{"gene":"ELMO2","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2009,"finding":"ELMO2 forms a novel tripartite complex with integrin-linked kinase (ILK) and RhoG. This complex localizes specifically to the leading lamellipodia of polarized cells. RhoG binding to ELMO2 is required for ILK-induced cell polarization, and expression of dominant-negative ELMO2 mutants abolishes ILK's ability to promote front-rear polarity, placing RhoG-ELMO2-ILK complexes as essential mediators of cell polarity and haptotactic migration.","method":"Co-immunoprecipitation, dominant-negative mutant expression, live cell imaging/localization, functional migration assays with loss-of-function","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, dominant-negative mutants, localization experiments with functional consequence, replicated across multiple studies","pmids":["19439446"],"is_preprint":false},{"year":2011,"finding":"EGF stimulation induces front-rear polarity and directional migration in keratinocytes through a pathway requiring ILK, ELMO2, integrin β1, and Rac1. EGF selectively (not other growth factors) promotes formation of active RhoG-ELMO2-ILK complexes that mediate this response, requiring EGF receptor tyrosine kinase activity.","method":"Pharmacological inhibition of EGFR kinase, siRNA knockdown, chemotaxis assays, Co-immunoprecipitation with active RhoG","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, knockdown, migration assays, pharmacological inhibition), two papers from the same lab confirming the complex","pmids":["22160594"],"is_preprint":false},{"year":2015,"finding":"ELMO2-RhoG-ILK (ERI) tripartite complexes modulate microtubule dynamics in an integrin-independent manner in differentiated keratinocytes. ERI complexes activate Rac1, which stabilizes microtubules via two routes: (1) phosphorylation/inactivation of stathmin, and (2) GSK-3β phosphorylation/inactivation leading to CRMP2 activation. Loss of ERI complexes impairs Ca2+-mediated adherens junction formation.","method":"Conditional Ilk gene knockout, exogenous ELMO2/RhoG expression, microtubule dynamics imaging, phosphorylation assays for stathmin and GSK-3β/CRMP2","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined phenotype, multiple downstream pathway readouts, two orthogonal mechanistic routes identified","pmids":["25995380"],"is_preprint":false},{"year":2015,"finding":"ClipR-59 interacts with ELMO2 via the atypical PH domain of ELMO2 and the Glu-Pro-rich domain of ClipR-59. This interaction is regulated by Rho-GTPase. Formation of the ELMO2-ClipR-59 complex enhances Rac1 activation and is required for myoblast fusion.","method":"Yeast two-hybrid screen, Co-immunoprecipitation, domain mapping, Rac1 activation assay (GTP-loading), siRNA knockdown in C2C12 cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus Co-IP with domain mapping and functional Rac1 activation assay, single lab","pmids":["25572395"],"is_preprint":false},{"year":2016,"finding":"Loss-of-function mutations in ELMO2 cause intraosseous vascular malformation. Absence of ELMO2 in primary fibroblasts correlates with significant downregulation of binding partner DOCK1, resulting in deficient RAC1-dependent cell migration.","method":"Human genetic analysis, primary fibroblast analysis from affected individuals (ELMO2 and DOCK1 protein levels, RAC1 activation/migration assays)","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human loss-of-function genetics with primary patient cells showing molecular pathway defects, single cohort study","pmids":["27476657"],"is_preprint":false},{"year":2016,"finding":"ELMO2 and ILK localize to Rab4- and Rab11a-containing recycling endosomes during Ca2+-induced keratinocyte differentiation. ELMO2- or ILK-deficient keratinocytes show disrupted positioning of long-loop Rab11a-positive endosomes adjacent to cell-cell contacts and impaired E-cadherin localization to cell borders.","method":"Fluorescence microscopy/co-localization, ELMO2/ILK knockdown or knockout, E-cadherin localization assay, recycling endosome fractionation","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with functional consequence (E-cadherin delivery), loss-of-function with specific phenotypic readout, single lab","pmids":["27627840"],"is_preprint":false},{"year":2016,"finding":"ELMO2, RhoG, and ILK form a signaling pathway that mediates Rac1-dependent phagocytosis in human trabecular meshwork cells. Knockdown of ELMO2 reduced phagocytosis by ~51%, indicating a functional role for ELMO2 in this process.","method":"siRNA knockdown in TM-1 and primary HTM cells, phagocytosis assays, Rac1 inhibitor studies","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with specific phagocytosis readout, consistent with established ILK-ELMO2-RhoG-Rac1 axis; single lab","pmids":["27539661"],"is_preprint":false},{"year":2016,"finding":"ELMO2 is required for insulin-induced RAC1 GTP loading and promotes the insulin-induced membrane association of Akt (but not AKT activation per se). ELMO2 overexpression enhances insulin-dependent GLUT4 membrane translocation, while knockdown suppresses it in adipocytes and skeletal muscle cells.","method":"Overexpression and siRNA knockdown in 3T3-L1 adipocytes and L6 skeletal muscle cells, Rac1 GTP-loading assay, Akt membrane fractionation, GLUT4 translocation assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with multiple downstream readouts (Rac1 activation, Akt membrane localization, GLUT4 translocation), single lab","pmids":["27226625"],"is_preprint":false},{"year":2018,"finding":"HGF induces formation of a MET-AXL-ELMO2-DOCK180 complex on the plasma membrane in glioblastoma cells, which promotes RAC1-dependent cytoskeleton reorganization, cell migration and invasion. ELMO2 and DOCK180 are recruited to the MET-AXL complex upon HGF stimulation.","method":"Co-immunoprecipitation, siRNA knockdown, RAC1 activation assay, migration/invasion assays, confocal imaging of receptor clustering","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with functional loss-of-function assays, multiple cell lines tested; single lab","pmids":["30108175"],"is_preprint":false},{"year":2019,"finding":"An evolutionarily conserved fragment in the C-terminal cytoplasmic tail of BAI-adhesion GPCRs is specifically recognized by the RBD-ARR-ELMO (RAE) supramodule of ELMO2. Crystal structures of ELMO2-RAE and its complex with BAI1 define the molecular basis of BAI/ELMO interactions. Disease-causing mutations in BAI and ELMO were mapped and shown to affect complex formation.","method":"X-ray crystallography, structure-function analysis, mutagenesis of disease-associated variants, binding assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure of ELMO2 RAE supramodule and complex with BAI1, mutagenesis confirming interface residues, identification of additional receptor (GPR128) using structural information","pmids":["30604775"],"is_preprint":false},{"year":2020,"finding":"ELMO2 interacts with Gαi2, and CXCL12 triggers Gαi2-dependent membrane translocation of ELMO2. ELMO2 knockdown inhibits pancreatic cancer cell chemotaxis, migration, invasion, and F-actin polymerization.","method":"Co-immunoprecipitation, siRNA knockdown, chemotaxis/migration/invasion assays, F-actin polymerization assay, subcellular fractionation","journal":"PeerJ","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP identifying novel binding partner, loss-of-function with phenotypic readout, single lab with single methods per finding","pmids":["32292657"],"is_preprint":false},{"year":2022,"finding":"ELMO2 conformational state regulates myoblast fusion. A mutation biasing ELMO2 toward an open conformation increases RAC1-DOCK1 signaling and enhances myoblast fusion during development and muscle regeneration. Combined Elmo1 knockout with muscle-specific Elmo2 knockout caused severe myoblast fusion defects, demonstrating their cooperative role. Expression of open-conformation ELMO2 reversed dystrophic features in Dysferlin-null mice.","method":"Mouse genetic models (Elmo1 KO, muscle-specific Elmo2 KO, conformational mutant knock-in), myoblast fusion quantification, muscle regeneration assays, Dysferlin-null disease model rescue experiment","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple genetic mouse models including conformational mutants, in vivo rescue of muscular dystrophy, mechanistic link to RAC1/DOCK1 signaling pathway established","pmids":["36400788"],"is_preprint":false},{"year":2025,"finding":"Global Elmo2 inactivation in mice causes midgestation lethality due to dilation of 3rd pharyngeal arch arteries and carotid aneurysm formation, associated with defects in vascular smooth muscle cell organization. Neural crest-specific deletion phenocopies this. In vitro, ELMO2 regulates vascular smooth muscle cell adhesion, spreading, and contractility through Rac1 activation and modulation of actin dynamics.","method":"Global and conditional (neural crest-specific) Elmo2 knockout mice, vascular morphology analysis, in vitro vascular smooth muscle cell adhesion/spreading/contractility assays, Rac1 activation assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with defined cellular mechanism (Rac1/actin), phenotypic rescue via tissue-specific deletion confirming cell-autonomous role, in vitro mechanistic validation","pmids":["40456777"],"is_preprint":false},{"year":2026,"finding":"ELMO2 suppression in mesenchymal-like cancer cells induces excessive autophagy and cell death via FAK activity inhibition. ELMO3 acts as a functional paralog that compensates for ELMO2 loss (synthetic lethal interaction). ZEB1 represses ELMO3 transcription in mesenchymal-like cells, rendering them sensitive to ELMO2 blockade. A structure-based small-molecule ELMO2 inhibitor (C52) was identified that kills ELMO3-low lung cancer cells.","method":"siRNA knockdown, epistasis analysis, FAK activity assays, autophagy markers, ZEB1 ChIP/transcriptional assays, structure-based drug screening, cell viability assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined molecular pathway (FAK), synthetic lethality established, transcriptional regulation by ZEB1 shown; single lab, limited mechanistic detail in abstract","pmids":["41997974"],"is_preprint":false}],"current_model":"ELMO2 is a scaffold protein that operates primarily through tripartite complexes with RhoG and ILK (and bipartite complexes with DOCK1/DOCK180) to activate RAC1, thereby driving directed cell migration, phagocytosis, myoblast fusion, vascular smooth muscle cell organization, and microtubule stabilization; upstream inputs include adhesion GPCRs (BAI1), receptor tyrosine kinases (EGFR, MET/AXL), and Gαi2-coupled chemokine receptors (CXCR4), all converging on ELMO2's RAE supramodule or PH domain to control its conformational state and membrane recruitment, with loss-of-function causing deficient RAC1 signaling and human diseases including intraosseous vascular malformation and Ramon syndrome."},"narrative":{"mechanistic_narrative":"ELMO2 is a scaffold protein that orchestrates RAC1 activation to drive directed cell migration, phagocytosis, myoblast fusion, and vascular morphogenesis [PMID:19439446, PMID:36400788, PMID:40456777]. Its central mechanism is the assembly of a tripartite RhoG-ELMO2-ILK (ERI) complex that localizes to the leading lamellipodia of polarized cells, where RhoG binding to ELMO2 is required for ILK-induced front-rear polarity and haptotactic migration [PMID:19439446]; this same ERI module activates RAC1 to stabilize microtubules through stathmin and GSK-3β/CRMP2 phosphorylation and to support Ca2+-dependent adherens junction formation and E-cadherin delivery via Rab11a recycling endosomes [PMID:25995380, PMID:27627840]. ELMO2 also pairs with DOCK1/DOCK180 to form the RAC1 GEF effector arm, and its activity is gated by conformational state: a mutation biasing ELMO2 toward an open conformation increases RAC1-DOCK1 signaling and rescues dystrophic muscle in vivo [PMID:36400788]. Upstream inputs converge on ELMO2 through diverse receptors—EGFR tyrosine kinase activity promotes active ERI complex formation [PMID:22160594], HGF triggers assembly of a MET-AXL-ELMO2-DOCK180 complex driving glioblastoma invasion [PMID:30108175], and the Gαi2-coupled chemokine axis (CXCL12) triggers ELMO2 membrane translocation [PMID:32292657]—while crystal structures define how the RBD-ARR-ELMO (RAE) supramodule recognizes the cytoplasmic tail of BAI adhesion GPCRs [PMID:30604775]. Loss-of-function mutations in ELMO2 cause intraosseous vascular malformation, with patient fibroblasts showing downregulation of DOCK1 and deficient RAC1-dependent migration [PMID:27476657]. ELMO2 suppression in mesenchymal-like cancer cells induces lethal autophagy via FAK inhibition, with ELMO3 acting as a ZEB1-repressed paralog in a synthetic lethal relationship [PMID:41997974].","teleology":[{"year":2009,"claim":"Established ELMO2's core scaffolding role by showing it bridges RhoG and ILK into a complex required for cell polarity, defining the molecular basis of haptotactic migration.","evidence":"Co-IP, dominant-negative mutants, and live-cell imaging with functional migration assays in polarized cells","pmids":["19439446"],"confidence":"High","gaps":["Did not define the upstream receptor inputs that initiate ERI assembly","Structural basis of RhoG-ELMO2 binding not resolved"]},{"year":2011,"claim":"Identified EGFR as a selective upstream activator, answering how an extracellular signal triggers active ERI complex formation and directional migration.","evidence":"EGFR pharmacological inhibition, siRNA knockdown, chemotaxis assays, and Co-IP with active RhoG in keratinocytes","pmids":["22160594"],"confidence":"High","gaps":["Mechanism by which EGFR activity converts to RhoG loading not detailed","Specificity over other growth factors not mechanistically explained"]},{"year":2015,"claim":"Extended ERI function beyond migration to cytoskeletal control, showing RAC1 activation by the complex stabilizes microtubules and supports adherens junctions.","evidence":"Conditional Ilk knockout, microtubule dynamics imaging, and stathmin / GSK-3β/CRMP2 phosphorylation assays","pmids":["25995380"],"confidence":"High","gaps":["Did not establish whether microtubule effects are direct or solely RAC1-mediated","Integrin-independent recruitment mechanism unclear"]},{"year":2015,"claim":"Mapped the ELMO2 atypical PH domain as a docking site for ClipR-59, linking a new partner to RAC1 activation during myoblast fusion.","evidence":"Yeast two-hybrid screen, Co-IP with domain mapping, and Rac1 GTP-loading assays in C2C12 cells","pmids":["25572395"],"confidence":"Medium","gaps":["Single lab; reciprocal in vivo validation absent","How Rho-GTPase regulation of the interaction is achieved not defined"]},{"year":2016,"claim":"Connected ELMO2 to human disease, demonstrating loss-of-function mutations cause intraosseous vascular malformation through DOCK1 destabilization and deficient RAC1 signaling.","evidence":"Human genetic analysis and primary patient fibroblast assays of ELMO2/DOCK1 levels and RAC1 activation","pmids":["27476657"],"confidence":"Medium","gaps":["Single cohort; cell-autonomous vascular mechanism not addressed in vivo","Mechanism of DOCK1 downregulation upon ELMO2 loss unknown"]},{"year":2016,"claim":"Broadened the functional repertoire of the ELMO2-RhoG-ILK axis to phagocytosis, insulin-dependent GLUT4 trafficking, and endosomal E-cadherin delivery.","evidence":"siRNA knockdown/overexpression with phagocytosis, Rac1 GTP-loading, GLUT4 translocation, and endosome co-localization assays across trabecular meshwork, adipocyte/muscle, and keratinocyte systems","pmids":["27539661","27226625","27627840"],"confidence":"Medium","gaps":["Each role established in a single lab/system","Whether a common molecular mechanism underlies these diverse outputs not tested"]},{"year":2018,"claim":"Showed receptor tyrosine kinase signaling recruits ELMO2-DOCK180 into a MET-AXL complex, defining how HGF drives RAC1-dependent cancer invasion.","evidence":"Co-IP, siRNA knockdown, RAC1 activation, and migration/invasion assays in glioblastoma cells","pmids":["30108175"],"confidence":"Medium","gaps":["Direct vs. indirect ELMO2-MET/AXL contacts not resolved","Single lab"]},{"year":2019,"claim":"Provided structural definition of ELMO2's RAE supramodule recognizing BAI adhesion GPCR tails, establishing the atomic basis of receptor-ELMO coupling and disease variant effects.","evidence":"X-ray crystallography of ELMO2-RAE and its BAI1 complex with mutagenesis of disease variants and binding assays","pmids":["30604775"],"confidence":"High","gaps":["Did not capture full-length autoinhibited ELMO2 conformation","Downstream signaling consequences of BAI1 binding not assayed structurally"]},{"year":2020,"claim":"Identified Gαi2 as a chemokine-coupled input, showing CXCL12 drives Gαi2-dependent ELMO2 membrane translocation to promote cancer chemotaxis.","evidence":"Co-IP, fractionation, siRNA knockdown, and chemotaxis/invasion/F-actin assays in pancreatic cancer cells","pmids":["32292657"],"confidence":"Medium","gaps":["Single lab with single method per finding","Direct vs. indirect Gαi2 binding not established"]},{"year":2022,"claim":"Demonstrated that ELMO2 conformational state gates RAC1-DOCK1 output, with open-conformation ELMO2 enhancing myoblast fusion and rescuing muscular dystrophy in vivo.","evidence":"Mouse genetic models including conformational knock-in and muscle-specific Elmo2/Elmo1 knockouts, fusion and regeneration assays, and Dysferlin-null rescue","pmids":["36400788"],"confidence":"High","gaps":["Structural details of the conformational transition not resolved","Generality of conformational regulation to non-muscle contexts untested"]},{"year":2025,"claim":"Established a developmental vascular role, showing ELMO2 is required cell-autonomously in neural-crest-derived smooth muscle for pharyngeal artery integrity via RAC1/actin control.","evidence":"Global and neural-crest-specific Elmo2 knockout mice with vascular morphology analysis and in vitro smooth muscle adhesion/spreading/contractility and Rac1 assays","pmids":["40456777"],"confidence":"High","gaps":["Upstream receptors driving ELMO2 in smooth muscle not identified","Link between this phenotype and human ELMO2 disease not formally tested"]},{"year":2026,"claim":"Revealed a therapeutic vulnerability, showing ELMO2 loss triggers FAK-dependent lethal autophagy and that ELMO3 is a ZEB1-repressed synthetic lethal paralog targetable with a small molecule.","evidence":"siRNA knockdown, epistasis, FAK and autophagy assays, ZEB1 ChIP/transcriptional analysis, and structure-based inhibitor screening in lung cancer cells","pmids":["41997974"],"confidence":"Medium","gaps":["Single lab; mechanistic detail of FAK-autophagy link limited","In vivo efficacy and selectivity of the C52 inhibitor not established"]},{"year":null,"claim":"How distinct upstream receptors (EGFR, MET/AXL, BAI GPCRs, Gαi2) selectively engage ELMO2's conformational switch and direct context-specific RAC1 outputs remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking receptor input to ELMO2 open/closed transition","Full-length autoinhibited structure not solved","Determinants of paralog (ELMO1/ELMO3) functional redundancy across tissues unclear"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,8,11]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,7,11]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[3]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[8,10]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,8]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[11,12]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[13]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4]}],"complexes":["RhoG-ELMO2-ILK (ERI) complex","MET-AXL-ELMO2-DOCK180 complex","ELMO2-DOCK1/DOCK180 GEF complex"],"partners":["ILK","RHOG","DOCK1","CLIPR-59","MET","AXL","GNAI2","BAI1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96JJ3","full_name":"Engulfment and cell motility protein 2","aliases":["Protein ced-12 homolog A","hCed-12A"],"length_aa":720,"mass_kda":82.6,"function":"Involved in cytoskeletal rearrangements required for phagocytosis of apoptotic cells and cell motility. Acts in association with DOCK1 and CRK. Was initially proposed to be required in complex with DOCK1 to activate Rac Rho small GTPases. May enhance the guanine nucleotide exchange factor (GEF) activity of DOCK1","subcellular_location":"Cytoplasm; Cytoplasm, cytosol; Membrane","url":"https://www.uniprot.org/uniprotkb/Q96JJ3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ELMO2","classification":"Not Classified","n_dependent_lines":329,"n_total_lines":1208,"dependency_fraction":0.2723509933774834},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"DRG1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ELMO2","total_profiled":1310},"omim":[{"mim_id":"620492","title":"MEDIATOR COMPLEX SUBUNIT 31; MED31","url":"https://www.omim.org/entry/620492"},{"mim_id":"618871","title":"RHO GUANINE NUCLEOTIDE EXCHANGE FACTOR 16; ARHGEF16","url":"https://www.omim.org/entry/618871"},{"mim_id":"607679","title":"DEDICATOR OF CYTOKINESIS 4; DOCK4","url":"https://www.omim.org/entry/607679"},{"mim_id":"607422","title":"GLYCINE C-ACETYLTRANSFERASE; GCAT","url":"https://www.omim.org/entry/607422"},{"mim_id":"607382","title":"CAP-GLY DOMAIN-CONTAINING LINKER PROTEIN 3; CLIP3","url":"https://www.omim.org/entry/607382"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ELMO2"},"hgnc":{"alias_symbol":["CED12","ELMO-2","CED-12","KIAA1834","FLJ11656"],"prev_symbol":[]},"alphafold":{"accession":"Q96JJ3","domains":[{"cath_id":"3.10.20.90","chopping":"6-79","consensus_level":"high","plddt":93.2489,"start":6,"end":79},{"cath_id":"1.25.10.10","chopping":"82-300","consensus_level":"medium","plddt":92.339,"start":82,"end":300},{"cath_id":"-","chopping":"309-328_338-512","consensus_level":"high","plddt":93.0749,"start":309,"end":512},{"cath_id":"2.30.29.30","chopping":"537-675","consensus_level":"high","plddt":83.4728,"start":537,"end":675}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96JJ3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96JJ3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96JJ3-F1-predicted_aligned_error_v6.png","plddt_mean":88.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ELMO2","jax_strain_url":"https://www.jax.org/strain/search?query=ELMO2"},"sequence":{"accession":"Q96JJ3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96JJ3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96JJ3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96JJ3"}},"corpus_meta":[{"pmid":"22160594","id":"PMC_22160594","title":"Epidermal growth factor induction of front-rear polarity and migration in keratinocytes is mediated by integrin-linked kinase and ELMO2.","date":"2011","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/22160594","citation_count":38,"is_preprint":false},{"pmid":"19439446","id":"PMC_19439446","title":"Integrin-linked kinase interactions with ELMO2 modulate cell polarity.","date":"2009","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/19439446","citation_count":32,"is_preprint":false},{"pmid":"30604775","id":"PMC_30604775","title":"Structure of BAI1/ELMO2 complex reveals an action mechanism of adhesion GPCRs via ELMO family scaffolds.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/30604775","citation_count":31,"is_preprint":false},{"pmid":"30108175","id":"PMC_30108175","title":"HGF-induced formation of the MET-AXL-ELMO2-DOCK180 complex promotes RAC1 activation, receptor clustering, and cancer cell migration and invasion.","date":"2018","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30108175","citation_count":30,"is_preprint":false},{"pmid":"25995380","id":"PMC_25995380","title":"An ELMO2-RhoG-ILK network modulates microtubule dynamics.","date":"2015","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/25995380","citation_count":26,"is_preprint":false},{"pmid":"27476657","id":"PMC_27476657","title":"Loss-of-Function Mutations in ELMO2 Cause Intraosseous Vascular Malformation by Impeding RAC1 Signaling.","date":"2016","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27476657","citation_count":26,"is_preprint":false},{"pmid":"27539661","id":"PMC_27539661","title":"Involvement of Tiam1, RhoG and ELMO2/ILK in Rac1-mediated phagocytosis in human trabecular meshwork cells.","date":"2016","source":"Experimental cell 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modulates myoblast fusion.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25572395","citation_count":9,"is_preprint":false},{"pmid":"27226625","id":"PMC_27226625","title":"Elmo2 Is a Regulator of Insulin-dependent Glut4 Membrane Translocation.","date":"2016","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27226625","citation_count":9,"is_preprint":false},{"pmid":"27627840","id":"PMC_27627840","title":"Integrin-linked kinase and ELMO2 modulate recycling endosomes in keratinocytes.","date":"2016","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/27627840","citation_count":8,"is_preprint":false},{"pmid":"32292657","id":"PMC_32292657","title":"ELMO2 association with Gαi2 regulates pancreatic cancer cell chemotaxis and metastasis.","date":"2020","source":"PeerJ","url":"https://pubmed.ncbi.nlm.nih.gov/32292657","citation_count":6,"is_preprint":false},{"pmid":"35874819","id":"PMC_35874819","title":"Comparative Morphological, Metabolic and Transcriptome Analyses in elmo1  , elmo2  , and elmo3  Zebrafish Mutants Identified a Functional Non-Redundancy of the Elmo Proteins.","date":"2022","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/35874819","citation_count":4,"is_preprint":false},{"pmid":"38517102","id":"PMC_38517102","title":"ELMO2 biallelic pathogenic variants in a patient with gingival hypertrophy and cherubism phenotype: Case report and molecular review.","date":"2024","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/38517102","citation_count":3,"is_preprint":false},{"pmid":"40456777","id":"PMC_40456777","title":"ELMO2 is an essential regulator of carotid artery development.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/40456777","citation_count":1,"is_preprint":false},{"pmid":"41997974","id":"PMC_41997974","title":"ELMO2 is a therapeutic vulnerability in mesenchymal-like and drug-resistant non-small cell lung cancer.","date":"2026","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/41997974","citation_count":0,"is_preprint":false},{"pmid":"41149120","id":"PMC_41149120","title":"Primary Intraosseous Vascular Malformation in a Child with ELMO2 Mutation: Diagnostic and Dental Management Challenges.","date":"2025","source":"Dentistry journal","url":"https://pubmed.ncbi.nlm.nih.gov/41149120","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10571,"output_tokens":3787,"usd":0.044259,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11547,"output_tokens":4361,"usd":0.08338,"stage2_stop_reason":"end_turn"},"total_usd":0.127639,"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\": 2009,\n      \"finding\": \"ELMO2 forms a novel tripartite complex with integrin-linked kinase (ILK) and RhoG. This complex localizes specifically to the leading lamellipodia of polarized cells. RhoG binding to ELMO2 is required for ILK-induced cell polarization, and expression of dominant-negative ELMO2 mutants abolishes ILK's ability to promote front-rear polarity, placing RhoG-ELMO2-ILK complexes as essential mediators of cell polarity and haptotactic migration.\",\n      \"method\": \"Co-immunoprecipitation, dominant-negative mutant expression, live cell imaging/localization, functional migration assays with loss-of-function\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, dominant-negative mutants, localization experiments with functional consequence, replicated across multiple studies\",\n      \"pmids\": [\"19439446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"EGF stimulation induces front-rear polarity and directional migration in keratinocytes through a pathway requiring ILK, ELMO2, integrin β1, and Rac1. EGF selectively (not other growth factors) promotes formation of active RhoG-ELMO2-ILK complexes that mediate this response, requiring EGF receptor tyrosine kinase activity.\",\n      \"method\": \"Pharmacological inhibition of EGFR kinase, siRNA knockdown, chemotaxis assays, Co-immunoprecipitation with active RhoG\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, knockdown, migration assays, pharmacological inhibition), two papers from the same lab confirming the complex\",\n      \"pmids\": [\"22160594\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ELMO2-RhoG-ILK (ERI) tripartite complexes modulate microtubule dynamics in an integrin-independent manner in differentiated keratinocytes. ERI complexes activate Rac1, which stabilizes microtubules via two routes: (1) phosphorylation/inactivation of stathmin, and (2) GSK-3β phosphorylation/inactivation leading to CRMP2 activation. Loss of ERI complexes impairs Ca2+-mediated adherens junction formation.\",\n      \"method\": \"Conditional Ilk gene knockout, exogenous ELMO2/RhoG expression, microtubule dynamics imaging, phosphorylation assays for stathmin and GSK-3β/CRMP2\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined phenotype, multiple downstream pathway readouts, two orthogonal mechanistic routes identified\",\n      \"pmids\": [\"25995380\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ClipR-59 interacts with ELMO2 via the atypical PH domain of ELMO2 and the Glu-Pro-rich domain of ClipR-59. This interaction is regulated by Rho-GTPase. Formation of the ELMO2-ClipR-59 complex enhances Rac1 activation and is required for myoblast fusion.\",\n      \"method\": \"Yeast two-hybrid screen, Co-immunoprecipitation, domain mapping, Rac1 activation assay (GTP-loading), siRNA knockdown in C2C12 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus Co-IP with domain mapping and functional Rac1 activation assay, single lab\",\n      \"pmids\": [\"25572395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Loss-of-function mutations in ELMO2 cause intraosseous vascular malformation. Absence of ELMO2 in primary fibroblasts correlates with significant downregulation of binding partner DOCK1, resulting in deficient RAC1-dependent cell migration.\",\n      \"method\": \"Human genetic analysis, primary fibroblast analysis from affected individuals (ELMO2 and DOCK1 protein levels, RAC1 activation/migration assays)\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human loss-of-function genetics with primary patient cells showing molecular pathway defects, single cohort study\",\n      \"pmids\": [\"27476657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ELMO2 and ILK localize to Rab4- and Rab11a-containing recycling endosomes during Ca2+-induced keratinocyte differentiation. ELMO2- or ILK-deficient keratinocytes show disrupted positioning of long-loop Rab11a-positive endosomes adjacent to cell-cell contacts and impaired E-cadherin localization to cell borders.\",\n      \"method\": \"Fluorescence microscopy/co-localization, ELMO2/ILK knockdown or knockout, E-cadherin localization assay, recycling endosome fractionation\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with functional consequence (E-cadherin delivery), loss-of-function with specific phenotypic readout, single lab\",\n      \"pmids\": [\"27627840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ELMO2, RhoG, and ILK form a signaling pathway that mediates Rac1-dependent phagocytosis in human trabecular meshwork cells. Knockdown of ELMO2 reduced phagocytosis by ~51%, indicating a functional role for ELMO2 in this process.\",\n      \"method\": \"siRNA knockdown in TM-1 and primary HTM cells, phagocytosis assays, Rac1 inhibitor studies\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with specific phagocytosis readout, consistent with established ILK-ELMO2-RhoG-Rac1 axis; single lab\",\n      \"pmids\": [\"27539661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ELMO2 is required for insulin-induced RAC1 GTP loading and promotes the insulin-induced membrane association of Akt (but not AKT activation per se). ELMO2 overexpression enhances insulin-dependent GLUT4 membrane translocation, while knockdown suppresses it in adipocytes and skeletal muscle cells.\",\n      \"method\": \"Overexpression and siRNA knockdown in 3T3-L1 adipocytes and L6 skeletal muscle cells, Rac1 GTP-loading assay, Akt membrane fractionation, GLUT4 translocation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with multiple downstream readouts (Rac1 activation, Akt membrane localization, GLUT4 translocation), single lab\",\n      \"pmids\": [\"27226625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HGF induces formation of a MET-AXL-ELMO2-DOCK180 complex on the plasma membrane in glioblastoma cells, which promotes RAC1-dependent cytoskeleton reorganization, cell migration and invasion. ELMO2 and DOCK180 are recruited to the MET-AXL complex upon HGF stimulation.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, RAC1 activation assay, migration/invasion assays, confocal imaging of receptor clustering\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with functional loss-of-function assays, multiple cell lines tested; single lab\",\n      \"pmids\": [\"30108175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"An evolutionarily conserved fragment in the C-terminal cytoplasmic tail of BAI-adhesion GPCRs is specifically recognized by the RBD-ARR-ELMO (RAE) supramodule of ELMO2. Crystal structures of ELMO2-RAE and its complex with BAI1 define the molecular basis of BAI/ELMO interactions. Disease-causing mutations in BAI and ELMO were mapped and shown to affect complex formation.\",\n      \"method\": \"X-ray crystallography, structure-function analysis, mutagenesis of disease-associated variants, binding assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure of ELMO2 RAE supramodule and complex with BAI1, mutagenesis confirming interface residues, identification of additional receptor (GPR128) using structural information\",\n      \"pmids\": [\"30604775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ELMO2 interacts with Gαi2, and CXCL12 triggers Gαi2-dependent membrane translocation of ELMO2. ELMO2 knockdown inhibits pancreatic cancer cell chemotaxis, migration, invasion, and F-actin polymerization.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, chemotaxis/migration/invasion assays, F-actin polymerization assay, subcellular fractionation\",\n      \"journal\": \"PeerJ\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP identifying novel binding partner, loss-of-function with phenotypic readout, single lab with single methods per finding\",\n      \"pmids\": [\"32292657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ELMO2 conformational state regulates myoblast fusion. A mutation biasing ELMO2 toward an open conformation increases RAC1-DOCK1 signaling and enhances myoblast fusion during development and muscle regeneration. Combined Elmo1 knockout with muscle-specific Elmo2 knockout caused severe myoblast fusion defects, demonstrating their cooperative role. Expression of open-conformation ELMO2 reversed dystrophic features in Dysferlin-null mice.\",\n      \"method\": \"Mouse genetic models (Elmo1 KO, muscle-specific Elmo2 KO, conformational mutant knock-in), myoblast fusion quantification, muscle regeneration assays, Dysferlin-null disease model rescue experiment\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple genetic mouse models including conformational mutants, in vivo rescue of muscular dystrophy, mechanistic link to RAC1/DOCK1 signaling pathway established\",\n      \"pmids\": [\"36400788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Global Elmo2 inactivation in mice causes midgestation lethality due to dilation of 3rd pharyngeal arch arteries and carotid aneurysm formation, associated with defects in vascular smooth muscle cell organization. Neural crest-specific deletion phenocopies this. In vitro, ELMO2 regulates vascular smooth muscle cell adhesion, spreading, and contractility through Rac1 activation and modulation of actin dynamics.\",\n      \"method\": \"Global and conditional (neural crest-specific) Elmo2 knockout mice, vascular morphology analysis, in vitro vascular smooth muscle cell adhesion/spreading/contractility assays, Rac1 activation assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with defined cellular mechanism (Rac1/actin), phenotypic rescue via tissue-specific deletion confirming cell-autonomous role, in vitro mechanistic validation\",\n      \"pmids\": [\"40456777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ELMO2 suppression in mesenchymal-like cancer cells induces excessive autophagy and cell death via FAK activity inhibition. ELMO3 acts as a functional paralog that compensates for ELMO2 loss (synthetic lethal interaction). ZEB1 represses ELMO3 transcription in mesenchymal-like cells, rendering them sensitive to ELMO2 blockade. A structure-based small-molecule ELMO2 inhibitor (C52) was identified that kills ELMO3-low lung cancer cells.\",\n      \"method\": \"siRNA knockdown, epistasis analysis, FAK activity assays, autophagy markers, ZEB1 ChIP/transcriptional assays, structure-based drug screening, cell viability assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined molecular pathway (FAK), synthetic lethality established, transcriptional regulation by ZEB1 shown; single lab, limited mechanistic detail in abstract\",\n      \"pmids\": [\"41997974\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ELMO2 is a scaffold protein that operates primarily through tripartite complexes with RhoG and ILK (and bipartite complexes with DOCK1/DOCK180) to activate RAC1, thereby driving directed cell migration, phagocytosis, myoblast fusion, vascular smooth muscle cell organization, and microtubule stabilization; upstream inputs include adhesion GPCRs (BAI1), receptor tyrosine kinases (EGFR, MET/AXL), and Gαi2-coupled chemokine receptors (CXCR4), all converging on ELMO2's RAE supramodule or PH domain to control its conformational state and membrane recruitment, with loss-of-function causing deficient RAC1 signaling and human diseases including intraosseous vascular malformation and Ramon syndrome.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ELMO2 is a scaffold protein that orchestrates RAC1 activation to drive directed cell migration, phagocytosis, myoblast fusion, and vascular morphogenesis [#0, #11, #12]. Its central mechanism is the assembly of a tripartite RhoG-ELMO2-ILK (ERI) complex that localizes to the leading lamellipodia of polarized cells, where RhoG binding to ELMO2 is required for ILK-induced front-rear polarity and haptotactic migration [#0]; this same ERI module activates RAC1 to stabilize microtubules through stathmin and GSK-3\\u03b2/CRMP2 phosphorylation and to support Ca2+-dependent adherens junction formation and E-cadherin delivery via Rab11a recycling endosomes [#2, #5]. ELMO2 also pairs with DOCK1/DOCK180 to form the RAC1 GEF effector arm, and its activity is gated by conformational state: a mutation biasing ELMO2 toward an open conformation increases RAC1-DOCK1 signaling and rescues dystrophic muscle in vivo [#11]. Upstream inputs converge on ELMO2 through diverse receptors\\u2014EGFR tyrosine kinase activity promotes active ERI complex formation [#1], HGF triggers assembly of a MET-AXL-ELMO2-DOCK180 complex driving glioblastoma invasion [#8], and the G\\u03b1i2-coupled chemokine axis (CXCL12) triggers ELMO2 membrane translocation [#10]\\u2014while crystal structures define how the RBD-ARR-ELMO (RAE) supramodule recognizes the cytoplasmic tail of BAI adhesion GPCRs [#9]. Loss-of-function mutations in ELMO2 cause intraosseous vascular malformation, with patient fibroblasts showing downregulation of DOCK1 and deficient RAC1-dependent migration [#4]. ELMO2 suppression in mesenchymal-like cancer cells induces lethal autophagy via FAK inhibition, with ELMO3 acting as a ZEB1-repressed paralog in a synthetic lethal relationship [#13].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Established ELMO2's core scaffolding role by showing it bridges RhoG and ILK into a complex required for cell polarity, defining the molecular basis of haptotactic migration.\",\n      \"evidence\": \"Co-IP, dominant-negative mutants, and live-cell imaging with functional migration assays in polarized cells\",\n      \"pmids\": [\"19439446\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the upstream receptor inputs that initiate ERI assembly\", \"Structural basis of RhoG-ELMO2 binding not resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified EGFR as a selective upstream activator, answering how an extracellular signal triggers active ERI complex formation and directional migration.\",\n      \"evidence\": \"EGFR pharmacological inhibition, siRNA knockdown, chemotaxis assays, and Co-IP with active RhoG in keratinocytes\",\n      \"pmids\": [\"22160594\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which EGFR activity converts to RhoG loading not detailed\", \"Specificity over other growth factors not mechanistically explained\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Extended ERI function beyond migration to cytoskeletal control, showing RAC1 activation by the complex stabilizes microtubules and supports adherens junctions.\",\n      \"evidence\": \"Conditional Ilk knockout, microtubule dynamics imaging, and stathmin / GSK-3\\u03b2/CRMP2 phosphorylation assays\",\n      \"pmids\": [\"25995380\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish whether microtubule effects are direct or solely RAC1-mediated\", \"Integrin-independent recruitment mechanism unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Mapped the ELMO2 atypical PH domain as a docking site for ClipR-59, linking a new partner to RAC1 activation during myoblast fusion.\",\n      \"evidence\": \"Yeast two-hybrid screen, Co-IP with domain mapping, and Rac1 GTP-loading assays in C2C12 cells\",\n      \"pmids\": [\"25572395\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; reciprocal in vivo validation absent\", \"How Rho-GTPase regulation of the interaction is achieved not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected ELMO2 to human disease, demonstrating loss-of-function mutations cause intraosseous vascular malformation through DOCK1 destabilization and deficient RAC1 signaling.\",\n      \"evidence\": \"Human genetic analysis and primary patient fibroblast assays of ELMO2/DOCK1 levels and RAC1 activation\",\n      \"pmids\": [\"27476657\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single cohort; cell-autonomous vascular mechanism not addressed in vivo\", \"Mechanism of DOCK1 downregulation upon ELMO2 loss unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Broadened the functional repertoire of the ELMO2-RhoG-ILK axis to phagocytosis, insulin-dependent GLUT4 trafficking, and endosomal E-cadherin delivery.\",\n      \"evidence\": \"siRNA knockdown/overexpression with phagocytosis, Rac1 GTP-loading, GLUT4 translocation, and endosome co-localization assays across trabecular meshwork, adipocyte/muscle, and keratinocyte systems\",\n      \"pmids\": [\"27539661\", \"27226625\", \"27627840\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Each role established in a single lab/system\", \"Whether a common molecular mechanism underlies these diverse outputs not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed receptor tyrosine kinase signaling recruits ELMO2-DOCK180 into a MET-AXL complex, defining how HGF drives RAC1-dependent cancer invasion.\",\n      \"evidence\": \"Co-IP, siRNA knockdown, RAC1 activation, and migration/invasion assays in glioblastoma cells\",\n      \"pmids\": [\"30108175\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. indirect ELMO2-MET/AXL contacts not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Provided structural definition of ELMO2's RAE supramodule recognizing BAI adhesion GPCR tails, establishing the atomic basis of receptor-ELMO coupling and disease variant effects.\",\n      \"evidence\": \"X-ray crystallography of ELMO2-RAE and its BAI1 complex with mutagenesis of disease variants and binding assays\",\n      \"pmids\": [\"30604775\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not capture full-length autoinhibited ELMO2 conformation\", \"Downstream signaling consequences of BAI1 binding not assayed structurally\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified G\\u03b1i2 as a chemokine-coupled input, showing CXCL12 drives G\\u03b1i2-dependent ELMO2 membrane translocation to promote cancer chemotaxis.\",\n      \"evidence\": \"Co-IP, fractionation, siRNA knockdown, and chemotaxis/invasion/F-actin assays in pancreatic cancer cells\",\n      \"pmids\": [\"32292657\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab with single method per finding\", \"Direct vs. indirect G\\u03b1i2 binding not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated that ELMO2 conformational state gates RAC1-DOCK1 output, with open-conformation ELMO2 enhancing myoblast fusion and rescuing muscular dystrophy in vivo.\",\n      \"evidence\": \"Mouse genetic models including conformational knock-in and muscle-specific Elmo2/Elmo1 knockouts, fusion and regeneration assays, and Dysferlin-null rescue\",\n      \"pmids\": [\"36400788\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural details of the conformational transition not resolved\", \"Generality of conformational regulation to non-muscle contexts untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established a developmental vascular role, showing ELMO2 is required cell-autonomously in neural-crest-derived smooth muscle for pharyngeal artery integrity via RAC1/actin control.\",\n      \"evidence\": \"Global and neural-crest-specific Elmo2 knockout mice with vascular morphology analysis and in vitro smooth muscle adhesion/spreading/contractility and Rac1 assays\",\n      \"pmids\": [\"40456777\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream receptors driving ELMO2 in smooth muscle not identified\", \"Link between this phenotype and human ELMO2 disease not formally tested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Revealed a therapeutic vulnerability, showing ELMO2 loss triggers FAK-dependent lethal autophagy and that ELMO3 is a ZEB1-repressed synthetic lethal paralog targetable with a small molecule.\",\n      \"evidence\": \"siRNA knockdown, epistasis, FAK and autophagy assays, ZEB1 ChIP/transcriptional analysis, and structure-based inhibitor screening in lung cancer cells\",\n      \"pmids\": [\"41997974\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; mechanistic detail of FAK-autophagy link limited\", \"In vivo efficacy and selectivity of the C52 inhibitor not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How distinct upstream receptors (EGFR, MET/AXL, BAI GPCRs, G\\u03b1i2) selectively engage ELMO2's conformational switch and direct context-specific RAC1 outputs remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking receptor input to ELMO2 open/closed transition\", \"Full-length autoinhibited structure not solved\", \"Determinants of paralog (ELMO1/ELMO3) functional redundancy across tissues unclear\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 8, 11]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 7, 11]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [8, 10]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 8]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [11, 12]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [\n      \"RhoG-ELMO2-ILK (ERI) complex\",\n      \"MET-AXL-ELMO2-DOCK180 complex\",\n      \"ELMO2-DOCK1/DOCK180 GEF complex\"\n    ],\n    \"partners\": [\n      \"ILK\",\n      \"RhoG\",\n      \"DOCK1\",\n      \"ClipR-59\",\n      \"MET\",\n      \"AXL\",\n      \"GNAI2\",\n      \"BAI1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}