{"gene":"DCBLD2","run_date":"2026-06-09T23:54:41","timeline":{"discoveries":[{"year":2001,"finding":"ESDN/DCBLD2 is a type-I transmembrane protein containing a CUB domain, a coagulation factor V/VIII homology domain, and an LCCL domain, and harbors the longest cleavable secretory signal sequence among eukaryotes. Overexpression of ESDN in 293T cells suppressed BrdU uptake, indicating a role in inhibiting cell proliferation.","method":"Signal sequence trap cloning, domain analysis, overexpression in 293T cells with BrdU uptake assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional assay (BrdU suppression) with overexpression, domain architecture established by sequence analysis; single lab, single paper","pmids":["11447234"],"is_preprint":false},{"year":2007,"finding":"DCBLD2 (ESDN) is upregulated in proliferating vascular smooth muscle cells (VSMCs); ESDN overexpression in VSMCs decreased growth, while ESDN knockdown increased VSMC proliferation, establishing ESDN as a regulator of VSMC proliferation.","method":"VSMC culture with ESDN overexpression and siRNA knockdown; growth curve analysis","journal":"American journal of transplantation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function and gain-of-function in primary VSMCs with defined proliferation readout; single lab","pmids":["17697260"],"is_preprint":false},{"year":2007,"finding":"DCBLD2 is a novel tyrosine phosphorylation target of EGF/EGFR signaling, identified and validated by phosphoproteomics; phosphorylation is blocked by the EGFR inhibitor Iressa.","method":"cICAT-based LC-MS/MS phosphoproteomics from EGF-treated A431 cells, validated by western blot with EGFR inhibitor","journal":"Proteomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mass spectrometry identification plus pharmacological validation; single lab","pmids":["17570516"],"is_preprint":false},{"year":2008,"finding":"Ectopic expression of DCBLD2 in gastric cancer cell lines inhibited colony formation (anchorage-dependent and -independent) and inhibited invasion through collagen matrix, demonstrating a suppressive role in gastric cancer cell proliferation and invasion.","method":"Ectopic expression in gastric cancer cell lines; colony formation assay, collagen matrix invasion assay","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function with two orthogonal functional readouts (colony formation + invasion); single lab","pmids":["18314483"],"is_preprint":false},{"year":2010,"finding":"The long signal peptide of DCBLD2 can be dissected into functional N and C subdomains per the NtraC model: the C-domain is sufficient and essential for ER targeting, whereas the N-domain is dispensable and thus available for additional functions.","method":"Deletion/chimeric construct expression; ER targeting assay","journal":"Molecular bioSystems","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional dissection of signal peptide subdomains using defined constructs; single lab, single paper","pmids":["21183991"],"is_preprint":false},{"year":2013,"finding":"DCBLD2 (ESDN) intracellular tyrosines in YxxP motifs are phosphorylated by Src family kinases (SFKs); phosphorylation at Y565, Y621, Y750, and Y715 (non-YxxP) recruits the SH2 domain of the signaling adaptor CrkL. Antibody-mediated ESDN clustering induces tyrosine phosphorylation and CrkL-SH2 binding.","method":"Mutagenesis of seven intracellular tyrosines; quantitative mass spectrometry; SH2 domain pulldown; pharmacological SFK inhibition; antibody clustering assay","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 / Strong — site-directed mutagenesis combined with quantitative MS and multiple functional binding assays; multiple orthogonal methods in single rigorous study","pmids":["23770091"],"is_preprint":false},{"year":2013,"finding":"ESDN/DCBLD2 promotes VEGF-induced endothelial cell proliferation and migration; it associates with VEGFR-2 and regulates VEGFR-2 complex formation with the negative regulators PTP1B, TC-PTP, and VE-cadherin. Loss of ESDN in EC-specific knockout mice blunted VEGF responses and VEGFR-2 signaling in vivo.","method":"Global and EC-specific Esdn knockout mice; zebrafish dcbld2 knockdown; Co-IP of ESDN with VEGFR-2, PTP1B, TC-PTP, and VE-cadherin; VEGFR-2 signaling assays","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — genetic knockout (global + EC-specific + zebrafish), reciprocal co-IP with multiple partners, and in vivo signaling assays in one study","pmids":["24177422"],"is_preprint":false},{"year":2014,"finding":"EGFR phosphorylates DCBLD2 at tyrosine 750 (Y750), which lies within a TRAF6-binding motif. Phospho-Y750 recruits TRAF6, leading to increased TRAF6 E3 ubiquitin ligase activity and subsequent AKT activation, thereby promoting EGFR-driven tumorigenesis.","method":"Phospho-specific antibodies; Co-IP of DCBLD2 Y750 with TRAF6; TRAF6 E3 ubiquitin ligase activity assay; AKT activation assays; tumor xenograft models; Y750 mutagenesis","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — site-specific mutagenesis, co-IP, in vitro E3 ligase assay, and in vivo tumor model; multiple orthogonal methods establishing a complete mechanistic pathway","pmids":["25061874"],"is_preprint":false},{"year":2016,"finding":"ESDN/DCBLD2 inhibits insulin receptor signaling by interacting with the insulin receptor and altering its interaction with the regulatory adaptor-E3 ubiquitin ligase pairs APS-c-Cbl and GRB10-NEDD4. Esdn gene deletion enhances insulin-induced AKT and MAPK activation, VSMC proliferation/migration, and improves insulin sensitivity and glucose homeostasis in vivo.","method":"Esdn knockout mice; in vivo glucose/insulin tolerance tests; Co-IP of ESDN with insulin receptor; western blot for AKT/MAPK phosphorylation; VSMC proliferation/migration assays","journal":"American journal of physiology. Heart and circulatory physiology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — genetic knockout with in vivo metabolic phenotype, Co-IP establishing protein-protein interaction, and mechanistic dissection of adaptor complex regulation; multiple orthogonal methods","pmids":["26921437"],"is_preprint":false},{"year":2017,"finding":"DCBLD2 intracellular YxxP motifs are phosphorylated by Src family kinases (SFKs; specifically Fyn) and Abl kinase, which differentially promote CRKL-SH2 domain binding to DCBLD2. Site-specific quantitative phosphoproteomics mapped the SFK vs. Abl preferences for individual YxxP sites on DCBLD2.","method":"HPLC-coupled tandem mass spectrometry; kinase overexpression; CRKL-SH2 pulldown; pharmacological kinase inhibition","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — quantitative site-specific phosphoproteomics plus functional binding assays; multiple orthogonal methods in single study","pmids":["29025973"],"is_preprint":false},{"year":2021,"finding":"DCBLD2 stabilizes β-catenin by phosphorylating GSK3β; accumulated β-catenin is transported to the nucleus to promote EMT-related transcription factor expression, mediating cisplatin-induced metastasis in lung adenocarcinoma.","method":"siRNA knockdown, western blot for GSK3β phosphorylation and β-catenin nuclear translocation, in vitro migration/invasion assays, in vivo metastasis model with nanoparticle-delivered siRNA","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with mechanistic signaling readouts (GSK3β phosphorylation, β-catenin localization) and in vivo validation; single lab","pmids":["33808696"],"is_preprint":false},{"year":2021,"finding":"A homozygous nonsense variant (p.W27*) in DCBLD2 in a patient results in reduced cell proliferation, impaired cell cycle progression, and altered intracellular ROS and Ca2+ levels in patient-derived skin fibroblasts, functionally characterizing this loss-of-function variant.","method":"Whole-exome sequencing; in vitro functional studies on patient skin fibroblasts (proliferation, cell cycle, ROS, Ca2+ assays)","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient-derived fibroblast functional studies with multiple cellular readouts; single lab, no rescue experiment","pmids":["34145321"],"is_preprint":false},{"year":2021,"finding":"DCBLD2 binds ITGB1 (integrin β1, a key focal adhesion pathway component) as identified by TAP-MS and confirmed by Co-IP, implicating DCBLD2 in the focal adhesion pathway in colorectal cancer cells.","method":"TAP-MS affinity purification followed by Co-IP validation","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — TAP-MS identification confirmed by Co-IP; single lab","pmids":["34095137"],"is_preprint":false},{"year":2021,"finding":"In endothelial cells, ESDN/DCBLD2 loss leads to increased E-selectin transcript and protein levels, enhanced melanoma cell adhesion and extravasation, and increased metastasis in Esdn-null mice. ESDN suppresses E-selectin transcription, potentially through STAT3.","method":"Esdn-null mouse melanoma injection model; endothelial cell adhesion assay; E-selectin mRNA/protein quantification; cimetidine (E-selectin inhibitor) rescue experiment","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout mouse model with in vivo metastasis readout and mechanistic rescue; STAT3 link is proposed but not directly demonstrated by mechanistic experiment","pmids":["33862151"],"is_preprint":false},{"year":2022,"finding":"DCBLD2 inhibits caveolae-dependent endocytosis of PDGFR-β in VSMCs by anchoring PDGFR-β on the cell membrane via competition with Caveolin-1 (Cav-1). DCBLD2 deletion increases PDGFR-β–Cav-1 binding and accelerates PDGF-induced PDGFR-β internalization to lysosomes.","method":"VSMC-conditional and germline Dcbld2 knockout mice; Co-IP of PDGFR-β with Cav-1 and DCBLD2; biotin surface labeling; membrane/cytosol fractionation; double immunofluorescence","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — genetic knockout (germline + conditional), Co-IP, surface biotinylation, fractionation, and imaging; multiple orthogonal methods establishing a receptor endocytosis mechanism","pmids":["35929441"],"is_preprint":false},{"year":2023,"finding":"CD146 protein physically interacts with DCBLD2 and prevents its degradation, thereby stabilizing DCBLD2 and activating downstream PI3K/AKT signaling in breast phyllodes tumor cells.","method":"Co-immunoprecipitation, pull-down assay, transcriptome and proteomic analysis, functional proliferation/invasion assays","journal":"Cancer communications (London, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and pulldown establish interaction; single lab with multiple methods","pmids":["37856423"],"is_preprint":false},{"year":2024,"finding":"DCBLD2 deletion in endothelial cells inhibits insulin receptor recycling in a Rab11-dependent manner, reduces membrane InsR levels, and attenuates InsR/PI3K/Akt signaling, exacerbating endothelial dysfunction and vascular remodeling in diabetic mice.","method":"Endothelium-specific and global Dcbld2 knockout mice; streptozotocin-induced diabetes model; Co-IP for InsR interactions; membrane/cytoplasm fractionation; glycolytic rate assay; western blot","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — endothelium-specific genetic knockout with in vivo metabolic and vascular phenotype, Co-IP, subcellular fractionation establishing Rab11-dependent recycling mechanism; multiple orthogonal methods","pmids":["38872483"],"is_preprint":false},{"year":2025,"finding":"DCBLD2 and VEGFA act synergistically in choroidal endothelial cells to enhance proliferation, migration, and angiogenic tube formation; DCBLD2 potentiates VEGFA-driven effects by increasing VEGFR2 phosphorylation and activating downstream AKT and ERK1/2 signaling cascades.","method":"Functional validation in choroidal endothelial cells (proliferation, migration, tube formation assays); VEGFR2 phosphorylation western blot; AKT/ERK1/2 activation assays","journal":"Journal of proteome research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct cell-based functional assays with signaling readouts; single lab, single paper, no genetic rescue or mutagenesis","pmids":["41110167"],"is_preprint":false},{"year":2026,"finding":"DCBLD2 loss in endothelial cells enhances TGF-β signaling by increasing clathrin-mediated endocytosis of TGF-β receptor (TGF-βR); DCBLD2 interacts with TGF-βR and clathrin, and its loss promotes EndMT. DCBLD2 knockout mice show higher prevalence of calcific aortic valve disease.","method":"DCBLD2 knockout mice; immunoprecipitation of DCBLD2 with TGF-βR and clathrin; western blot for TGF-β pathway phosphorylation; Pitstop 2 clathrin inhibitor rescue; immunofluorescence; endothelial migration assay","journal":"Journal of molecular and cellular cardiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with in vivo phenotype, Co-IP establishing protein interactions, and pharmacological rescue; single lab","pmids":["42178133"],"is_preprint":false},{"year":2026,"finding":"DCBLD2 overexpression inhibits osteogenic differentiation of BMSCs and suppresses PI3K/AKT pathway activation; miR-34c-3p directly binds DCBLD2 mRNA (confirmed by AGO2-RIP and dual-luciferase assay) to suppress its expression and thereby promote osteogenic differentiation.","method":"Overexpression and knockdown of DCBLD2 in BMSCs; ALP and alizarin red staining; PI3K activator rescue; AGO2-RIP; dual-luciferase reporter assay","journal":"Journal of molecular histology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional differentiation assays plus validated miRNA-target interaction with two orthogonal methods; single lab","pmids":["41721921"],"is_preprint":false},{"year":2024,"finding":"The signal sequence (SS) of DCBLD2 is not cleaved in the mature protein and directly interacts with VEGFR2 via its hydrophobic 'traC' segment (specifically the L5VL5/L10 sequence). The SS promotes VEGF-induced signaling, and a synthetic traC-derived peptide (L10) enhances VEGFR2 signaling in vitro and promotes angiogenesis and blood flow recovery in vivo.","method":"Co-immunoprecipitation of DCBLD2 domain constructs with VEGFR2 in HEK293T and endothelial cells; synthetic peptide signaling assays; matrigel plug and corneal micropocket angiogenesis assays; hindlimb ischemia model","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mapping by Co-IP with multiple constructs, peptide functional assays in vitro and in vivo; preprint, not yet peer-reviewed","pmids":[],"is_preprint":true}],"current_model":"DCBLD2/ESDN is a type-I transmembrane neuropilin-like scaffolding receptor whose intracellular YxxP motifs are phosphorylated by EGFR, Src family kinases (Fyn), and Abl, enabling recruitment of signaling adaptors (CrkL, TRAF6); phospho-Y750 specifically recruits TRAF6 to amplify AKT activation downstream of oncogenic EGFR, while the extracellular/transmembrane region (including its retained signal sequence 'traC' segment) associates with VEGFR-2 to promote VEGF signaling by displacing negative regulators (PTP1B, TC-PTP) and, in the context of PDGFR-β and insulin receptor, DCBLD2 anchors these receptors at the plasma membrane to prevent their Caveolin-1-mediated endocytosis, thereby sustaining their downstream signaling; in endothelial cells DCBLD2 similarly blocks clathrin-mediated TGF-βR endocytosis to suppress EndMT, and promotes insulin receptor Rab11-dependent recycling to sustain InsR/PI3K/Akt activity."},"narrative":{"mechanistic_narrative":"DCBLD2 (ESDN) is a type-I transmembrane neuropilin-like receptor that functions as a phosphorylation-dependent scaffold controlling the cell-surface residence and downstream signaling of multiple growth factor and cytokine receptors [PMID:11447234, PMID:24177422]. Its intracellular YxxP motifs are phosphorylated by EGFR, Src-family kinases (notably Fyn), and Abl, and these phosphosites differentially recruit the SH2 adaptor CrkL; phosphorylation at Y565, Y621, Y715, and Y750 mediates CrkL binding, and antibody-induced receptor clustering is sufficient to trigger this phosphorylation [PMID:23770091, PMID:29025973]. A distinct phosphosite, EGFR-driven phospho-Y750, lies within a TRAF6-binding motif and recruits TRAF6 to stimulate its E3 ubiquitin ligase activity and amplify AKT activation, driving EGFR-dependent tumorigenesis [PMID:25061874]. In the vasculature, DCBLD2 associates with VEGFR-2 and regulates its complex with the negative regulators PTP1B, TC-PTP, and VE-cadherin to promote VEGF-induced endothelial proliferation, migration, and angiogenesis [PMID:24177422, PMID:41110167]. A recurring mechanistic theme is control of receptor trafficking: DCBLD2 anchors PDGFR-β at the plasma membrane by competing with Caveolin-1 to block caveolae-dependent endocytosis [PMID:35929441], sustains insulin receptor surface levels through Rab11-dependent recycling [PMID:38872483], and limits clathrin-mediated TGF-β receptor endocytosis to suppress endothelial-to-mesenchymal transition [PMID:42178133]. Consistent with an early-defined growth-suppressive role, DCBLD2 overexpression inhibits proliferation and tumor cell colony formation and invasion [PMID:11447234, PMID:18314483], yet it also negatively regulates insulin receptor signaling via the APS-c-Cbl and GRB10-NEDD4 adaptor-ligase pairs, such that Esdn deletion improves insulin sensitivity in vivo [PMID:26921437]. A homozygous nonsense variant (p.W27*) in a patient impairs fibroblast proliferation and alters ROS and Ca2+ homeostasis, functionally characterizing loss of DCBLD2 [PMID:34145321].","teleology":[{"year":2001,"claim":"Established DCBLD2/ESDN as a distinctive type-I transmembrane protein with CUB, coagulation factor V/VIII, and LCCL domains and an unusually long signal sequence, and gave the first functional clue that it restrains proliferation.","evidence":"Signal-sequence trap cloning, domain analysis, and BrdU uptake after overexpression in 293T cells","pmids":["11447234"],"confidence":"Medium","gaps":["No binding partners or signaling mechanism identified","Antiproliferative effect based on overexpression only"]},{"year":2007,"claim":"Connected DCBLD2 to vascular biology by showing it regulates proliferation of vascular smooth muscle cells bidirectionally with gene dose.","evidence":"ESDN overexpression and siRNA knockdown in primary VSMCs with growth-curve readout","pmids":["17697260"],"confidence":"Medium","gaps":["Molecular mechanism of growth control unresolved","No receptor partner defined"]},{"year":2007,"claim":"Identified DCBLD2 as a tyrosine-phosphorylation substrate of EGFR signaling, placing it downstream of growth-factor receptor activation.","evidence":"cICAT phosphoproteomics in EGF-treated A431 cells with EGFR-inhibitor (Iressa) validation","pmids":["17570516"],"confidence":"Medium","gaps":["Specific phosphosites not mapped","Functional consequence of phosphorylation not shown"]},{"year":2010,"claim":"Dissected the long signal sequence into NtraC subdomains, showing the C-domain alone drives ER targeting and freeing the N-domain for additional functions.","evidence":"Deletion/chimeric constructs with ER-targeting assays","pmids":["21183991"],"confidence":"Medium","gaps":["Function of the dispensable N-domain not defined","No partner identified for the retained segment at this stage"]},{"year":2013,"claim":"Defined the phosphorylation logic of the cytoplasmic tail, showing SFKs phosphorylate YxxP tyrosines that recruit the CrkL SH2 domain and that receptor clustering activates this circuit.","evidence":"Site-directed mutagenesis of seven tyrosines, quantitative MS, SH2 pulldowns, SFK inhibition, and antibody clustering","pmids":["23770091"],"confidence":"High","gaps":["Downstream output of CrkL recruitment not traced","Physiological clustering ligand unknown"]},{"year":2013,"claim":"Established DCBLD2 as a positive regulator of VEGFR-2 signaling in endothelium by genetic loss and partner mapping, distinguishing it from its growth-suppressive role elsewhere.","evidence":"Global, EC-specific, and zebrafish loss-of-function; reciprocal Co-IP with VEGFR-2, PTP1B, TC-PTP, VE-cadherin; in vivo VEGF signaling assays","pmids":["24177422"],"confidence":"High","gaps":["Structural basis of VEGFR-2 association not resolved","Mechanism of displacing PTP1B/TC-PTP not detailed"]},{"year":2014,"claim":"Resolved a specific oncogenic phosphosite pathway: EGFR-phosphorylated Y750 recruits TRAF6 to boost its ligase activity and AKT signaling, driving tumorigenesis.","evidence":"Phospho-specific antibodies, Y750 mutagenesis, TRAF6 Co-IP and E3 ligase assays, AKT readouts, and xenograft models","pmids":["25061874"],"confidence":"High","gaps":["TRAF6 ubiquitination substrate in this context not defined","Link between Y750 and the CrkL-binding sites not integrated"]},{"year":2016,"claim":"Showed DCBLD2 negatively regulates insulin receptor signaling through adaptor-E3 ligase pairs, giving it a systemic metabolic role.","evidence":"Esdn knockout mice with glucose/insulin tolerance tests, InsR Co-IP, AKT/MAPK blots, and VSMC assays","pmids":["26921437"],"confidence":"High","gaps":["How DCBLD2 modulates APS-c-Cbl and GRB10-NEDD4 binding mechanistically unclear","Reconciliation with later positive InsR-recycling role unresolved"]},{"year":2017,"claim":"Refined the kinase-phosphosite code by showing Fyn and Abl differentially phosphorylate individual YxxP sites to tune CrkL recruitment.","evidence":"Site-specific quantitative phosphoproteomics, kinase overexpression, CrkL-SH2 pulldowns, and kinase inhibition","pmids":["29025973"],"confidence":"High","gaps":["Cellular contexts engaging Fyn versus Abl not defined","Downstream signaling differences between sites not measured"]},{"year":2021,"claim":"Expanded the partner repertoire and disease links: DCBLD2 binds ITGB1 (focal adhesion), stabilizes β-catenin via GSK3β to drive lung adenocarcinoma metastasis, suppresses endothelial E-selectin to limit melanoma extravasation, and a nonsense variant impairs fibroblast proliferation.","evidence":"TAP-MS/Co-IP (ITGB1); siRNA with GSK3β/β-catenin readouts and in vivo metastasis; Esdn-null melanoma model with E-selectin quantification; whole-exome sequencing and patient fibroblast assays","pmids":["34095137","33808696","33862151","34145321"],"confidence":"Medium","gaps":["STAT3 link to E-selectin not directly demonstrated","No rescue for the p.W27* patient variant","Mechanism linking DCBLD2 to GSK3β phosphorylation unresolved"]},{"year":2022,"claim":"Defined a trafficking mechanism: DCBLD2 retains PDGFR-β at the membrane by competing with Caveolin-1 to block caveolae-dependent internalization and lysosomal degradation.","evidence":"Germline and conditional Dcbld2 knockout mice, PDGFR-β/Cav-1/DCBLD2 Co-IP, surface biotinylation, fractionation, and imaging","pmids":["35929441"],"confidence":"High","gaps":["Whether the same competition applies to other receptors not tested here","Structural basis of Cav-1 competition unknown"]},{"year":2023,"claim":"Identified CD146 as a stabilizer of DCBLD2 protein that activates PI3K/AKT in phyllodes tumor cells, adding upstream regulation of DCBLD2 abundance.","evidence":"Reciprocal Co-IP, pulldown, omics, and proliferation/invasion assays","pmids":["37856423"],"confidence":"Medium","gaps":["Degradation pathway prevented by CD146 not defined","Single tumor context"]},{"year":2024,"claim":"Extended the trafficking model to insulin receptor recycling, showing DCBLD2 sustains InsR surface levels and InsR/PI3K/Akt signaling via Rab11-dependent recycling, with vascular consequences in diabetes.","evidence":"Endothelium-specific and global Dcbld2 knockout mice, streptozotocin diabetes model, InsR Co-IP, fractionation, glycolytic and signaling assays","pmids":["38872483"],"confidence":"High","gaps":["Apparent contrast with earlier negative InsR regulation not mechanistically reconciled","Direct role in Rab11 recruitment not shown"]},{"year":2024,"claim":"Provided a molecular basis for VEGFR-2 association by showing the uncleaved signal sequence's hydrophobic traC segment binds VEGFR-2, and a derived peptide promotes angiogenesis.","evidence":"Co-IP of DCBLD2 domain constructs with VEGFR2, synthetic peptide signaling assays, matrigel/corneal angiogenesis, and hindlimb ischemia (preprint)","pmids":[],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","Structural detail of the traC–VEGFR2 interface limited"]},{"year":2026,"claim":"Generalized the endocytosis-blocking mechanism to TGF-βR, where DCBLD2 binds TGF-βR and clathrin to limit clathrin-mediated internalization, suppress EndMT, and protect against calcific aortic valve disease.","evidence":"DCBLD2 knockout mice, DCBLD2–TGF-βR/clathrin Co-IP, TGF-β pathway blots, Pitstop 2 rescue, and migration assays","pmids":["42178133"],"confidence":"Medium","gaps":["Direct competition with the clathrin machinery not quantified","Single lab"]},{"year":2026,"claim":"Identified miR-34c-3p as a direct upstream repressor of DCBLD2 mRNA controlling osteogenic differentiation through PI3K/AKT.","evidence":"DCBLD2 overexpression/knockdown in BMSCs, ALP/alizarin red staining, PI3K activator rescue, AGO2-RIP, and dual-luciferase reporter","pmids":["41721921"],"confidence":"Medium","gaps":["In vivo relevance to bone not tested","Receptor partner mediating PI3K/AKT in BMSCs not defined"]},{"year":null,"claim":"How DCBLD2's growth-suppressive versus signaling-amplifying roles and its opposing effects on insulin receptor activity are integrated into a single regulatory logic remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model reconciling negative InsR regulation (2016) with InsR-recycling support (2024)","No structural model of the full receptor or its receptor-binding interfaces","Endogenous ligand/clustering trigger for the cytoplasmic phosphorylation circuit unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[5,7,9]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[6,14,16,18]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,14,16]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,7,8,17]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[14,16,18]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[7,10,11]}],"complexes":[],"partners":["EGFR","VEGFR2","TRAF6","CRKL","PDGFRB","INSR","ITGB1","CAV1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96PD2","full_name":"Discoidin, CUB and LCCL domain-containing protein 2","aliases":["CUB, LCCL and coagulation factor V/VIII-homology domains protein 1","Endothelial and smooth muscle cell-derived neuropilin-like protein"],"length_aa":775,"mass_kda":85.0,"function":"","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q96PD2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DCBLD2","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":[],"url":"https://opencell.sf.czbiohub.org/search/DCBLD2","total_profiled":1310},"omim":[{"mim_id":"616889","title":"CENTROSOMAL PROTEIN, 68-KD; CEP68","url":"https://www.omim.org/entry/616889"},{"mim_id":"608880","title":"ZINC FINGER FYVE DOMAIN-CONTAINING PROTEIN 16; ZFYVE16","url":"https://www.omim.org/entry/608880"},{"mim_id":"608698","title":"DISCOIDIN, CUB, AND LCCL DOMAIN-CONTAINING PROTEIN 2; DCBLD2","url":"https://www.omim.org/entry/608698"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"},{"location":"Golgi apparatus","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/DCBLD2"},"hgnc":{"alias_symbol":["CLCP1","ESDN"],"prev_symbol":[]},"alphafold":{"accession":"Q96PD2","domains":[{"cath_id":"2.60.120.290","chopping":"72-190","consensus_level":"medium","plddt":90.9418,"start":72,"end":190},{"cath_id":"2.170.130.20","chopping":"191-290","consensus_level":"medium","plddt":95.0103,"start":191,"end":290},{"cath_id":"2.60.120.260","chopping":"295-451","consensus_level":"high","plddt":95.0692,"start":295,"end":451}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96PD2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96PD2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96PD2-F1-predicted_aligned_error_v6.png","plddt_mean":67.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DCBLD2","jax_strain_url":"https://www.jax.org/strain/search?query=DCBLD2"},"sequence":{"accession":"Q96PD2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96PD2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96PD2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96PD2"}},"corpus_meta":[{"pmid":"25061874","id":"PMC_25061874","title":"EGFR phosphorylation of DCBLD2 recruits TRAF6 and stimulates AKT-promoted tumorigenesis.","date":"2014","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/25061874","citation_count":75,"is_preprint":false},{"pmid":"11447234","id":"PMC_11447234","title":"ESDN, a novel neuropilin-like membrane protein cloned from vascular cells with the longest secretory signal sequence among eukaryotes, is up-regulated after vascular injury.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11447234","citation_count":61,"is_preprint":false},{"pmid":"24177422","id":"PMC_24177422","title":"Transmembrane protein ESDN promotes endothelial VEGF signaling and regulates angiogenesis.","date":"2013","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/24177422","citation_count":57,"is_preprint":false},{"pmid":"18314483","id":"PMC_18314483","title":"Epigenetic down-regulation and suppressive role of DCBLD2 in gastric cancer cell proliferation and invasion.","date":"2008","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/18314483","citation_count":46,"is_preprint":false},{"pmid":"17570516","id":"PMC_17570516","title":"Phosphoproteomics identified Endofin, DCBLD2, and KIAA0582 as novel tyrosine phosphorylation targets of EGF signaling and Iressa in human cancer cells.","date":"2007","source":"Proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/17570516","citation_count":44,"is_preprint":false},{"pmid":"34095137","id":"PMC_34095137","title":"DCBLD2 Affects the Development of Colorectal Cancer via EMT and Angiogenesis and Modulates 5-FU Drug Resistance.","date":"2021","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/34095137","citation_count":29,"is_preprint":false},{"pmid":"17697260","id":"PMC_17697260","title":"ESDN is a marker of vascular remodeling and regulator of cell proliferation in graft arteriosclerosis.","date":"2007","source":"American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons","url":"https://pubmed.ncbi.nlm.nih.gov/17697260","citation_count":22,"is_preprint":false},{"pmid":"29025973","id":"PMC_29025973","title":"Dynamic multi-site phosphorylation by Fyn and Abl drives the interaction between CRKL and the novel scaffolding receptors DCBLD1 and DCBLD2.","date":"2017","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/29025973","citation_count":20,"is_preprint":false},{"pmid":"26921437","id":"PMC_26921437","title":"The neuropilin-like protein ESDN regulates insulin signaling and sensitivity.","date":"2016","source":"American journal of physiology. Heart and circulatory physiology","url":"https://pubmed.ncbi.nlm.nih.gov/26921437","citation_count":18,"is_preprint":false},{"pmid":"33808696","id":"PMC_33808696","title":"DCBLD2 Mediates Epithelial-Mesenchymal Transition-Induced Metastasis by Cisplatin in Lung Adenocarcinoma.","date":"2021","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/33808696","citation_count":18,"is_preprint":false},{"pmid":"35929441","id":"PMC_35929441","title":"DCBLD2 regulates vascular hyperplasia by modulating the platelet derived growth factor receptor-β endocytosis through Caveolin-1 in vascular smooth muscle cells.","date":"2022","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/35929441","citation_count":17,"is_preprint":false},{"pmid":"37856423","id":"PMC_37856423","title":"CD146 promotes malignant progression of breast phyllodes tumor through suppressing DCBLD2 degradation and activating the AKT pathway.","date":"2023","source":"Cancer communications (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/37856423","citation_count":16,"is_preprint":false},{"pmid":"23770091","id":"PMC_23770091","title":"Tyrosine phosphorylation of the orphan receptor ESDN/DCBLD2 serves as a scaffold for the signaling adaptor CrkL.","date":"2013","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/23770091","citation_count":14,"is_preprint":false},{"pmid":"36252912","id":"PMC_36252912","title":"miR-451a suppresses papillary thyroid cancer cell proliferation and invasion and facilitates apoptosis through targeting DCBLD2 and AKT1.","date":"2022","source":"Molecular and cellular probes","url":"https://pubmed.ncbi.nlm.nih.gov/36252912","citation_count":11,"is_preprint":false},{"pmid":"34145321","id":"PMC_34145321","title":"A homozygous nonsense mutation in DCBLD2 is a candidate cause of developmental delay, dysmorphic features and restrictive cardiomyopathy.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/34145321","citation_count":11,"is_preprint":false},{"pmid":"22261696","id":"PMC_22261696","title":"DCBLD2 gene variations correlate with nasal polyposis in Korean asthma patients.","date":"2012","source":"Lung","url":"https://pubmed.ncbi.nlm.nih.gov/22261696","citation_count":9,"is_preprint":false},{"pmid":"33862151","id":"PMC_33862151","title":"ESDN inhibits melanoma progression by blocking E-selectin expression in endothelial cells via STAT3.","date":"2021","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/33862151","citation_count":7,"is_preprint":false},{"pmid":"38602284","id":"PMC_38602284","title":"LncRNA MIR100HG affects the proliferation and metastasis of lung cancer cells through mediating the microRNA-5590-3p/DCBLD2 axis.","date":"2024","source":"Immunity, inflammation and disease","url":"https://pubmed.ncbi.nlm.nih.gov/38602284","citation_count":6,"is_preprint":false},{"pmid":"22468095","id":"PMC_22468095","title":"Potential association of DCBLD2 polymorphisms with fall rates of FEV(1) by aspirin provocation in Korean asthmatics.","date":"2012","source":"Journal of Korean medical science","url":"https://pubmed.ncbi.nlm.nih.gov/22468095","citation_count":6,"is_preprint":false},{"pmid":"38872483","id":"PMC_38872483","title":"DCBLD2 deletion increases hyperglycemia and induces vascular remodeling by inhibiting insulin receptor recycling in endothelial cells.","date":"2024","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/38872483","citation_count":5,"is_preprint":false},{"pmid":"21183991","id":"PMC_21183991","title":"Long signal peptides of RGMa and DCBLD2 are dissectible into subdomains according to the NtraC model.","date":"2010","source":"Molecular bioSystems","url":"https://pubmed.ncbi.nlm.nih.gov/21183991","citation_count":4,"is_preprint":false},{"pmid":"37477789","id":"PMC_37477789","title":"Engineering siRNA-loaded and RGDfC-targeted selenium nanoparticles for highly efficient silencing of DCBLD2 gene for colorectal cancer treatment.","date":"2023","source":"Discover nano","url":"https://pubmed.ncbi.nlm.nih.gov/37477789","citation_count":3,"is_preprint":false},{"pmid":"41110167","id":"PMC_41110167","title":"Integrating OLINK Proteomics and Single-Cell Analysis Reveals that DCBLD2 Potentiates VEGFA-Driven Angiogenesis in Retinal Detachment with Choroidal Detachment.","date":"2025","source":"Journal of proteome research","url":"https://pubmed.ncbi.nlm.nih.gov/41110167","citation_count":0,"is_preprint":false},{"pmid":"42148317","id":"PMC_42148317","title":"Integrative analysis identifies DCBLD2 and immune-related biomarkers for major depressive disorder: evidence from human peripheral blood, post-mortem brain, and rat models.","date":"2026","source":"Frontiers in human neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/42148317","citation_count":0,"is_preprint":false},{"pmid":"42178133","id":"PMC_42178133","title":"The mechanistic of DCBLD2 in inhibiting TGF-β induced endothelial-mesenchymal transition in calcific aortic valve disease.","date":"2026","source":"Journal of molecular and cellular cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/42178133","citation_count":0,"is_preprint":false},{"pmid":"41427028","id":"PMC_41427028","title":"Integrated Multiomics Unravels Hedgehog (HH) Signaling Characteristics in Pancreatic Cancer (PC) and DCBLD2 Regulates HH Signaling to Drive PC Progression.","date":"2025","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/41427028","citation_count":0,"is_preprint":false},{"pmid":"41721921","id":"PMC_41721921","title":"miR-34c-3p promotes osteogenic differentiation of BMSCs by inhibiting DCBLD2 activation of the PI3K/AKT signaling pathway.","date":"2026","source":"Journal of molecular histology","url":"https://pubmed.ncbi.nlm.nih.gov/41721921","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.08.22.609269","title":"Regulation of angiogenesis by signal sequence-derived peptides","date":"2024-08-23","source":"bioRxiv","url":"https://doi.org/10.1101/2024.08.22.609269","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":17500,"output_tokens":5369,"usd":0.066517,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13852,"output_tokens":5235,"usd":0.100068,"stage2_stop_reason":"end_turn"},"total_usd":0.166585,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"ESDN/DCBLD2 is a type-I transmembrane protein containing a CUB domain, a coagulation factor V/VIII homology domain, and an LCCL domain, and harbors the longest cleavable secretory signal sequence among eukaryotes. Overexpression of ESDN in 293T cells suppressed BrdU uptake, indicating a role in inhibiting cell proliferation.\",\n      \"method\": \"Signal sequence trap cloning, domain analysis, overexpression in 293T cells with BrdU uptake assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional assay (BrdU suppression) with overexpression, domain architecture established by sequence analysis; single lab, single paper\",\n      \"pmids\": [\"11447234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"DCBLD2 (ESDN) is upregulated in proliferating vascular smooth muscle cells (VSMCs); ESDN overexpression in VSMCs decreased growth, while ESDN knockdown increased VSMC proliferation, establishing ESDN as a regulator of VSMC proliferation.\",\n      \"method\": \"VSMC culture with ESDN overexpression and siRNA knockdown; growth curve analysis\",\n      \"journal\": \"American journal of transplantation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function and gain-of-function in primary VSMCs with defined proliferation readout; single lab\",\n      \"pmids\": [\"17697260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"DCBLD2 is a novel tyrosine phosphorylation target of EGF/EGFR signaling, identified and validated by phosphoproteomics; phosphorylation is blocked by the EGFR inhibitor Iressa.\",\n      \"method\": \"cICAT-based LC-MS/MS phosphoproteomics from EGF-treated A431 cells, validated by western blot with EGFR inhibitor\",\n      \"journal\": \"Proteomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mass spectrometry identification plus pharmacological validation; single lab\",\n      \"pmids\": [\"17570516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Ectopic expression of DCBLD2 in gastric cancer cell lines inhibited colony formation (anchorage-dependent and -independent) and inhibited invasion through collagen matrix, demonstrating a suppressive role in gastric cancer cell proliferation and invasion.\",\n      \"method\": \"Ectopic expression in gastric cancer cell lines; colony formation assay, collagen matrix invasion assay\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function with two orthogonal functional readouts (colony formation + invasion); single lab\",\n      \"pmids\": [\"18314483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The long signal peptide of DCBLD2 can be dissected into functional N and C subdomains per the NtraC model: the C-domain is sufficient and essential for ER targeting, whereas the N-domain is dispensable and thus available for additional functions.\",\n      \"method\": \"Deletion/chimeric construct expression; ER targeting assay\",\n      \"journal\": \"Molecular bioSystems\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional dissection of signal peptide subdomains using defined constructs; single lab, single paper\",\n      \"pmids\": [\"21183991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"DCBLD2 (ESDN) intracellular tyrosines in YxxP motifs are phosphorylated by Src family kinases (SFKs); phosphorylation at Y565, Y621, Y750, and Y715 (non-YxxP) recruits the SH2 domain of the signaling adaptor CrkL. Antibody-mediated ESDN clustering induces tyrosine phosphorylation and CrkL-SH2 binding.\",\n      \"method\": \"Mutagenesis of seven intracellular tyrosines; quantitative mass spectrometry; SH2 domain pulldown; pharmacological SFK inhibition; antibody clustering assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — site-directed mutagenesis combined with quantitative MS and multiple functional binding assays; multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"23770091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ESDN/DCBLD2 promotes VEGF-induced endothelial cell proliferation and migration; it associates with VEGFR-2 and regulates VEGFR-2 complex formation with the negative regulators PTP1B, TC-PTP, and VE-cadherin. Loss of ESDN in EC-specific knockout mice blunted VEGF responses and VEGFR-2 signaling in vivo.\",\n      \"method\": \"Global and EC-specific Esdn knockout mice; zebrafish dcbld2 knockdown; Co-IP of ESDN with VEGFR-2, PTP1B, TC-PTP, and VE-cadherin; VEGFR-2 signaling assays\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — genetic knockout (global + EC-specific + zebrafish), reciprocal co-IP with multiple partners, and in vivo signaling assays in one study\",\n      \"pmids\": [\"24177422\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"EGFR phosphorylates DCBLD2 at tyrosine 750 (Y750), which lies within a TRAF6-binding motif. Phospho-Y750 recruits TRAF6, leading to increased TRAF6 E3 ubiquitin ligase activity and subsequent AKT activation, thereby promoting EGFR-driven tumorigenesis.\",\n      \"method\": \"Phospho-specific antibodies; Co-IP of DCBLD2 Y750 with TRAF6; TRAF6 E3 ubiquitin ligase activity assay; AKT activation assays; tumor xenograft models; Y750 mutagenesis\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — site-specific mutagenesis, co-IP, in vitro E3 ligase assay, and in vivo tumor model; multiple orthogonal methods establishing a complete mechanistic pathway\",\n      \"pmids\": [\"25061874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ESDN/DCBLD2 inhibits insulin receptor signaling by interacting with the insulin receptor and altering its interaction with the regulatory adaptor-E3 ubiquitin ligase pairs APS-c-Cbl and GRB10-NEDD4. Esdn gene deletion enhances insulin-induced AKT and MAPK activation, VSMC proliferation/migration, and improves insulin sensitivity and glucose homeostasis in vivo.\",\n      \"method\": \"Esdn knockout mice; in vivo glucose/insulin tolerance tests; Co-IP of ESDN with insulin receptor; western blot for AKT/MAPK phosphorylation; VSMC proliferation/migration assays\",\n      \"journal\": \"American journal of physiology. Heart and circulatory physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — genetic knockout with in vivo metabolic phenotype, Co-IP establishing protein-protein interaction, and mechanistic dissection of adaptor complex regulation; multiple orthogonal methods\",\n      \"pmids\": [\"26921437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"DCBLD2 intracellular YxxP motifs are phosphorylated by Src family kinases (SFKs; specifically Fyn) and Abl kinase, which differentially promote CRKL-SH2 domain binding to DCBLD2. Site-specific quantitative phosphoproteomics mapped the SFK vs. Abl preferences for individual YxxP sites on DCBLD2.\",\n      \"method\": \"HPLC-coupled tandem mass spectrometry; kinase overexpression; CRKL-SH2 pulldown; pharmacological kinase inhibition\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — quantitative site-specific phosphoproteomics plus functional binding assays; multiple orthogonal methods in single study\",\n      \"pmids\": [\"29025973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DCBLD2 stabilizes β-catenin by phosphorylating GSK3β; accumulated β-catenin is transported to the nucleus to promote EMT-related transcription factor expression, mediating cisplatin-induced metastasis in lung adenocarcinoma.\",\n      \"method\": \"siRNA knockdown, western blot for GSK3β phosphorylation and β-catenin nuclear translocation, in vitro migration/invasion assays, in vivo metastasis model with nanoparticle-delivered siRNA\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with mechanistic signaling readouts (GSK3β phosphorylation, β-catenin localization) and in vivo validation; single lab\",\n      \"pmids\": [\"33808696\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A homozygous nonsense variant (p.W27*) in DCBLD2 in a patient results in reduced cell proliferation, impaired cell cycle progression, and altered intracellular ROS and Ca2+ levels in patient-derived skin fibroblasts, functionally characterizing this loss-of-function variant.\",\n      \"method\": \"Whole-exome sequencing; in vitro functional studies on patient skin fibroblasts (proliferation, cell cycle, ROS, Ca2+ assays)\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient-derived fibroblast functional studies with multiple cellular readouts; single lab, no rescue experiment\",\n      \"pmids\": [\"34145321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DCBLD2 binds ITGB1 (integrin β1, a key focal adhesion pathway component) as identified by TAP-MS and confirmed by Co-IP, implicating DCBLD2 in the focal adhesion pathway in colorectal cancer cells.\",\n      \"method\": \"TAP-MS affinity purification followed by Co-IP validation\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — TAP-MS identification confirmed by Co-IP; single lab\",\n      \"pmids\": [\"34095137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In endothelial cells, ESDN/DCBLD2 loss leads to increased E-selectin transcript and protein levels, enhanced melanoma cell adhesion and extravasation, and increased metastasis in Esdn-null mice. ESDN suppresses E-selectin transcription, potentially through STAT3.\",\n      \"method\": \"Esdn-null mouse melanoma injection model; endothelial cell adhesion assay; E-selectin mRNA/protein quantification; cimetidine (E-selectin inhibitor) rescue experiment\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout mouse model with in vivo metastasis readout and mechanistic rescue; STAT3 link is proposed but not directly demonstrated by mechanistic experiment\",\n      \"pmids\": [\"33862151\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DCBLD2 inhibits caveolae-dependent endocytosis of PDGFR-β in VSMCs by anchoring PDGFR-β on the cell membrane via competition with Caveolin-1 (Cav-1). DCBLD2 deletion increases PDGFR-β–Cav-1 binding and accelerates PDGF-induced PDGFR-β internalization to lysosomes.\",\n      \"method\": \"VSMC-conditional and germline Dcbld2 knockout mice; Co-IP of PDGFR-β with Cav-1 and DCBLD2; biotin surface labeling; membrane/cytosol fractionation; double immunofluorescence\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — genetic knockout (germline + conditional), Co-IP, surface biotinylation, fractionation, and imaging; multiple orthogonal methods establishing a receptor endocytosis mechanism\",\n      \"pmids\": [\"35929441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CD146 protein physically interacts with DCBLD2 and prevents its degradation, thereby stabilizing DCBLD2 and activating downstream PI3K/AKT signaling in breast phyllodes tumor cells.\",\n      \"method\": \"Co-immunoprecipitation, pull-down assay, transcriptome and proteomic analysis, functional proliferation/invasion assays\",\n      \"journal\": \"Cancer communications (London, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and pulldown establish interaction; single lab with multiple methods\",\n      \"pmids\": [\"37856423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DCBLD2 deletion in endothelial cells inhibits insulin receptor recycling in a Rab11-dependent manner, reduces membrane InsR levels, and attenuates InsR/PI3K/Akt signaling, exacerbating endothelial dysfunction and vascular remodeling in diabetic mice.\",\n      \"method\": \"Endothelium-specific and global Dcbld2 knockout mice; streptozotocin-induced diabetes model; Co-IP for InsR interactions; membrane/cytoplasm fractionation; glycolytic rate assay; western blot\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — endothelium-specific genetic knockout with in vivo metabolic and vascular phenotype, Co-IP, subcellular fractionation establishing Rab11-dependent recycling mechanism; multiple orthogonal methods\",\n      \"pmids\": [\"38872483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DCBLD2 and VEGFA act synergistically in choroidal endothelial cells to enhance proliferation, migration, and angiogenic tube formation; DCBLD2 potentiates VEGFA-driven effects by increasing VEGFR2 phosphorylation and activating downstream AKT and ERK1/2 signaling cascades.\",\n      \"method\": \"Functional validation in choroidal endothelial cells (proliferation, migration, tube formation assays); VEGFR2 phosphorylation western blot; AKT/ERK1/2 activation assays\",\n      \"journal\": \"Journal of proteome research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct cell-based functional assays with signaling readouts; single lab, single paper, no genetic rescue or mutagenesis\",\n      \"pmids\": [\"41110167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"DCBLD2 loss in endothelial cells enhances TGF-β signaling by increasing clathrin-mediated endocytosis of TGF-β receptor (TGF-βR); DCBLD2 interacts with TGF-βR and clathrin, and its loss promotes EndMT. DCBLD2 knockout mice show higher prevalence of calcific aortic valve disease.\",\n      \"method\": \"DCBLD2 knockout mice; immunoprecipitation of DCBLD2 with TGF-βR and clathrin; western blot for TGF-β pathway phosphorylation; Pitstop 2 clathrin inhibitor rescue; immunofluorescence; endothelial migration assay\",\n      \"journal\": \"Journal of molecular and cellular cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with in vivo phenotype, Co-IP establishing protein interactions, and pharmacological rescue; single lab\",\n      \"pmids\": [\"42178133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"DCBLD2 overexpression inhibits osteogenic differentiation of BMSCs and suppresses PI3K/AKT pathway activation; miR-34c-3p directly binds DCBLD2 mRNA (confirmed by AGO2-RIP and dual-luciferase assay) to suppress its expression and thereby promote osteogenic differentiation.\",\n      \"method\": \"Overexpression and knockdown of DCBLD2 in BMSCs; ALP and alizarin red staining; PI3K activator rescue; AGO2-RIP; dual-luciferase reporter assay\",\n      \"journal\": \"Journal of molecular histology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional differentiation assays plus validated miRNA-target interaction with two orthogonal methods; single lab\",\n      \"pmids\": [\"41721921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The signal sequence (SS) of DCBLD2 is not cleaved in the mature protein and directly interacts with VEGFR2 via its hydrophobic 'traC' segment (specifically the L5VL5/L10 sequence). The SS promotes VEGF-induced signaling, and a synthetic traC-derived peptide (L10) enhances VEGFR2 signaling in vitro and promotes angiogenesis and blood flow recovery in vivo.\",\n      \"method\": \"Co-immunoprecipitation of DCBLD2 domain constructs with VEGFR2 in HEK293T and endothelial cells; synthetic peptide signaling assays; matrigel plug and corneal micropocket angiogenesis assays; hindlimb ischemia model\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mapping by Co-IP with multiple constructs, peptide functional assays in vitro and in vivo; preprint, not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"DCBLD2/ESDN is a type-I transmembrane neuropilin-like scaffolding receptor whose intracellular YxxP motifs are phosphorylated by EGFR, Src family kinases (Fyn), and Abl, enabling recruitment of signaling adaptors (CrkL, TRAF6); phospho-Y750 specifically recruits TRAF6 to amplify AKT activation downstream of oncogenic EGFR, while the extracellular/transmembrane region (including its retained signal sequence 'traC' segment) associates with VEGFR-2 to promote VEGF signaling by displacing negative regulators (PTP1B, TC-PTP) and, in the context of PDGFR-β and insulin receptor, DCBLD2 anchors these receptors at the plasma membrane to prevent their Caveolin-1-mediated endocytosis, thereby sustaining their downstream signaling; in endothelial cells DCBLD2 similarly blocks clathrin-mediated TGF-βR endocytosis to suppress EndMT, and promotes insulin receptor Rab11-dependent recycling to sustain InsR/PI3K/Akt activity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DCBLD2 (ESDN) is a type-I transmembrane neuropilin-like receptor that functions as a phosphorylation-dependent scaffold controlling the cell-surface residence and downstream signaling of multiple growth factor and cytokine receptors [#0, #6]. Its intracellular YxxP motifs are phosphorylated by EGFR, Src-family kinases (notably Fyn), and Abl, and these phosphosites differentially recruit the SH2 adaptor CrkL; phosphorylation at Y565, Y621, Y715, and Y750 mediates CrkL binding, and antibody-induced receptor clustering is sufficient to trigger this phosphorylation [#5, #9]. A distinct phosphosite, EGFR-driven phospho-Y750, lies within a TRAF6-binding motif and recruits TRAF6 to stimulate its E3 ubiquitin ligase activity and amplify AKT activation, driving EGFR-dependent tumorigenesis [#7]. In the vasculature, DCBLD2 associates with VEGFR-2 and regulates its complex with the negative regulators PTP1B, TC-PTP, and VE-cadherin to promote VEGF-induced endothelial proliferation, migration, and angiogenesis [#6, #17]. A recurring mechanistic theme is control of receptor trafficking: DCBLD2 anchors PDGFR-\\u03b2 at the plasma membrane by competing with Caveolin-1 to block caveolae-dependent endocytosis [#14], sustains insulin receptor surface levels through Rab11-dependent recycling [#16], and limits clathrin-mediated TGF-\\u03b2 receptor endocytosis to suppress endothelial-to-mesenchymal transition [#18]. Consistent with an early-defined growth-suppressive role, DCBLD2 overexpression inhibits proliferation and tumor cell colony formation and invasion [#0, #3], yet it also negatively regulates insulin receptor signaling via the APS-c-Cbl and GRB10-NEDD4 adaptor-ligase pairs, such that Esdn deletion improves insulin sensitivity in vivo [#8]. A homozygous nonsense variant (p.W27*) in a patient impairs fibroblast proliferation and alters ROS and Ca2+ homeostasis, functionally characterizing loss of DCBLD2 [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established DCBLD2/ESDN as a distinctive type-I transmembrane protein with CUB, coagulation factor V/VIII, and LCCL domains and an unusually long signal sequence, and gave the first functional clue that it restrains proliferation.\",\n      \"evidence\": \"Signal-sequence trap cloning, domain analysis, and BrdU uptake after overexpression in 293T cells\",\n      \"pmids\": [\"11447234\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No binding partners or signaling mechanism identified\", \"Antiproliferative effect based on overexpression only\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Connected DCBLD2 to vascular biology by showing it regulates proliferation of vascular smooth muscle cells bidirectionally with gene dose.\",\n      \"evidence\": \"ESDN overexpression and siRNA knockdown in primary VSMCs with growth-curve readout\",\n      \"pmids\": [\"17697260\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of growth control unresolved\", \"No receptor partner defined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified DCBLD2 as a tyrosine-phosphorylation substrate of EGFR signaling, placing it downstream of growth-factor receptor activation.\",\n      \"evidence\": \"cICAT phosphoproteomics in EGF-treated A431 cells with EGFR-inhibitor (Iressa) validation\",\n      \"pmids\": [\"17570516\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific phosphosites not mapped\", \"Functional consequence of phosphorylation not shown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Dissected the long signal sequence into NtraC subdomains, showing the C-domain alone drives ER targeting and freeing the N-domain for additional functions.\",\n      \"evidence\": \"Deletion/chimeric constructs with ER-targeting assays\",\n      \"pmids\": [\"21183991\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Function of the dispensable N-domain not defined\", \"No partner identified for the retained segment at this stage\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined the phosphorylation logic of the cytoplasmic tail, showing SFKs phosphorylate YxxP tyrosines that recruit the CrkL SH2 domain and that receptor clustering activates this circuit.\",\n      \"evidence\": \"Site-directed mutagenesis of seven tyrosines, quantitative MS, SH2 pulldowns, SFK inhibition, and antibody clustering\",\n      \"pmids\": [\"23770091\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream output of CrkL recruitment not traced\", \"Physiological clustering ligand unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Established DCBLD2 as a positive regulator of VEGFR-2 signaling in endothelium by genetic loss and partner mapping, distinguishing it from its growth-suppressive role elsewhere.\",\n      \"evidence\": \"Global, EC-specific, and zebrafish loss-of-function; reciprocal Co-IP with VEGFR-2, PTP1B, TC-PTP, VE-cadherin; in vivo VEGF signaling assays\",\n      \"pmids\": [\"24177422\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of VEGFR-2 association not resolved\", \"Mechanism of displacing PTP1B/TC-PTP not detailed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Resolved a specific oncogenic phosphosite pathway: EGFR-phosphorylated Y750 recruits TRAF6 to boost its ligase activity and AKT signaling, driving tumorigenesis.\",\n      \"evidence\": \"Phospho-specific antibodies, Y750 mutagenesis, TRAF6 Co-IP and E3 ligase assays, AKT readouts, and xenograft models\",\n      \"pmids\": [\"25061874\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"TRAF6 ubiquitination substrate in this context not defined\", \"Link between Y750 and the CrkL-binding sites not integrated\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed DCBLD2 negatively regulates insulin receptor signaling through adaptor-E3 ligase pairs, giving it a systemic metabolic role.\",\n      \"evidence\": \"Esdn knockout mice with glucose/insulin tolerance tests, InsR Co-IP, AKT/MAPK blots, and VSMC assays\",\n      \"pmids\": [\"26921437\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How DCBLD2 modulates APS-c-Cbl and GRB10-NEDD4 binding mechanistically unclear\", \"Reconciliation with later positive InsR-recycling role unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Refined the kinase-phosphosite code by showing Fyn and Abl differentially phosphorylate individual YxxP sites to tune CrkL recruitment.\",\n      \"evidence\": \"Site-specific quantitative phosphoproteomics, kinase overexpression, CrkL-SH2 pulldowns, and kinase inhibition\",\n      \"pmids\": [\"29025973\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular contexts engaging Fyn versus Abl not defined\", \"Downstream signaling differences between sites not measured\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Expanded the partner repertoire and disease links: DCBLD2 binds ITGB1 (focal adhesion), stabilizes \\u03b2-catenin via GSK3\\u03b2 to drive lung adenocarcinoma metastasis, suppresses endothelial E-selectin to limit melanoma extravasation, and a nonsense variant impairs fibroblast proliferation.\",\n      \"evidence\": \"TAP-MS/Co-IP (ITGB1); siRNA with GSK3\\u03b2/\\u03b2-catenin readouts and in vivo metastasis; Esdn-null melanoma model with E-selectin quantification; whole-exome sequencing and patient fibroblast assays\",\n      \"pmids\": [\"34095137\", \"33808696\", \"33862151\", \"34145321\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"STAT3 link to E-selectin not directly demonstrated\", \"No rescue for the p.W27* patient variant\", \"Mechanism linking DCBLD2 to GSK3\\u03b2 phosphorylation unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined a trafficking mechanism: DCBLD2 retains PDGFR-\\u03b2 at the membrane by competing with Caveolin-1 to block caveolae-dependent internalization and lysosomal degradation.\",\n      \"evidence\": \"Germline and conditional Dcbld2 knockout mice, PDGFR-\\u03b2/Cav-1/DCBLD2 Co-IP, surface biotinylation, fractionation, and imaging\",\n      \"pmids\": [\"35929441\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the same competition applies to other receptors not tested here\", \"Structural basis of Cav-1 competition unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified CD146 as a stabilizer of DCBLD2 protein that activates PI3K/AKT in phyllodes tumor cells, adding upstream regulation of DCBLD2 abundance.\",\n      \"evidence\": \"Reciprocal Co-IP, pulldown, omics, and proliferation/invasion assays\",\n      \"pmids\": [\"37856423\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Degradation pathway prevented by CD146 not defined\", \"Single tumor context\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended the trafficking model to insulin receptor recycling, showing DCBLD2 sustains InsR surface levels and InsR/PI3K/Akt signaling via Rab11-dependent recycling, with vascular consequences in diabetes.\",\n      \"evidence\": \"Endothelium-specific and global Dcbld2 knockout mice, streptozotocin diabetes model, InsR Co-IP, fractionation, glycolytic and signaling assays\",\n      \"pmids\": [\"38872483\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Apparent contrast with earlier negative InsR regulation not mechanistically reconciled\", \"Direct role in Rab11 recruitment not shown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Provided a molecular basis for VEGFR-2 association by showing the uncleaved signal sequence's hydrophobic traC segment binds VEGFR-2, and a derived peptide promotes angiogenesis.\",\n      \"evidence\": \"Co-IP of DCBLD2 domain constructs with VEGFR2, synthetic peptide signaling assays, matrigel/corneal angiogenesis, and hindlimb ischemia (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not yet peer-reviewed\", \"Structural detail of the traC\\u2013VEGFR2 interface limited\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Generalized the endocytosis-blocking mechanism to TGF-\\u03b2R, where DCBLD2 binds TGF-\\u03b2R and clathrin to limit clathrin-mediated internalization, suppress EndMT, and protect against calcific aortic valve disease.\",\n      \"evidence\": \"DCBLD2 knockout mice, DCBLD2\\u2013TGF-\\u03b2R/clathrin Co-IP, TGF-\\u03b2 pathway blots, Pitstop 2 rescue, and migration assays\",\n      \"pmids\": [\"42178133\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct competition with the clathrin machinery not quantified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified miR-34c-3p as a direct upstream repressor of DCBLD2 mRNA controlling osteogenic differentiation through PI3K/AKT.\",\n      \"evidence\": \"DCBLD2 overexpression/knockdown in BMSCs, ALP/alizarin red staining, PI3K activator rescue, AGO2-RIP, and dual-luciferase reporter\",\n      \"pmids\": [\"41721921\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance to bone not tested\", \"Receptor partner mediating PI3K/AKT in BMSCs not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How DCBLD2's growth-suppressive versus signaling-amplifying roles and its opposing effects on insulin receptor activity are integrated into a single regulatory logic remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model reconciling negative InsR regulation (2016) with InsR-recycling support (2024)\", \"No structural model of the full receptor or its receptor-binding interfaces\", \"Endogenous ligand/clustering trigger for the cytoplasmic phosphorylation circuit unidentified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [5, 7, 9]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [6, 14, 16, 18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 14, 16]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 7, 8, 17]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [14, 16, 18]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [7, 10, 11]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"EGFR\", \"VEGFR2\", \"TRAF6\", \"CRKL\", \"PDGFRB\", \"INSR\", \"ITGB1\", \"CAV1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":7,"faith_total":7,"faith_pct":100.0}}