- and wildtype-RAS cells.","method":"Co-immunoprecipitation (RASSF1A-DAB2IP), shRNA knockdown and stable overexpression, Ras-GTP pull-down assay, in vitro and in vivo growth assays","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for interaction, Ras-GTP assay for functional readout, single lab","pmids":["33348649"],"is_preprint":false},{"year":2020,"finding":"DAB2IP physically interacts with KIF3a (kinesin-2 family member) through its PH domain, and this interaction is important for primary cilia stability. Loss of DAB2IP in normal kidney epithelial cells significantly impairs primary cilia formation.","method":"Mass spectrometry identification of DAB2IP-interacting proteins (KIF3a), co-immunoprecipitation, domain mapping (PH domain), immunofluorescence for primary cilia","journal":"Neoplasia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-based interactome identification, Co-IP with domain mapping, cellular phenotype readout, single lab","pmids":["33341566"],"is_preprint":false},{"year":2021,"finding":"DAB2IP is phosphorylated by Cdks during mitosis, mediating its interaction with PLK1 and activation of the PLK1-Mps1 pathway. DAB2IP acts as a scaffold to facilitate PLK1-Mps1 targeting of Cdc20. DAB2IP interacts with Cdc20 in a phosphorylation-independent manner; however, DAB2IP phosphorylation inhibits Cdc20 ubiquitylation during SAC, blocking premature APC/C-MCC release. Loss of Cdk-mediated DAB2IP phosphorylation destabilizes the mitotic checkpoint complex (MCC), impairs SAC, and causes chromosomal instability.","method":"Phosphorylation site identification and mutagenesis (Cdk sites), co-immunoprecipitation (DAB2IP-PLK1, DAB2IP-Cdc20, PLK1-Mps1), Cdc20 ubiquitylation assay, SAC and chromosomal segregation assays, anaphase bridge/53BP1 body quantification","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — phospho-site mutagenesis, multiple Co-IPs, ubiquitylation assay, in-cell functional phenotypes; multiple orthogonal methods","pmids":["34775484"],"is_preprint":false},{"year":2022,"finding":"DAB2IP interacts with the chaperone GRP75 via its Ras-GAP domain, competitively blocking GRP75-driven ubiquitination and proteasomal degradation of wild-type p53. This DAB2IP-GRP75 interaction stabilizes p53 and mediates tumor-suppressive effects in colon cancer cells.","method":"Mass spectrometry (identification of DAB2IP-p53-GRP75 complex), co-immunoprecipitation, competitive binding assay, ubiquitination assay, domain-deletion mutants (Ras-GAP domain required), in vivo tumor experiments","journal":"Cancer Letters","confidence":"High","confidence_rationale":"Tier 2 / Strong — MS-based complex identification, competitive Co-IP, domain mapping, ubiquitination assay, in vivo validation","pmids":["35150809"],"is_preprint":false},{"year":2022,"finding":"DAB2IP inhibits intratumoral testosterone synthesis in castration-resistant prostate cancer by suppressing AKR1C3 promoter activity and the conversion of DHEA to testosterone through the PI3K/AKT/mTOR/ETS1 signaling pathway, thereby reducing AR re-activation under androgen-depleted conditions.","method":"DAB2IP knockdown/overexpression, AKR1C3 promoter luciferase reporter assay, testosterone synthesis measurement, signaling pathway inhibition, in vivo castration model with DAB2IP-/- mice and DHEA supplementation","journal":"Cellular Signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay, functional rescue, and in vivo KO mouse validation, single lab","pmids":["35452821"],"is_preprint":false},{"year":2022,"finding":"DAB2IP downregulates HSP90AA1 expression through the HSP90AA1/SRP9/ASK1/JNK signaling axis to promote apoptosis in colorectal cancer cells. Mechanistic studies confirmed the DAB2IP-HSP90AA1 regulatory connection through bioinformatic prediction plus in vitro validation.","method":"Bioinformatic pathway analysis, in vitro knockdown/overexpression, apoptosis flow cytometry, Western blot for ASK1/JNK activation, in vivo xenograft","journal":"BMC Cancer","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pathway analysis plus single-method functional assays; mechanism of direct regulation not fully characterized at molecular level","pmids":["35590292"],"is_preprint":false},{"year":2022,"finding":"DAB2IP inhibits β-catenin nuclear transport by competitively interacting with RAC1, thereby reducing β-catenin accumulation in the cell nucleus and attenuating cancer stem cell properties and chemoresistance in triple-negative breast cancer.","method":"Co-immunoprecipitation (DAB2IP-RAC1 competitive interaction), nuclear/cytoplasmic fractionation of β-catenin, DAB2IP knockdown/overexpression, in vivo xenograft experiments","journal":"Clinical and Translational Medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — competitive Co-IP with fractionation and functional phenotype readout, single lab","pmids":["36536485"],"is_preprint":false},{"year":2023,"finding":"DAB2IP suppresses invadopodia formation and breast cancer metastasis by destabilizing anaplastic lymphoma kinase (ALK) through antagonizing the interaction between the deubiquitinase USP10 and ALK, leading to decreased ALK protein abundance, reduced Cortactin tyrosine phosphorylation, and prevention of invadopodia formation.","method":"Co-immunoprecipitation (DAB2IP-USP10-ALK competitive binding), Cortactin phosphorylation assay, invadopodia formation assay, in vivo metastasis model, ALK protein stability assays","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — competitive Co-IP, substrate phosphorylation readout, in vivo validation, single lab","pmids":["37664607"],"is_preprint":false},{"year":2023,"finding":"DAB2IP expression is regulated by cell confluency (cell contact). DAB2IP depletion in confluent cells alters cell morphology (reduced cell packing, increased stiffness), favors YAP/TAZ nuclear localization and transcriptional activity, while ectopic DAB2IP expression in subconfluent cells increases YAP/TAZ cytoplasmic retention.","method":"DAB2IP knockdown and overexpression, YAP/TAZ nuclear/cytoplasmic localization by immunofluorescence, atomic force microscopy for cell stiffness, confluency-dependent expression analysis","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional perturbation with YAP/TAZ localization readout and biophysical measurements, single lab","pmids":["37444489"],"is_preprint":false},{"year":2023,"finding":"DAB2IP is a bifunctional tumor suppressor in KRAS-mutant colorectal cancer: (1) it restrains wild-type H-RAS and N-RAS (required for robust RAS effector pathway activation even in KRAS-mutant tumors), and (2) its loss triggers production of inflammatory mediators and recruitment of protumorigenic macrophages in vivo. Tumor growth was suppressed by macrophage depletion or JAK/TBK1 inhibition in DAB2IP-depleted tumors.","method":"DAB2IP genetic loss in colorectal cancer models, Ras-GTP activation assay (H-/N-Ras), cytokine/inflammatory mediator profiling, macrophage depletion in vivo, JAK/TBK1 inhibitor treatment, histological analysis of tumor microenvironment","journal":"Cancer Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RAS-GTP assay plus in vivo macrophage depletion rescue, two mechanistically distinct findings, single lab","pmids":["36939385"],"is_preprint":false},{"year":2024,"finding":"A DAB2IP missense variant (p.D239N) in the C2 domain impairs its interaction with VEGFR2, altering the subcellular localization of VEGFR2: wild-type DAB2IP colocalizes with VEGFR2 intracellularly, while the D239N mutant retains VEGFR2 at the cell membrane. This implicates DAB2IP in regulating endothelial VEGF/VEGFR2 signaling and vascular permeability.","method":"Whole exome sequencing, protein structure modeling, subcellular localization assay (transfection + immunofluorescence colocalization of DAB2IP variant and VEGFR2), co-localization quantification","journal":"The Journal of Allergy and Clinical Immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with functional variant, structural modeling, single lab/family study","pmids":["38823490"],"is_preprint":false},{"year":2024,"finding":"DAB2IP inhibits glucose uptake under hypoxia by interacting with the E3 ubiquitin ligase STUB1 via its PER domain, facilitating STUB1-mediated ubiquitylation and degradation of HIF-1α. Deletion of the PER domain abolishes DAB2IP-mediated inhibition of glucose uptake, ATP production, and lactic acid production.","method":"Co-immunoprecipitation (DAB2IP-STUB1-HIF-1α), domain deletion mutagenesis (PER domain), HIF-1α ubiquitylation assay, glucose uptake assay, metabolic assays (ATP, lactate), in vitro and in vivo experiments","journal":"Oncogenesis","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain mutagenesis defining PER domain requirement, Co-IP, ubiquitylation assay, multiple metabolic readouts; multiple orthogonal methods","pmids":["38862467"],"is_preprint":false},{"year":2025,"finding":"Nuclear DAB2IP localizes to the nucleus, where it interacts with the histone acetyltransferase HBO1 and enhances the HBO1-PLK1 interaction. DAB2IP facilitates PLK1-mediated phosphorylation of HBO1, which promotes HBO1-directed H3K14 acetylation, enabling MCM complex loading onto chromatin and supporting DNA replication origin firing. ATR regulates CDK1-mediated phosphorylation of DAB2IP, which is required for HBO1-PLK1 complex formation and activation. Loss of this phosphorylation increases genomic instability (anaphase bridges, 53BP1 nuclear bodies).","method":"Nuclear fractionation, co-immunoprecipitation (DAB2IP-HBO1, HBO1-PLK1), PLK1 kinase assay for HBO1 phosphorylation, ChIP for H3K14Ac at replication origins, MCM loading assay, CDK1 phosphorylation site mutagenesis, genomic instability assays (anaphase bridge/53BP1 quantification)","journal":"Nucleic Acids Research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple Co-IPs, kinase assay, ChIP, MCM loading, and phospho-site mutagenesis with genomic stability readout; multiple orthogonal methods in one study","pmids":["41261855"],"is_preprint":false}],"current_model":"DAB2IP is a multifunctional scaffold protein and Ras-GTPase-activating protein (RasGAP) that integrates multiple signaling pathways: it suppresses Ras/PI3K-AKT and ERK mitogenic signals via its GAP domain; modulates TNF/TRAF2-ASK1-JNK versus IKK-NF-κB balance by dynamic membrane-to-cytoplasm translocation; inhibits androgen receptor nuclear signaling and c-Src; interacts with PLK1 to regulate spindle assembly checkpoint integrity and DNA replication initiation (via HBO1-mediated H3K14 acetylation and MCM loading); promotes p53 stability by competing for GRP75; inhibits HIF-1α via STUB1-mediated ubiquitylation; suppresses YAP/TAZ activity at cell confluence; and is itself regulated by EZH2-mediated epigenetic silencing, Akt1/Fbw7/Smurf1-mediated proteasomal degradation, and direct inhibition by mutant p53."},"narrative":{"mechanistic_narrative":"DAB2IP is a multidomain scaffold and Ras-GTPase-activating protein that functions as a tumor suppressor by restraining mitogenic and survival signaling while licensing apoptotic and checkpoint responses [PMID:11812785, PMID:19903888]. Originally cloned as a RasGAP-family protein interacting with DOC-2/DAB2 through a Ras-GAP homology domain, proline repeats, and a leucine zipper [PMID:11812785, PMID:11944990], it directly restrains H-, N-, and wild-type RAS GTP-loading to suppress mitogenic signaling [PMID:33348649, PMID:36939385], an activity supported by stabilizing partners such as RASSF1A [PMID:33348649]. As a scaffold it partitions TNF signaling: at the plasma membrane DAB2IP (AIP1) sits in a closed conformation bound to TNFR1, and upon TNF stimulation translocates to the cytoplasm where its PERIOD-like domain engages the TRAF2 RING to enhance ASK1/JNK activation while inhibiting IKK-NF-κB signaling [PMID:15310755], and its proline-rich and PER domains concurrently suppress PI3K-Akt survival signaling [PMID:19903888]. Through these and related circuits DAB2IP suppresses epithelial-to-mesenchymal transition and cancer stem-cell properties by limiting nuclear β-catenin/TCF activity, c-kit–PI3K–Akt–mTOR–ZEB1 signaling, and noncanonical WNT/RAC1 signaling [PMID:20080667, PMID:25043300, PMID:32816909, PMID:36536485], and it antagonizes androgen receptor genomic and non-genomic (c-Src) signaling and intratumoral testosterone synthesis [PMID:23604126, PMID:35452821]. DAB2IP additionally controls mitotic fidelity and DNA replication: it directly binds PLK1 to sustain kinase activity, BubR1 kinetochore loading, and spindle-assembly-checkpoint integrity [PMID:27568005], is phosphorylated by Cdks to scaffold the PLK1-Mps1-Cdc20 axis and stabilize the mitotic checkpoint complex [PMID:34775484], and in the nucleus promotes HBO1-PLK1-mediated H3K14 acetylation enabling MCM loading and origin firing under ATR/CDK1 control [PMID:41261855]. It stabilizes wild-type p53 by competing with GRP75 [PMID:35150809] and inhibits HIF-1α by bridging the E3 ligase STUB1 [PMID:38862467], while being itself inactivated by direct binding of mutant p53 [PMID:25454946, PMID:28667123], epigenetic EZH2-mediated silencing [PMID:22696229, PMID:32816909], and Akt/Fbw7/Skp2/Smurf1-driven proteasomal degradation [PMID:24912918, PMID:25115390, PMID:27036023]. A C2-domain missense variant impairing DAB2IP-VEGFR2 interaction links the protein to endothelial VEGF/VEGFR2 signaling and vascular permeability [PMID:38823490].","teleology":[{"year":2002,"claim":"Established DAB2IP's molecular identity, defining it as a RasGAP-family scaffold that partners with DOC-2/DAB2 to block mitogenic gene expression and prostate cancer growth.","evidence":"Yeast two-hybrid cloning, reciprocal Co-IP, domain characterization and growth assays; promoter mapping and luciferase reporters","pmids":["11812785","11944990"],"confidence":"High","gaps":["Did not resolve which RAS isoforms are direct GAP substrates","Mechanism of epigenetic promoter silencing not defined at the chromatin level"]},{"year":2003,"claim":"Connected DAB2IP to neuronal signaling by showing it binds the Dab1 PTB domain via an NPxY motif, positioning it downstream of Reelin signaling in the developing brain.","evidence":"Yeast two-hybrid, Co-IP from brain lysates, domain mapping, in situ hybridization","pmids":["12877983"],"confidence":"Medium","gaps":["Functional consequence of the Dab1 interaction for Ras signaling not tested in vivo"]},{"year":2004,"claim":"Revealed the conformational switch underlying DAB2IP's TNF scaffolding: TNF releases it from TNFR1 to form a TRADD/RIP1/TRAF2 complex that drives ASK1 while suppressing NF-κB.","evidence":"Co-IP, subcellular fractionation, deletion-mutant and domain mapping, signaling reporters in endothelial cells","pmids":["15310755"],"confidence":"High","gaps":["Trigger for the conformational opening not defined biochemically","Stoichiometry of the multiprotein signaling complex unresolved"]},{"year":2009,"claim":"Defined DAB2IP as a dual-function scaffold that suppresses PI3K-Akt while enhancing ASK1 apoptotic signaling, with distinct domains assigned to each arm and validated in a knockout mouse.","evidence":"Domain-deletion mutagenesis, signaling Westerns, DAB2IP knockout mouse, xenograft","pmids":["19903888"],"confidence":"High","gaps":["How the two signaling arms are temporally coordinated not addressed"]},{"year":2013,"claim":"Extended DAB2IP's tumor-suppressor reach to EMT, androgen receptor signaling, chemoresistance and cancer stemness, defining multiple downstream transcriptional and kinase circuits it restrains.","evidence":"Cell-line gain/loss-of-function, reporter assays, c-Src kinase assays, domain mutants, KO mouse models, clinical specimens","pmids":["20080667","23604126","23838317","25043300"],"confidence":"High","gaps":["Direct versus indirect nature of several transcriptional effects (β-catenin/TCF, c-kit) not fully separated","How a single scaffold engages so many pathways in one cell unresolved"]},{"year":2014,"claim":"Identified the post-translational regulatory network that inactivates DAB2IP, including Akt1 phosphorylation, Fbw7/Skp2-mediated degradation, and direct mutant-p53 binding that reroutes TNF signaling toward NF-κB.","evidence":"In vitro kinase assays, Co-IP, ubiquitination/proteasome assays, phospho-degron mutants, STAT3 domain mapping, xenografts","pmids":["24912918","25115390","26512963","25454946"],"confidence":"High","gaps":["Relative contributions of competing E3 ligases in vivo not ranked","Whether mutp53 binding is direct or bridged not fully resolved"]},{"year":2016,"claim":"Uncovered DAB2IP's mitotic role, showing it directly binds PLK1 to sustain kinase activity, BubR1 kinetochore loading, and spindle-assembly-checkpoint integrity.","evidence":"Co-IP, PLK1 kinase activity assay, BubR1 phosphorylation, kinetochore immunofluorescence, chromosomal segregation and drug-sensitivity assays","pmids":["27568005"],"confidence":"High","gaps":["Whether DAB2IP is a PLK1 substrate or allosteric activator at this stage unclear","Nuclear/mitotic localization mechanism not defined"]},{"year":2017,"claim":"Broadened DAB2IP's GAP repertoire beyond RAS to RAB40C, linking its GAP domain to lipid droplet homeostasis, and added KIF3a binding tying it to primary cilia stability.","evidence":"Co-IP, GAP-defective mutants, CRISPR knockout, lipid droplet imaging; mass-spec interactome and PH-domain mapping for KIF3a","pmids":["29156729","33341566"],"confidence":"Medium","gaps":["Direct GAP activity on RAB40C not measured biochemically","Cilia phenotype mechanism beyond KIF3a binding unresolved"]},{"year":2021,"claim":"Defined a Cdk-phosphorylation-dependent mode in which DAB2IP scaffolds the PLK1-Mps1-Cdc20 axis to stabilize the mitotic checkpoint complex and prevent premature APC/C activation.","evidence":"Cdk phospho-site mutagenesis, multiple Co-IPs, Cdc20 ubiquitylation assay, SAC and genomic-instability readouts","pmids":["34775484"],"confidence":"High","gaps":["Which Cdk(s) phosphorylate DAB2IP in vivo not pinpointed","Structural basis of MCC stabilization unknown"]},{"year":2022,"claim":"Established DAB2IP as a regulator of p53 stability and tumor metabolism, competing with GRP75 to protect wild-type p53 and bridging STUB1 to degrade HIF-1α.","evidence":"Mass-spec complex identification, competitive Co-IP, ubiquitination assays, domain mapping, glucose/ATP/lactate metabolic readouts, in vivo","pmids":["35150809","38862467"],"confidence":"High","gaps":["Whether p53 stabilization and HIF-1α degradation occur in the same cellular context not tested","Domain assignments differ (Ras-GAP vs PER) across substrates without unifying model"]},{"year":2023,"claim":"Linked DAB2IP to mechanotransduction and the tumor microenvironment, showing confluency-dependent suppression of YAP/TAZ and that its loss recruits protumorigenic macrophages via inflammatory signaling.","evidence":"Bidirectional perturbation with YAP/TAZ localization, atomic force microscopy; RAS-GTP assays, cytokine profiling, in vivo macrophage depletion and JAK/TBK1 inhibition","pmids":["37444489","36939385"],"confidence":"Medium","gaps":["Molecular link between DAB2IP and the YAP/TAZ machinery not defined","Direct versus secondary nature of inflammatory mediator induction unresolved"]},{"year":2025,"claim":"Defined a nuclear, replication-licensing function in which ATR/CDK1-phosphorylated DAB2IP scaffolds HBO1-PLK1 to drive H3K14 acetylation, MCM loading and origin firing.","evidence":"Nuclear fractionation, Co-IPs, PLK1 kinase assay, ChIP for H3K14Ac at origins, MCM loading assay, phospho-site mutagenesis, genomic-instability readouts","pmids":["41261855"],"confidence":"High","gaps":["Mechanism of DAB2IP nuclear import not established","How nuclear replication role coordinates with cytoplasmic GAP/scaffold functions unknown"]},{"year":null,"claim":"How a single multidomain scaffold dynamically partitions among plasma membrane, cytoplasm, and nucleus to selectively engage RAS-GAP, TNF/ASK1, checkpoint, and replication functions remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No integrated model of spatial/temporal regulation across compartments","No structural model of full-length DAB2IP with partners","Direct GAP activity quantified for only a subset of GTPases"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,3,4,30,38]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,27,36,23]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[19,29,39]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,37]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3,12,22]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[39]},{"term_id":"GO:0005811","term_label":"lipid droplet","supporting_discovery_ids":[23]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[28]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,4,27,36]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[19,29,39]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[4,15,32]},{"term_id":"R-HSA-69306","term_label":"DNA Replication","supporting_discovery_ids":[39]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[12,22]}],"complexes":["TNFR1-TRADD-RIP1-TRAF2 signaling complex","PLK1-Mps1-Cdc20 mitotic checkpoint module","DAB2IP-p53-GRP75 complex","HBO1-PLK1 replication-licensing complex"],"partners":["DAB2","TRAF2","PLK1","CDC20","HBO1","GRP75","STUB1","RASSF1A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q5VWQ8","full_name":"Disabled homolog 2-interacting protein","aliases":["ASK-interacting protein 1","AIP-1","DOC-2/DAB-2 interactive protein"],"length_aa":1189,"mass_kda":131.6,"function":"Functions as a scaffold protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Involved in several processes such as innate immune response, inflammation and cell growth inhibition, apoptosis, cell survival, angiogenesis, cell migration and maturation. Also plays a role in cell cycle checkpoint control; reduces G1 phase cyclin levels resulting in G0/G1 cell cycle arrest. Mediates signal transduction by receptor-mediated inflammatory signals, such as the tumor necrosis factor (TNF), interferon (IFN) or lipopolysaccharide (LPS). Modulates the balance between phosphatidylinositol 3-kinase (PI3K)-AKT-mediated cell survival and apoptosis stimulated kinase (MAP3K5)-JNK signaling pathways; sequesters both AKT1 and MAP3K5 and counterbalances the activity of each kinase by modulating their phosphorylation status in response to pro-inflammatory stimuli. Acts as a regulator of the endoplasmic reticulum (ER) unfolded protein response (UPR) pathway; specifically involved in transduction of the ER stress-response to the JNK cascade through ERN1. Mediates TNF-induced apoptosis activation by facilitating dissociation of inhibitor 14-3-3 from MAP3K5; recruits the PP2A phosphatase complex which dephosphorylates MAP3K5 on 'Ser-966', leading to the dissociation of 13-3-3 proteins and activation of the MAP3K5-JNK signaling pathway in endothelial cells. Also mediates TNF/TRAF2-induced MAP3K5-JNK activation, while it inhibits CHUK-NF-kappa-B signaling. Acts a negative regulator in the IFN-gamma-mediated JAK-STAT signaling cascade by inhibiting smooth muscle cell (VSMCs) proliferation and intimal expansion, and thus, prevents graft arteriosclerosis (GA). Acts as a GTPase-activating protein (GAP) for the ADP ribosylation factor 6 (ARF6), Ras and RAB40C (PubMed:29156729). Promotes hydrolysis of the ARF6-bound GTP and thus, negatively regulates phosphatidylinositol 4,5-bisphosphate (PIP2)-dependent TLR4-TIRAP-MyD88 and NF-kappa-B signaling pathways in endothelial cells in response to lipopolysaccharides (LPS). Binds specifically to phosphatidylinositol 4-phosphate (PtdIns4P) and phosphatidylinositol 3-phosphate (PtdIns3P). In response to vascular endothelial growth factor (VEGFA), acts as a negative regulator of the VEGFR2-PI3K-mediated angiogenic signaling pathway by inhibiting endothelial cell migration and tube formation. In the developing brain, promotes both the transition from the multipolar to the bipolar stage and the radial migration of cortical neurons from the ventricular zone toward the superficial layer of the neocortex in a glial-dependent locomotion process. Probable downstream effector of the Reelin signaling pathway; promotes Purkinje cell (PC) dendrites development and formation of cerebellar synapses. Also functions as a tumor suppressor protein in prostate cancer progression; prevents cell proliferation and epithelial-to-mesenchymal transition (EMT) through activation of the glycogen synthase kinase-3 beta (GSK3B)-induced beta-catenin and inhibition of PI3K-AKT and Ras-MAPK survival downstream signaling cascades, respectively","subcellular_location":"Cytoplasm; Cell membrane; Membrane; Cell projection, dendrite","url":"https://www.uniprot.org/uniprotkb/Q5VWQ8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DAB2IP","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CSNK1A1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/DAB2IP","total_profiled":1310},"omim":[{"mim_id":"609205","title":"DAB2-INTERACTING PROTEIN; DAB2IP","url":"https://www.omim.org/entry/609205"},{"mim_id":"601573","title":"ENHANCER OF ZESTE 2 POLYCOMB REPRESSIVE COMPLEX 2 SUBUNIT; EZH2","url":"https://www.omim.org/entry/601573"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":144.8}],"url":"https://www.proteinatlas.org/search/DAB2IP"},"hgnc":{"alias_symbol":["AF9Q34","DIP1/2","KIAA1743","AIP1"],"prev_symbol":[]},"alphafold":{"accession":"Q5VWQ8","domains":[{"cath_id":"2.30.29.30","chopping":"147-208","consensus_level":"medium","plddt":82.4323,"start":147,"end":208},{"cath_id":"2.60.40.150","chopping":"211-338","consensus_level":"high","plddt":87.8084,"start":211,"end":338},{"cath_id":"1.10.506.10","chopping":"387-608","consensus_level":"medium","plddt":91.8854,"start":387,"end":608}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5VWQ8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5VWQ8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5VWQ8-F1-predicted_aligned_error_v6.png","plddt_mean":64.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DAB2IP","jax_strain_url":"https://www.jax.org/strain/search?query=DAB2IP"},"sequence":{"accession":"Q5VWQ8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5VWQ8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5VWQ8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5VWQ8"}},"corpus_meta":[{"pmid":"20080667","id":"PMC_20080667","title":"Role of DAB2IP in modulating epithelial-to-mesenchymal transition and prostate cancer metastasis.","date":"2010","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/20080667","citation_count":203,"is_preprint":false},{"pmid":"31776329","id":"PMC_31776329","title":"CircRNA-5692 inhibits the progression of hepatocellular carcinoma by sponging miR-328-5p to enhance DAB2IP expression.","date":"2019","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/31776329","citation_count":195,"is_preprint":false},{"pmid":"198184","id":"PMC_198184","title":"Gene mapping in Mus musculus by interspecific cell hybridization: assignment of the genes for tripeptidase-1 to chromosome 10, dipeptidase-2 to chromosome 18, acid phosphatase-1 to chromosome 12, and adenylate kinase-1 to chromosome 2.","date":"1977","source":"Cytogenetics and cell genetics","url":"https://pubmed.ncbi.nlm.nih.gov/198184","citation_count":172,"is_preprint":false},{"pmid":"19903888","id":"PMC_19903888","title":"DAB2IP coordinates both PI3K-Akt and ASK1 pathways for cell survival and apoptosis.","date":"2009","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/19903888","citation_count":166,"is_preprint":false},{"pmid":"25454946","id":"PMC_25454946","title":"Mutant p53 reprograms TNF signaling in cancer cells through interaction with the tumor suppressor DAB2IP.","date":"2014","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/25454946","citation_count":145,"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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It contains a Ras-GAP homology domain, 10 proline repeats, and a leucine zipper. Interaction between DOC-2/DAB2 and DIP1/2 is detected in normal brain and prostate tissues. The complex blocks mitogen-induced gene expression and inhibits prostate cancer growth.\",\n      \"method\": \"Yeast two-hybrid cloning, co-immunoprecipitation, structural domain characterization, functional growth assays\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, domain characterization, functional assays; foundational cloning paper with multiple orthogonal methods\",\n      \"pmids\": [\"11812785\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Human DAB2IP is a novel member of the Ras-GTPase-activating protein family that directly interacts with DAB2. The gene is located at 9q33.1-q33.3, spans ~96 kb with 15 exons, and its promoter lacks a TATA box. Transcriptional downregulation via epigenetic mechanisms (reduced promoter activity) is responsible for loss of DAB2IP expression in prostate cancer cells.\",\n      \"method\": \"Molecular cloning, promoter mapping and luciferase reporter assay, RT-PCR expression analysis\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter mapping with functional reporter assays, single lab, two orthogonal methods\",\n      \"pmids\": [\"11944990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Mouse Dab2IP interacts with the intracellular adapter protein Disabled-1 (Dab1) in brain lysates; the interaction is mediated by the Dab1-PTB domain and an NPxY motif in Dab2IP. This positions Dab2IP as a potential downstream effector in the Reelin signaling pathway that influences Ras signaling during brain development.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation from brain lysates, domain mapping, Northern blot, in situ hybridization, immunohistochemistry\",\n      \"journal\": \"Brain Research. Molecular Brain Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP from brain tissue, domain mapping confirmed by biochemical assay, single lab\",\n      \"pmids\": [\"12877983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"DAB2IP (AIP1) is localized on the plasma membrane of resting endothelial cells in a complex with TNFR1. TNF binding induces AIP1 release from TNFR1, cytoplasmic translocation, and formation of a signaling complex with TRADD, RIP1, TRAF2, and AIP1. A proline-rich region (aa 796–807) maintains AIP1 in a closed conformation associated with TNFR1; deletion of this region causes constitutive binding to TRAF2 and ASK1. A PERIOD-like domain (aa 591–719) binds the RING finger of TRAF2 and enhances TRAF2-induced ASK1 activation, while simultaneously inhibiting IKK-NF-κB signaling.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, deletion mutant analysis, domain mapping, signaling reporter assays\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, domain mutagenesis, multiple orthogonal methods defining mechanism in a single rigorous study\",\n      \"pmids\": [\"15310755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"DAB2IP functions as a scaffold protein that simultaneously suppresses the PI3K-Akt survival pathway and enhances ASK1 activation leading to apoptosis. Structural-functional analyses indicate that the proline-rich (PR) and PERIOD-like (PER) domains regulate PI3K-Akt activity, while the C2 domain is critical for ASK1 activity. Loss of DAB2IP in mice results in glandular epithelial hyperplasia and apoptotic defects.\",\n      \"method\": \"Gain-of-function and loss-of-function experiments, domain deletion mutagenesis, Western blot signaling analysis, DAB2IP knockout mouse model, in vivo xenograft\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — domain mutagenesis, in vivo knockout model, multiple orthogonal assays in a single study\",\n      \"pmids\": [\"19903888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Loss of DAB2IP initiates epithelial-to-mesenchymal transition (EMT) characterized by E-cadherin repression and vimentin upregulation in prostate epithelial and carcinoma cells. DAB2IP functions as a scaffold protein modulating EMT by regulating nuclear β-catenin/TCF transcriptional activity. Restoration of DAB2IP in metastatic PCa cells reversed EMT; knockdown in a xenograft model led to lymph node and distant organ metastases.\",\n      \"method\": \"Knockdown/overexpression in cell lines, DAB2IP knockout mouse model, human prostate xenograft-mouse model, reporter assays, clinical specimen IHC\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal models (KO mouse, xenograft, cell lines), replicated with gain- and loss-of-function\",\n      \"pmids\": [\"20080667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"DAB2IP is epigenetically silenced in medulloblastoma by EZH2-induced trimethylation of its promoter (H3K27me3). Ectopic DAB2IP expression enhances stress-induced apoptosis in medulloblastoma cells, and reduced DAB2IP confers resistance to irradiation-induced cell death.\",\n      \"method\": \"Gene expression meta-analysis, chromatin immunoprecipitation (EZH2/H3K27me3), ectopic expression functional assays, irradiation survival assays\",\n      \"journal\": \"Clinical Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP for epigenetic mechanism plus functional rescue assay, single lab\",\n      \"pmids\": [\"22696229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"DAB2IP is required for proper neuronal migration in the embryonic mouse neocortex. Knockdown disrupts the transition from multipolar to bipolar neuronal morphology in the intermediate zone and impairs neurite development, associated with reduced expression of neuronal microtubule-associated proteins (MAPs). Both PH and GRD (GAP-related) domains are required for neuronal migration.\",\n      \"method\": \"In utero electroporation (shRNA knockdown and overexpression), immunohistochemistry, domain deletion in vivo structure-function analysis, ex vivo neuronal culture\",\n      \"journal\": \"PLoS ONE\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo domain structure-function, bidirectional perturbation (KD and OE), multiple cellular phenotype readouts\",\n      \"pmids\": [\"23056358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"DAB2IP regulates autophagy in prostate cancer cells. Restoring DAB2IP expression decreases autophagy-associated proteins (LC3B, Beclin-1) and reduces phosphorylation of S6K and mTOR, shifting cells toward apoptosis in response to combined radiation and DNA-PKcs inhibition.\",\n      \"method\": \"DAB2IP knockdown/restoration in cell lines, Western blot for autophagy markers and mTOR signaling, apoptosis assays, colony formation, in vivo xenograft\",\n      \"journal\": \"Neoplasia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain/loss of function with mechanistic pathway readout, single lab\",\n      \"pmids\": [\"23308052\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"DAB2IP inhibits androgen receptor (AR) signaling through two distinct mechanisms: (1) suppressing AR nuclear translocation/phosphorylation in the genomic pathway and (2) inactivating c-Src via a unique functional domain in the non-genomic pathway. DAB2IP also inhibits constitutively active AR splice variants. In DAB2IP-/- mice, prostate epithelia show hyperplasia with more active AR.\",\n      \"method\": \"Cell line gain/loss of function, AR nuclear translocation assays, c-Src kinase assays, domain-specific mutants, DAB2IP knockout mouse model, tissue microarray\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two mechanistically distinct pathways defined with domain mutants, validated in KO mouse model and clinical specimens\",\n      \"pmids\": [\"23604126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"DAB2IP blocks cross-talk between Wnt/β-catenin and IGF-I signaling, suppressing Egr-1 expression which in turn controls Clusterin (an antiapoptotic factor). Loss of DAB2IP in chemoresistant prostate cancer cells leads to elevated Egr-1 and Clusterin via this pathway, conferring resistance to docetaxel and other chemotherapeutic drugs.\",\n      \"method\": \"Knockdown/overexpression in cell lines, luciferase reporter assay for Egr-1/Clusterin regulation, rescue experiments (Clusterin shRNA/OGX-011), Western blot signaling, DAB2IP KO mouse model, tissue microarray\",\n      \"journal\": \"Clinical Cancer Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic pathway defined by reporter assays, rescue experiments, and validated in KO mouse model\",\n      \"pmids\": [\"23838317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Dab2IP deficiency in mouse cerebellum produces a delay in Purkinje cell dendrite development, a decrease in parallel fiber synaptic marker VGluT1, and an increase in climbing fiber synaptic marker VGluT2, demonstrating a role for Dab2IP in dendrite development and synapse number regulation.\",\n      \"method\": \"Retrovirus gene trap Dab2IP knockdown mouse model, immunohistochemistry for synaptic markers, morphological analysis of Purkinje cell dendrites\",\n      \"journal\": \"PLoS ONE\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KD mouse model with specific cellular phenotype readouts, single lab\",\n      \"pmids\": [\"23326475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Mutant p53 (mutp53) binds and inhibits DAB2IP in the cytoplasm, thereby fueling NF-κB activation and dampening ASK1/JNK activation in response to TNFα. This leads to increased invasiveness of cancer cells responding to inflammatory cytokines. Interfering with the mutp53-DAB2IP interaction reduced cancer cell aggressiveness in xenografts.\",\n      \"method\": \"Co-immunoprecipitation (mutp53-DAB2IP interaction), cytoplasmic fractionation, NF-κB and ASK1/JNK signaling assays, xenograft mouse model, interference with interaction\",\n      \"journal\": \"Molecular Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP demonstrating direct interaction, multiple signaling readouts, validated in vivo with xenograft\",\n      \"pmids\": [\"25454946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"DAB2IP suppresses cancer stem cell (CSC) properties by (1) suppressing c-kit (CD117) gene expression through interaction with a silencer element in the c-kit gene, and (2) inhibiting c-kit–PI3K–Akt–mTOR signaling that increases c-Myc to activate ZEB1 gene expression. Loss of DAB2IP elevates ZEB1 and CD117, increasing CSC phenotypes.\",\n      \"method\": \"Gain/loss-of-function in cell lines, promoter-silencer reporter assay, signaling pathway analysis (Western blot), DAB2IP KO mouse model, clinical specimen correlation\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — silencer interaction defined by reporter assay, signaling cascade validated, confirmed in KO mouse\",\n      \"pmids\": [\"25043300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Akt1 phosphorylates DAB2IP on S847, which regulates the interaction between DAB2IP and its effector molecules H-Ras and TRAF2. Additionally, DAB2IP is degraded through the ubiquitin-proteasome pathway by SCF(Fbw7), which recognizes two Fbw7 phospho-degron motifs in DAB2IP regulated by the kinase CK1δ.\",\n      \"method\": \"In vitro kinase assay (Akt1 phosphorylation of DAB2IP), co-immunoprecipitation (DAB2IP-H-Ras/TRAF2), proteasome inhibitor experiments, phospho-degron mutant analysis, CK1δ kinase assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro phosphorylation assay and Co-IP for interaction mapping, single lab\",\n      \"pmids\": [\"24912918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"DAB2IP interacts with and suppresses STAT3 via its proline-rich (PR) domain, inhibiting STAT3 phosphorylation, transactivation, and downstream survivin expression. Loss of DAB2IP stabilizes mitochondrial transmembrane potential and prevents cytochrome c/Omi/Smac release, conferring resistance to androgen deprivation-induced apoptosis.\",\n      \"method\": \"Co-immunoprecipitation (DAB2IP-STAT3), domain mapping (PR domain), Western blot for apoptotic mediators, mitochondrial membrane potential assay, DAB2IP KO mouse model, luciferase reporter\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain-specific Co-IP, multiple apoptosis pathway readouts, validated in KO mouse\",\n      \"pmids\": [\"26512963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Skp2 (E3 ubiquitin ligase) mediates proteasome-dependent degradation of DAB2IP, with the ubiquitination site located in the N-terminal domain. Reciprocally, DAB2IP suppresses Skp2 protein expression through Akt signaling, forming a homeostatic feedback loop.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, proteasome inhibitor experiments, domain mapping (N-terminal), Western blot with Akt pathway inhibitors, tissue microarray IHC\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assay with domain mapping, single lab\",\n      \"pmids\": [\"25115390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"DAB2IP regulates neuronal positioning in the developing cortex by modulating Rap1 and integrin signaling. Dab2IP knockdown results in elevated activated Rap1 and integrin levels in the developing cortex, linking Dab2IP to multipolar-to-bipolar transition of migrating neurons via these signaling intermediates.\",\n      \"method\": \"Dab2IP knockdown mouse model (retroviral gene trap), BrdU birth dating, layer-specific marker immunohistochemistry, Rap1 and integrin activation assays\",\n      \"journal\": \"Developmental Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KD mouse model with signaling readouts, single lab\",\n      \"pmids\": [\"25721469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Smurf1 (E3 ubiquitin ligase) negatively regulates DAB2IP through ubiquitin-mediated degradation. Smurf1-mediated cell proliferation and migration are largely dependent on DAB2IP as a key effector. Akt1 and Akt2 phosphorylate Smurf1, increasing Smurf1 abundance and further reducing DAB2IP levels.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, knockdown rescue experiments, Akt phosphorylation assays, cell proliferation and migration assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assays with functional rescue, single lab\",\n      \"pmids\": [\"27036023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"DAB2IP loss impairs kinetochore-microtubule (KT-MT) attachment, compromises the spindle assembly checkpoint (SAC), and causes aberrant chromosomal segregation. Mechanistically, DAB2IP directly interacts with Plk1 and its loss inhibits Plk1 kinase activity, impairing Plk1-mediated BubR1 phosphorylation and reducing BubR1 localization at kinetochores during mitosis. DAB2IP restoration enhances sensitivity to microtubule-stabilizing drugs and a Plk1 inhibitor.\",\n      \"method\": \"Co-immunoprecipitation (DAB2IP-Plk1), kinase activity assay, BubR1 phosphorylation assay, kinetochore localization by immunofluorescence, chromosomal segregation analysis, drug sensitivity assays\",\n      \"journal\": \"Nucleic Acids Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct Co-IP, kinase activity measurement, functional rescue, multiple orthogonal readouts in one study\",\n      \"pmids\": [\"27568005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"DAB2IP suppresses PROX1 transcription in prostate cancer cells. In DAB2IP-deficient cells, PROX1 overexpression stabilizes HIF1α protein by inhibiting the ubiquitin-proteasome pathway, leading to EMT (E-cadherin repression, vimentin upregulation, MMP induction) and enhanced cell migration.\",\n      \"method\": \"Cell line gain/loss-of-function, promoter reporter assays for PROX1, HIF1α ubiquitination and stability assays, Western blot, migration assay, DAB2IP KO mouse model\",\n      \"journal\": \"Cellular Signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination and reporter assays, validated in KO mouse, single lab\",\n      \"pmids\": [\"27476001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Loss of DAB2IP in renal cell carcinoma activates ERK/RSK1 and PI3K/mTOR pathways, synergistically inducing HIF-2α expression. Elevated HIF-2α suppresses p21/WAF1, conferring resistance to mTOR inhibitors. Combined targeting of both pathways results in synergistic tumor inhibition.\",\n      \"method\": \"DAB2IP knockdown/overexpression in RCC cell lines, Western blot pathway analysis, HIF-2α knockdown rescue, drug sensitivity assays, in vivo xenograft\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain/loss-of-function with mechanistic pathway analysis and in vivo validation, single lab\",\n      \"pmids\": [\"26876207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Mutant p53 (mutp53) augments insulin-induced AKT1 activation by binding and inhibiting DAB2IP in the cytoplasm, providing a specific gain-of-function for mutant p53 in response to insulin stimulation and increasing cancer cell proliferation and invasiveness.\",\n      \"method\": \"Co-immunoprecipitation (mutp53-DAB2IP in cytoplasmic fractions), AKT1 phosphorylation assays, gain/loss-of-function with cell proliferation and invasion readouts\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for direct interaction, signaling and phenotypic readouts, single lab\",\n      \"pmids\": [\"28667123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"DAB2IP acts as a GAP toward RAB40C GTPase, binding RAB40C mainly via its GAP domain to regulate lipid droplet (LD) homeostasis. Overexpression of DAB2IP or its GAP-defective mutant, and siRNA depletion of DAB2IP, confirm that DAB2IP negatively regulates RAB40C-mediated LD accumulation.\",\n      \"method\": \"Co-immunoprecipitation (DAB2IP-RAB40C), CRISPR-Cas9 RAB40C knockout, GAP-defective mutant overexpression, siRNA depletion, lipid droplet quantification by imaging\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mutant validation and multiple perturbation approaches, single lab\",\n      \"pmids\": [\"29156729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Down-regulation of DAB2IP increases hnRNPK protein levels through the MAPK/ERK signaling pathway, causing translocation of hnRNPK into the nucleus where it enhances MMP2 transcription, thereby promoting invasion and metastasis of colorectal cancer cells.\",\n      \"method\": \"2D-DIGE proteomics to identify hnRNPK, cDNA microarray to identify MMP2, DAB2IP knockdown/overexpression, nuclear/cytoplasmic fractionation, MMP2 promoter reporter assay, invasion assays\",\n      \"journal\": \"International Journal of Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics-based target identification, fractionation, and reporter assay, single lab\",\n      \"pmids\": [\"28335083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"miR-149-3p is a direct post-transcriptional negative regulator of DAB2IP. Downregulation of DAB2IP by miR-149-3p enhances cancer cell motility and invasiveness, activates NF-κB signaling, promotes expression of pro-inflammatory and pro-angiogenic factors. Notably, miR-149-3p secreted by prostate cancer cells induces DAB2IP downregulation in recipient vascular endothelial cells, stimulating their proliferation and motility.\",\n      \"method\": \"High-throughput miRNA mimic screen, luciferase reporter assay for direct targeting, NF-κB signaling assays, endothelial cell transfer/co-culture experiments, tumor growth assays with endogenous miR-149-3p inhibition\",\n      \"journal\": \"Cell Death and Differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — screen plus direct validation by reporter and functional rescue, cell-autonomous and non-autonomous mechanism, single lab\",\n      \"pmids\": [\"29568059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In ovarian cancer stem cells (OCSCs), DAB2IP is silenced by EZH2-mediated H3K27 trimethylation of the DAB2IP promoter. CRISPR/Cas9 deletion of DAB2IP upregulates stemness genes and converts non-CSC to CSC. DAB2IP suppresses the CSC phenotype by inhibiting WNT5B expression, which reduces noncanonical WNT signaling via C-JUN activation downstream of RAC1.\",\n      \"method\": \"CRISPR/Cas9 deletion, ChIP for H3K27me3 at DAB2IP promoter, transcriptomic analysis, reverse phase protein array, RAC1 inhibition experiments, in vivo tumor growth assays\",\n      \"journal\": \"Cancer Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR KO, ChIP, transcriptomic plus protein array, in vivo validation; multiple orthogonal methods in one study\",\n      \"pmids\": [\"32816909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RASSF1A binds to DAB2IP and upregulates DAB2IP protein levels in NSCLC cells. Suppression of RASSF1A leads to downregulation of DAB2IP and enhanced GTP loading onto RAS (increased RAS activation), thereby increasing RAS mitogenic signaling in both mutant- and wildtype-RAS cells.\",\n      \"method\": \"Co-immunoprecipitation (RASSF1A-DAB2IP), shRNA knockdown and stable overexpression, Ras-GTP pull-down assay, in vitro and in vivo growth assays\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for interaction, Ras-GTP assay for functional readout, single lab\",\n      \"pmids\": [\"33348649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"DAB2IP physically interacts with KIF3a (kinesin-2 family member) through its PH domain, and this interaction is important for primary cilia stability. Loss of DAB2IP in normal kidney epithelial cells significantly impairs primary cilia formation.\",\n      \"method\": \"Mass spectrometry identification of DAB2IP-interacting proteins (KIF3a), co-immunoprecipitation, domain mapping (PH domain), immunofluorescence for primary cilia\",\n      \"journal\": \"Neoplasia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-based interactome identification, Co-IP with domain mapping, cellular phenotype readout, single lab\",\n      \"pmids\": [\"33341566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DAB2IP is phosphorylated by Cdks during mitosis, mediating its interaction with PLK1 and activation of the PLK1-Mps1 pathway. DAB2IP acts as a scaffold to facilitate PLK1-Mps1 targeting of Cdc20. DAB2IP interacts with Cdc20 in a phosphorylation-independent manner; however, DAB2IP phosphorylation inhibits Cdc20 ubiquitylation during SAC, blocking premature APC/C-MCC release. Loss of Cdk-mediated DAB2IP phosphorylation destabilizes the mitotic checkpoint complex (MCC), impairs SAC, and causes chromosomal instability.\",\n      \"method\": \"Phosphorylation site identification and mutagenesis (Cdk sites), co-immunoprecipitation (DAB2IP-PLK1, DAB2IP-Cdc20, PLK1-Mps1), Cdc20 ubiquitylation assay, SAC and chromosomal segregation assays, anaphase bridge/53BP1 body quantification\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — phospho-site mutagenesis, multiple Co-IPs, ubiquitylation assay, in-cell functional phenotypes; multiple orthogonal methods\",\n      \"pmids\": [\"34775484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DAB2IP interacts with the chaperone GRP75 via its Ras-GAP domain, competitively blocking GRP75-driven ubiquitination and proteasomal degradation of wild-type p53. This DAB2IP-GRP75 interaction stabilizes p53 and mediates tumor-suppressive effects in colon cancer cells.\",\n      \"method\": \"Mass spectrometry (identification of DAB2IP-p53-GRP75 complex), co-immunoprecipitation, competitive binding assay, ubiquitination assay, domain-deletion mutants (Ras-GAP domain required), in vivo tumor experiments\",\n      \"journal\": \"Cancer Letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — MS-based complex identification, competitive Co-IP, domain mapping, ubiquitination assay, in vivo validation\",\n      \"pmids\": [\"35150809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DAB2IP inhibits intratumoral testosterone synthesis in castration-resistant prostate cancer by suppressing AKR1C3 promoter activity and the conversion of DHEA to testosterone through the PI3K/AKT/mTOR/ETS1 signaling pathway, thereby reducing AR re-activation under androgen-depleted conditions.\",\n      \"method\": \"DAB2IP knockdown/overexpression, AKR1C3 promoter luciferase reporter assay, testosterone synthesis measurement, signaling pathway inhibition, in vivo castration model with DAB2IP-/- mice and DHEA supplementation\",\n      \"journal\": \"Cellular Signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay, functional rescue, and in vivo KO mouse validation, single lab\",\n      \"pmids\": [\"35452821\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DAB2IP downregulates HSP90AA1 expression through the HSP90AA1/SRP9/ASK1/JNK signaling axis to promote apoptosis in colorectal cancer cells. Mechanistic studies confirmed the DAB2IP-HSP90AA1 regulatory connection through bioinformatic prediction plus in vitro validation.\",\n      \"method\": \"Bioinformatic pathway analysis, in vitro knockdown/overexpression, apoptosis flow cytometry, Western blot for ASK1/JNK activation, in vivo xenograft\",\n      \"journal\": \"BMC Cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pathway analysis plus single-method functional assays; mechanism of direct regulation not fully characterized at molecular level\",\n      \"pmids\": [\"35590292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DAB2IP inhibits β-catenin nuclear transport by competitively interacting with RAC1, thereby reducing β-catenin accumulation in the cell nucleus and attenuating cancer stem cell properties and chemoresistance in triple-negative breast cancer.\",\n      \"method\": \"Co-immunoprecipitation (DAB2IP-RAC1 competitive interaction), nuclear/cytoplasmic fractionation of β-catenin, DAB2IP knockdown/overexpression, in vivo xenograft experiments\",\n      \"journal\": \"Clinical and Translational Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — competitive Co-IP with fractionation and functional phenotype readout, single lab\",\n      \"pmids\": [\"36536485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DAB2IP suppresses invadopodia formation and breast cancer metastasis by destabilizing anaplastic lymphoma kinase (ALK) through antagonizing the interaction between the deubiquitinase USP10 and ALK, leading to decreased ALK protein abundance, reduced Cortactin tyrosine phosphorylation, and prevention of invadopodia formation.\",\n      \"method\": \"Co-immunoprecipitation (DAB2IP-USP10-ALK competitive binding), Cortactin phosphorylation assay, invadopodia formation assay, in vivo metastasis model, ALK protein stability assays\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — competitive Co-IP, substrate phosphorylation readout, in vivo validation, single lab\",\n      \"pmids\": [\"37664607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DAB2IP expression is regulated by cell confluency (cell contact). DAB2IP depletion in confluent cells alters cell morphology (reduced cell packing, increased stiffness), favors YAP/TAZ nuclear localization and transcriptional activity, while ectopic DAB2IP expression in subconfluent cells increases YAP/TAZ cytoplasmic retention.\",\n      \"method\": \"DAB2IP knockdown and overexpression, YAP/TAZ nuclear/cytoplasmic localization by immunofluorescence, atomic force microscopy for cell stiffness, confluency-dependent expression analysis\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional perturbation with YAP/TAZ localization readout and biophysical measurements, single lab\",\n      \"pmids\": [\"37444489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DAB2IP is a bifunctional tumor suppressor in KRAS-mutant colorectal cancer: (1) it restrains wild-type H-RAS and N-RAS (required for robust RAS effector pathway activation even in KRAS-mutant tumors), and (2) its loss triggers production of inflammatory mediators and recruitment of protumorigenic macrophages in vivo. Tumor growth was suppressed by macrophage depletion or JAK/TBK1 inhibition in DAB2IP-depleted tumors.\",\n      \"method\": \"DAB2IP genetic loss in colorectal cancer models, Ras-GTP activation assay (H-/N-Ras), cytokine/inflammatory mediator profiling, macrophage depletion in vivo, JAK/TBK1 inhibitor treatment, histological analysis of tumor microenvironment\",\n      \"journal\": \"Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RAS-GTP assay plus in vivo macrophage depletion rescue, two mechanistically distinct findings, single lab\",\n      \"pmids\": [\"36939385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A DAB2IP missense variant (p.D239N) in the C2 domain impairs its interaction with VEGFR2, altering the subcellular localization of VEGFR2: wild-type DAB2IP colocalizes with VEGFR2 intracellularly, while the D239N mutant retains VEGFR2 at the cell membrane. This implicates DAB2IP in regulating endothelial VEGF/VEGFR2 signaling and vascular permeability.\",\n      \"method\": \"Whole exome sequencing, protein structure modeling, subcellular localization assay (transfection + immunofluorescence colocalization of DAB2IP variant and VEGFR2), co-localization quantification\",\n      \"journal\": \"The Journal of Allergy and Clinical Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with functional variant, structural modeling, single lab/family study\",\n      \"pmids\": [\"38823490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DAB2IP inhibits glucose uptake under hypoxia by interacting with the E3 ubiquitin ligase STUB1 via its PER domain, facilitating STUB1-mediated ubiquitylation and degradation of HIF-1α. Deletion of the PER domain abolishes DAB2IP-mediated inhibition of glucose uptake, ATP production, and lactic acid production.\",\n      \"method\": \"Co-immunoprecipitation (DAB2IP-STUB1-HIF-1α), domain deletion mutagenesis (PER domain), HIF-1α ubiquitylation assay, glucose uptake assay, metabolic assays (ATP, lactate), in vitro and in vivo experiments\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain mutagenesis defining PER domain requirement, Co-IP, ubiquitylation assay, multiple metabolic readouts; multiple orthogonal methods\",\n      \"pmids\": [\"38862467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Nuclear DAB2IP localizes to the nucleus, where it interacts with the histone acetyltransferase HBO1 and enhances the HBO1-PLK1 interaction. DAB2IP facilitates PLK1-mediated phosphorylation of HBO1, which promotes HBO1-directed H3K14 acetylation, enabling MCM complex loading onto chromatin and supporting DNA replication origin firing. ATR regulates CDK1-mediated phosphorylation of DAB2IP, which is required for HBO1-PLK1 complex formation and activation. Loss of this phosphorylation increases genomic instability (anaphase bridges, 53BP1 nuclear bodies).\",\n      \"method\": \"Nuclear fractionation, co-immunoprecipitation (DAB2IP-HBO1, HBO1-PLK1), PLK1 kinase assay for HBO1 phosphorylation, ChIP for H3K14Ac at replication origins, MCM loading assay, CDK1 phosphorylation site mutagenesis, genomic instability assays (anaphase bridge/53BP1 quantification)\",\n      \"journal\": \"Nucleic Acids Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple Co-IPs, kinase assay, ChIP, MCM loading, and phospho-site mutagenesis with genomic stability readout; multiple orthogonal methods in one study\",\n      \"pmids\": [\"41261855\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DAB2IP is a multifunctional scaffold protein and Ras-GTPase-activating protein (RasGAP) that integrates multiple signaling pathways: it suppresses Ras/PI3K-AKT and ERK mitogenic signals via its GAP domain; modulates TNF/TRAF2-ASK1-JNK versus IKK-NF-κB balance by dynamic membrane-to-cytoplasm translocation; inhibits androgen receptor nuclear signaling and c-Src; interacts with PLK1 to regulate spindle assembly checkpoint integrity and DNA replication initiation (via HBO1-mediated H3K14 acetylation and MCM loading); promotes p53 stability by competing for GRP75; inhibits HIF-1α via STUB1-mediated ubiquitylation; suppresses YAP/TAZ activity at cell confluence; and is itself regulated by EZH2-mediated epigenetic silencing, Akt1/Fbw7/Smurf1-mediated proteasomal degradation, and direct inhibition by mutant p53.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DAB2IP is a multidomain scaffold and Ras-GTPase-activating protein that functions as a tumor suppressor by restraining mitogenic and survival signaling while licensing apoptotic and checkpoint responses [#0, #4]. Originally cloned as a RasGAP-family protein interacting with DOC-2/DAB2 through a Ras-GAP homology domain, proline repeats, and a leucine zipper [#0, #1], it directly restrains H-, N-, and wild-type RAS GTP-loading to suppress mitogenic signaling [#27, #36], an activity supported by stabilizing partners such as RASSF1A [#27]. As a scaffold it partitions TNF signaling: at the plasma membrane DAB2IP (AIP1) sits in a closed conformation bound to TNFR1, and upon TNF stimulation translocates to the cytoplasm where its PERIOD-like domain engages the TRAF2 RING to enhance ASK1/JNK activation while inhibiting IKK-NF-\\u03baB signaling [#3], and its proline-rich and PER domains concurrently suppress PI3K-Akt survival signaling [#4]. Through these and related circuits DAB2IP suppresses epithelial-to-mesenchymal transition and cancer stem-cell properties by limiting nuclear \\u03b2-catenin/TCF activity, c-kit\\u2013PI3K\\u2013Akt\\u2013mTOR\\u2013ZEB1 signaling, and noncanonical WNT/RAC1 signaling [#5, #13, #26, #33], and it antagonizes androgen receptor genomic and non-genomic (c-Src) signaling and intratumoral testosterone synthesis [#9, #31]. DAB2IP additionally controls mitotic fidelity and DNA replication: it directly binds PLK1 to sustain kinase activity, BubR1 kinetochore loading, and spindle-assembly-checkpoint integrity [#19], is phosphorylated by Cdks to scaffold the PLK1-Mps1-Cdc20 axis and stabilize the mitotic checkpoint complex [#29], and in the nucleus promotes HBO1-PLK1-mediated H3K14 acetylation enabling MCM loading and origin firing under ATR/CDK1 control [#39]. It stabilizes wild-type p53 by competing with GRP75 [#30] and inhibits HIF-1\\u03b1 by bridging the E3 ligase STUB1 [#38], while being itself inactivated by direct binding of mutant p53 [#12, #22], epigenetic EZH2-mediated silencing [#6, #26], and Akt/Fbw7/Skp2/Smurf1-driven proteasomal degradation [#14, #16, #18]. A C2-domain missense variant impairing DAB2IP-VEGFR2 interaction links the protein to endothelial VEGF/VEGFR2 signaling and vascular permeability [#37].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established DAB2IP's molecular identity, defining it as a RasGAP-family scaffold that partners with DOC-2/DAB2 to block mitogenic gene expression and prostate cancer growth.\",\n      \"evidence\": \"Yeast two-hybrid cloning, reciprocal Co-IP, domain characterization and growth assays; promoter mapping and luciferase reporters\",\n      \"pmids\": [\"11812785\", \"11944990\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which RAS isoforms are direct GAP substrates\", \"Mechanism of epigenetic promoter silencing not defined at the chromatin level\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Connected DAB2IP to neuronal signaling by showing it binds the Dab1 PTB domain via an NPxY motif, positioning it downstream of Reelin signaling in the developing brain.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP from brain lysates, domain mapping, in situ hybridization\",\n      \"pmids\": [\"12877983\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the Dab1 interaction for Ras signaling not tested in vivo\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Revealed the conformational switch underlying DAB2IP's TNF scaffolding: TNF releases it from TNFR1 to form a TRADD/RIP1/TRAF2 complex that drives ASK1 while suppressing NF-\\u03baB.\",\n      \"evidence\": \"Co-IP, subcellular fractionation, deletion-mutant and domain mapping, signaling reporters in endothelial cells\",\n      \"pmids\": [\"15310755\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger for the conformational opening not defined biochemically\", \"Stoichiometry of the multiprotein signaling complex unresolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined DAB2IP as a dual-function scaffold that suppresses PI3K-Akt while enhancing ASK1 apoptotic signaling, with distinct domains assigned to each arm and validated in a knockout mouse.\",\n      \"evidence\": \"Domain-deletion mutagenesis, signaling Westerns, DAB2IP knockout mouse, xenograft\",\n      \"pmids\": [\"19903888\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the two signaling arms are temporally coordinated not addressed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended DAB2IP's tumor-suppressor reach to EMT, androgen receptor signaling, chemoresistance and cancer stemness, defining multiple downstream transcriptional and kinase circuits it restrains.\",\n      \"evidence\": \"Cell-line gain/loss-of-function, reporter assays, c-Src kinase assays, domain mutants, KO mouse models, clinical specimens\",\n      \"pmids\": [\"20080667\", \"23604126\", \"23838317\", \"25043300\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct versus indirect nature of several transcriptional effects (\\u03b2-catenin/TCF, c-kit) not fully separated\", \"How a single scaffold engages so many pathways in one cell unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified the post-translational regulatory network that inactivates DAB2IP, including Akt1 phosphorylation, Fbw7/Skp2-mediated degradation, and direct mutant-p53 binding that reroutes TNF signaling toward NF-\\u03baB.\",\n      \"evidence\": \"In vitro kinase assays, Co-IP, ubiquitination/proteasome assays, phospho-degron mutants, STAT3 domain mapping, xenografts\",\n      \"pmids\": [\"24912918\", \"25115390\", \"26512963\", \"25454946\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contributions of competing E3 ligases in vivo not ranked\", \"Whether mutp53 binding is direct or bridged not fully resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Uncovered DAB2IP's mitotic role, showing it directly binds PLK1 to sustain kinase activity, BubR1 kinetochore loading, and spindle-assembly-checkpoint integrity.\",\n      \"evidence\": \"Co-IP, PLK1 kinase activity assay, BubR1 phosphorylation, kinetochore immunofluorescence, chromosomal segregation and drug-sensitivity assays\",\n      \"pmids\": [\"27568005\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether DAB2IP is a PLK1 substrate or allosteric activator at this stage unclear\", \"Nuclear/mitotic localization mechanism not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Broadened DAB2IP's GAP repertoire beyond RAS to RAB40C, linking its GAP domain to lipid droplet homeostasis, and added KIF3a binding tying it to primary cilia stability.\",\n      \"evidence\": \"Co-IP, GAP-defective mutants, CRISPR knockout, lipid droplet imaging; mass-spec interactome and PH-domain mapping for KIF3a\",\n      \"pmids\": [\"29156729\", \"33341566\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct GAP activity on RAB40C not measured biochemically\", \"Cilia phenotype mechanism beyond KIF3a binding unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined a Cdk-phosphorylation-dependent mode in which DAB2IP scaffolds the PLK1-Mps1-Cdc20 axis to stabilize the mitotic checkpoint complex and prevent premature APC/C activation.\",\n      \"evidence\": \"Cdk phospho-site mutagenesis, multiple Co-IPs, Cdc20 ubiquitylation assay, SAC and genomic-instability readouts\",\n      \"pmids\": [\"34775484\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which Cdk(s) phosphorylate DAB2IP in vivo not pinpointed\", \"Structural basis of MCC stabilization unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established DAB2IP as a regulator of p53 stability and tumor metabolism, competing with GRP75 to protect wild-type p53 and bridging STUB1 to degrade HIF-1\\u03b1.\",\n      \"evidence\": \"Mass-spec complex identification, competitive Co-IP, ubiquitination assays, domain mapping, glucose/ATP/lactate metabolic readouts, in vivo\",\n      \"pmids\": [\"35150809\", \"38862467\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether p53 stabilization and HIF-1\\u03b1 degradation occur in the same cellular context not tested\", \"Domain assignments differ (Ras-GAP vs PER) across substrates without unifying model\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linked DAB2IP to mechanotransduction and the tumor microenvironment, showing confluency-dependent suppression of YAP/TAZ and that its loss recruits protumorigenic macrophages via inflammatory signaling.\",\n      \"evidence\": \"Bidirectional perturbation with YAP/TAZ localization, atomic force microscopy; RAS-GTP assays, cytokine profiling, in vivo macrophage depletion and JAK/TBK1 inhibition\",\n      \"pmids\": [\"37444489\", \"36939385\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between DAB2IP and the YAP/TAZ machinery not defined\", \"Direct versus secondary nature of inflammatory mediator induction unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a nuclear, replication-licensing function in which ATR/CDK1-phosphorylated DAB2IP scaffolds HBO1-PLK1 to drive H3K14 acetylation, MCM loading and origin firing.\",\n      \"evidence\": \"Nuclear fractionation, Co-IPs, PLK1 kinase assay, ChIP for H3K14Ac at origins, MCM loading assay, phospho-site mutagenesis, genomic-instability readouts\",\n      \"pmids\": [\"41261855\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of DAB2IP nuclear import not established\", \"How nuclear replication role coordinates with cytoplasmic GAP/scaffold functions unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single multidomain scaffold dynamically partitions among plasma membrane, cytoplasm, and nucleus to selectively engage RAS-GAP, TNF/ASK1, checkpoint, and replication functions remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No integrated model of spatial/temporal regulation across compartments\", \"No structural model of full-length DAB2IP with partners\", \"Direct GAP activity quantified for only a subset of GTPases\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 3, 4, 30, 38]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 27, 36, 23]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [19, 29, 39]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 37]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3, 12, 22]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [39]},\n      {\"term_id\": \"GO:0005811\", \"supporting_discovery_ids\": [23]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [28]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 4, 27, 36]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [19, 29, 39]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [4, 15, 32]},\n      {\"term_id\": \"R-HSA-69306\", \"supporting_discovery_ids\": [39]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [12, 22]}\n    ],\n    \"complexes\": [\n      \"TNFR1-TRADD-RIP1-TRAF2 signaling complex\",\n      \"PLK1-Mps1-Cdc20 mitotic checkpoint module\",\n      \"DAB2IP-p53-GRP75 complex\",\n      \"HBO1-PLK1 replication-licensing complex\"\n    ],\n    \"partners\": [\n      \"DAB2\",\n      \"TRAF2\",\n      \"PLK1\",\n      \"Cdc20\",\n      \"HBO1\",\n      \"GRP75\",\n      \"STUB1\",\n      \"RASSF1A\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}