Affinage

ELMO2

Engulfment and cell motility protein 2 · UniProt Q96JJ3

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

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2009 High

    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

    PMID:19439446

    Open questions at the time
    • Did not define the upstream receptor inputs that initiate ERI assembly
    • Structural basis of RhoG-ELMO2 binding not resolved
  2. 2011 High

    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

    PMID:22160594

    Open questions at the time
    • Mechanism by which EGFR activity converts to RhoG loading not detailed
    • Specificity over other growth factors not mechanistically explained
  3. 2015 High

    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

    PMID:25995380

    Open questions at the time
    • Did not establish whether microtubule effects are direct or solely RAC1-mediated
    • Integrin-independent recruitment mechanism unclear
  4. 2015 Medium

    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

    PMID:25572395

    Open questions at the time
    • Single lab; reciprocal in vivo validation absent
    • How Rho-GTPase regulation of the interaction is achieved not defined
  5. 2016 Medium

    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

    PMID:27476657

    Open questions at the time
    • Single cohort; cell-autonomous vascular mechanism not addressed in vivo
    • Mechanism of DOCK1 downregulation upon ELMO2 loss unknown
  6. 2016 Medium

    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

    PMID:27226625 PMID:27539661 PMID:27627840

    Open questions at the time
    • Each role established in a single lab/system
    • Whether a common molecular mechanism underlies these diverse outputs not tested
  7. 2018 Medium

    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

    PMID:30108175

    Open questions at the time
    • Direct vs. indirect ELMO2-MET/AXL contacts not resolved
    • Single lab
  8. 2019 High

    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

    PMID:30604775

    Open questions at the time
    • Did not capture full-length autoinhibited ELMO2 conformation
    • Downstream signaling consequences of BAI1 binding not assayed structurally
  9. 2020 Medium

    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

    PMID:32292657

    Open questions at the time
    • Single lab with single method per finding
    • Direct vs. indirect Gαi2 binding not established
  10. 2022 High

    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

    PMID:36400788

    Open questions at the time
    • Structural details of the conformational transition not resolved
    • Generality of conformational regulation to non-muscle contexts untested
  11. 2025 High

    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

    PMID:40456777

    Open questions at the time
    • Upstream receptors driving ELMO2 in smooth muscle not identified
    • Link between this phenotype and human ELMO2 disease not formally tested
  12. 2026 Medium

    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

    PMID:41997974

    Open questions at the time
    • Single lab; mechanistic detail of FAK-autophagy link limited
    • In vivo efficacy and selectivity of the C52 inhibitor not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How distinct upstream receptors (EGFR, MET/AXL, BAI GPCRs, Gαi2) selectively engage ELMO2's conformational switch and direct context-specific RAC1 outputs remains unresolved.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3 GO:0008289 lipid binding 1
Localization
GO:0005886 plasma membrane 2 GO:0005768 endosome 1 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1266738 Developmental Biology 2 R-HSA-1643685 Disease 1 R-HSA-9612973 Autophagy 1
Partners
AXLBAI1CLIPR-59DOCK1GNAI2ILKMETRHOG
Complex memberships
ELMO2-DOCK1/DOCK180 GEF complexMET-AXL-ELMO2-DOCK180 complexRhoG-ELMO2-ILK (ERI) complex

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 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. Co-immunoprecipitation, dominant-negative mutant expression, live cell imaging/localization, functional migration assays with loss-of-function Molecular biology of the cell High 19439446
2011 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. Pharmacological inhibition of EGFR kinase, siRNA knockdown, chemotaxis assays, Co-immunoprecipitation with active RhoG Molecular biology of the cell High 22160594
2015 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. Conditional Ilk gene knockout, exogenous ELMO2/RhoG expression, microtubule dynamics imaging, phosphorylation assays for stathmin and GSK-3β/CRMP2 Molecular biology of the cell High 25995380
2015 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. Yeast two-hybrid screen, Co-immunoprecipitation, domain mapping, Rac1 activation assay (GTP-loading), siRNA knockdown in C2C12 cells The Journal of biological chemistry Medium 25572395
2016 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. Human genetic analysis, primary fibroblast analysis from affected individuals (ELMO2 and DOCK1 protein levels, RAC1 activation/migration assays) American journal of human genetics Medium 27476657
2016 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. Fluorescence microscopy/co-localization, ELMO2/ILK knockdown or knockout, E-cadherin localization assay, recycling endosome fractionation Biochimica et biophysica acta Medium 27627840
2016 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. siRNA knockdown in TM-1 and primary HTM cells, phagocytosis assays, Rac1 inhibitor studies Experimental cell research Medium 27539661
2016 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. Overexpression and siRNA knockdown in 3T3-L1 adipocytes and L6 skeletal muscle cells, Rac1 GTP-loading assay, Akt membrane fractionation, GLUT4 translocation assay The Journal of biological chemistry Medium 27226625
2018 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. Co-immunoprecipitation, siRNA knockdown, RAC1 activation assay, migration/invasion assays, confocal imaging of receptor clustering The Journal of biological chemistry Medium 30108175
2019 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. X-ray crystallography, structure-function analysis, mutagenesis of disease-associated variants, binding assays Nature communications High 30604775
2020 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. Co-immunoprecipitation, siRNA knockdown, chemotaxis/migration/invasion assays, F-actin polymerization assay, subcellular fractionation PeerJ Medium 32292657
2022 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. 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 Nature communications High 36400788
2025 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. 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 Nature communications High 40456777
2026 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. siRNA knockdown, epistasis analysis, FAK activity assays, autophagy markers, ZEB1 ChIP/transcriptional assays, structure-based drug screening, cell viability assays Nature communications Medium 41997974

Source papers

Stage 0 corpus · 19 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Epidermal growth factor induction of front-rear polarity and migration in keratinocytes is mediated by integrin-linked kinase and ELMO2. Molecular biology of the cell 38 22160594
2009 Integrin-linked kinase interactions with ELMO2 modulate cell polarity. Molecular biology of the cell 32 19439446
2019 Structure of BAI1/ELMO2 complex reveals an action mechanism of adhesion GPCRs via ELMO family scaffolds. Nature communications 31 30604775
2018 HGF-induced formation of the MET-AXL-ELMO2-DOCK180 complex promotes RAC1 activation, receptor clustering, and cancer cell migration and invasion. The Journal of biological chemistry 30 30108175
2016 Loss-of-Function Mutations in ELMO2 Cause Intraosseous Vascular Malformation by Impeding RAC1 Signaling. American journal of human genetics 26 27476657
2015 An ELMO2-RhoG-ILK network modulates microtubule dynamics. Molecular biology of the cell 26 25995380
2016 Involvement of Tiam1, RhoG and ELMO2/ILK in Rac1-mediated phagocytosis in human trabecular meshwork cells. Experimental cell research 25 27539661
2018 Homozygous mutation in ELMO2 may cause Ramon syndrome. Clinical genetics 15 29095483
2012 Emerging role of ILK and ELMO2 in the integration of adhesion and migration pathways. Cell adhesion & migration 12 22568984
2022 Biasing the conformation of ELMO2 reveals that myoblast fusion can be exploited to improve muscle regeneration. Nature communications 10 36400788
2016 Elmo2 Is a Regulator of Insulin-dependent Glut4 Membrane Translocation. The Journal of biological chemistry 9 27226625
2015 ClipR-59 interacts with Elmo2 and modulates myoblast fusion. The Journal of biological chemistry 9 25572395
2016 Integrin-linked kinase and ELMO2 modulate recycling endosomes in keratinocytes. Biochimica et biophysica acta 8 27627840
2020 ELMO2 association with Gαi2 regulates pancreatic cancer cell chemotaxis and metastasis. PeerJ 6 32292657
2022 Comparative Morphological, Metabolic and Transcriptome Analyses in elmo1 , elmo2 , and elmo3 Zebrafish Mutants Identified a Functional Non-Redundancy of the Elmo Proteins. Frontiers in cell and developmental biology 4 35874819
2024 ELMO2 biallelic pathogenic variants in a patient with gingival hypertrophy and cherubism phenotype: Case report and molecular review. American journal of medical genetics. Part A 3 38517102
2025 ELMO2 is an essential regulator of carotid artery development. Nature communications 1 40456777
2026 ELMO2 is a therapeutic vulnerability in mesenchymal-like and drug-resistant non-small cell lung cancer. Nature communications 0 41997974
2025 Primary Intraosseous Vascular Malformation in a Child with ELMO2 Mutation: Diagnostic and Dental Management Challenges. Dentistry journal 0 41149120

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