{"gene":"MEMO1","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2004,"finding":"MEMO1 (Memo) was identified as a novel protein that interacts with a phospho-Tyr1227-containing peptide of ErbB2/Neu, most probably through the Shc adaptor protein. In Memo-defective cells, ErbB2-driven lamellipodia form normally but microtubule extension toward the cell cortex fails, establishing Memo as a relay between ErbB2 chemotactic signals and the microtubule cytoskeleton.","method":"Co-precipitation with ErbB2 phosphopeptide, dominant-negative/knockdown cell migration assays, live imaging of lamellipodia and microtubule dynamics","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-precipitation, functional knockdown with specific cytoskeletal phenotype, replicated in subsequent studies","pmids":["15156151"],"is_preprint":false},{"year":2007,"finding":"Crystal structure of human MEMO1 at 2.1 Å resolution revealed it is homologous to class III nonheme iron-dependent dioxygenases. No metal binding or classical enzymatic (dioxygenase) activity was detected, but MEMO1 directly binds an ErbB2-derived phosphopeptide encompassing Tyr-1227 via its vestigial enzymatic active site, defining it as a new class of phosphotyrosine-binding protein.","method":"X-ray crystallography (2.1 Å), in vitro phosphopeptide binding assay, active-site structural comparison","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus direct binding assay with mutagenesis-level structural comparison; foundational mechanistic paper","pmids":["18045866"],"is_preprint":false},{"year":2008,"finding":"Memo controls ErbB2-regulated microtubule dynamics by altering the transition frequency between MT growth and shortening phases. Memo is required for proper localization of RhoA GTPase and its effector mDia1 to the plasma membrane; Memo-RhoA-mDia1 signaling coordinates lamellipodial actin network organization, adhesion site formation, and microtubule outgrowth at the leading edge during cell migration.","method":"Memo siRNA knockdown, live MT dynamics imaging, immunofluorescence of RhoA/mDia1 localization, adhesion site quantification","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (live imaging, IF localization, genetic knockdown with defined cytoskeletal phenotypes), replicated in a dedicated mechanistic study","pmids":["18955552"],"is_preprint":false},{"year":2009,"finding":"Memo interacts directly with cofilin (identified by yeast two-hybrid and confirmed by in vitro pulldown with recombinant proteins and co-immunoprecipitation). Memo enhances cofilin F-actin depolymerizing and severing activity in vitro. In Memo-knockdown cells, HRG-induced PLCγ1 phosphorylation is reduced and GFP-cofilin recruitment to lamellipodia is impaired, placing Memo upstream of both PLCγ1 and cofilin in ErbB2-driven chemotaxis.","method":"Yeast two-hybrid, recombinant protein pulldown, co-immunoprecipitation, in vitro F-actin binding and depolymerization assay, Memo/PLCγ1 knockdown with live cell migration directionality tracking","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — yeast two-hybrid confirmed by in vitro reconstitution and Co-IP, plus in vitro functional actin assay and genetic epistasis","pmids":["19223396"],"is_preprint":false},{"year":2011,"finding":"Structural and functional analysis defined the minimum ErbB2 phosphopeptide sequence required for MEMO1 recognition. The interaction is pH-dependent and requires phosphorylation of Tyr-1227; a docking-based structural model of the MEMO1/phosphopeptide complex was generated and compared to SH2 and PTB phosphotyrosine motifs, identifying a novel phosphotyrosine recognition motif.","method":"NMR/docking structural modeling, peptide binding assays, mutagenesis of phosphopeptide variants","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — structural model plus binding validation with peptide variants, single lab","pmids":["21840311"],"is_preprint":false},{"year":2012,"finding":"MEMO1 binds to insulin receptor substrate 1 (IRS1), activates the downstream PI3K/Akt signaling pathway, upregulates Snail1, and thereby triggers the epithelial-mesenchymal transition (EMT) program in mammary epithelial cells downstream of IGF-IR signaling.","method":"Co-immunoprecipitation (MEMO1-IRS1 interaction), Western blot for PI3K/Akt activation and Snail1, EMT marker analysis, overexpression/knockdown functional assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus downstream signaling readouts, single lab, multiple functional assays","pmids":["22824790"],"is_preprint":false},{"year":2013,"finding":"MEMO1 physically interacts with estrogen receptor α (ERα) and, through its interactions with growth factor receptors IGF1R and ERBB2, mediates extranuclear ER functions including activation of MAPK and AKT. This leads to ERα phosphorylation and regulation of estrogen-responsive gene expression; MEMO1 is required for estrogen-induced breast tumor growth in vivo.","method":"Co-immunoprecipitation (MEMO-ERα, MEMO-IGF1R, MEMO-ERBB2), Western blot for MAPK/AKT activation and ERα phosphorylation, ERα reporter assay, xenograft tumor growth","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple Co-IPs, downstream signaling assays, and in vivo data, single lab","pmids":["23861392"],"is_preprint":false},{"year":2013,"finding":"Memo associates with the FGFR signalosome and is necessary for optimal activation of downstream FGF signaling. Loss of Memo in mouse embryonic fibroblasts reduces FGF-induced signaling responses. Memo conditional-knockout mice show reduced lifespan, premature aging phenotypes, elevated serum 1,25(OH)2D and calcium, identifying Memo as a novel regulator of FGFR signaling that controls vitamin D and calcium homeostasis.","method":"Co-immunoprecipitation (Memo-FGFR complex), Memo KO MEFs signaling assays, conditional knockout mouse model with phenotypic analysis","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and KO MEF signaling assays, plus in vivo KO phenotype, single lab","pmids":["24056085"],"is_preprint":false},{"year":2014,"finding":"Memo is a copper-dependent redox enzyme: biochemical assays showed Memo promotes a more oxidized intracellular milieu and stimulates ROS production in cellular structures involved in migration. Memo is required for sustained production of superoxide (O2−) by NADPH oxidase 1 (NOX1) in breast cancer cells. Memo is required for migration/invasion in vitro and spontaneous lung metastasis in vivo.","method":"Biochemical redox assays, ROS measurement (intracellular oxidation probes), NOX1 activity assays, Memo knockdown/overexpression, in vivo xenograft metastasis","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal biochemical and cell-based assays plus in vivo metastasis data","pmids":["24917593"],"is_preprint":false},{"year":2014,"finding":"Memo null MEFs are impaired in PDGF-induced migration due to a defect in sphingosine-1-phosphate (S1P) cell-autonomous signaling. In endothelial cells (HUVECs), Memo knockdown reduces junctional VE-cadherin and increases sprouting; these phenotypes are rescued by exogenous S1P, placing Memo in the cell-autonomous S1PR signaling pathway. Endothelial-specific Memo KO embryos show vascular defects from E13.5, mimicking S1PR-deficient phenotypes.","method":"Memo KO MEF migration assays with S1P rescue, HUVEC knockdown with VE-cadherin immunofluorescence and sprouting assays, conventional and endothelial-specific conditional Memo KO mice","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple cell-based rescue experiments and in vivo KO phenotype, single lab","pmids":["24714781"],"is_preprint":false},{"year":2015,"finding":"Neural crest cell-specific deletion of Memo1 causes failure of anterior cranial base ossification (cell-autonomous role), while palate formation is largely normal in these conditional mutants (suggesting a non-autonomous role for MEMO1 in palatal closure). Memo1 mutants show increased hypertrophic chondrocyte zones, reduced vascular invasion and mineralization, and reduced expression of matrix metalloproteinases and osteoblast lineage markers in the cranial base.","method":"ENU-induced recessive mutant mouse, non-complementation mapping to Memo1, neural crest-specific conditional Memo1 KO (Cre/lox), histology, gene expression analysis, micro-CT","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with cell-type-specific rescue experiment, cell-autonomous function established","pmids":["26746790"],"is_preprint":false},{"year":2016,"finding":"Memo interacts with c-Src and facilitates ERα–c-Src interaction, ERα Y537 phosphorylation, and ERα extra-nuclear localization downstream of heregulin and estrogen in breast cancer cells.","method":"Co-immunoprecipitation (Memo-c-Src, ERα-c-Src), Western blot for ERα Y537 phosphorylation, sub-cellular fractionation/immunofluorescence of ERα localization, Memo knockdown","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, phosphorylation assay, and subcellular localization with functional link, single lab","pmids":["27472465"],"is_preprint":false},{"year":2016,"finding":"HER2 activation drives MEMO1 expression in colorectal cancer cells through AhR/ARNT transcriptional complex recruitment to the MEMO1 gene promoter (established by reporter assays and chromatin IP). MEMO1 depletion negatively affects the cellular actin network and is required for HER2-mediated migration and invasion.","method":"Chromatin immunoprecipitation (AhR/ARNT on MEMO1 promoter), luciferase reporter assay, MEMO1 siRNA knockdown with actin immunofluorescence and migration/invasion assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assay confirm transcriptional mechanism; functional knockdown assays, single lab","pmids":["27941874"],"is_preprint":false},{"year":2017,"finding":"In C. elegans, MEMO-1 (the orthologue of mammalian MEMO1) inhibits BLI-3/NADPH oxidase. Loss of memo-1 results in enhanced interaction of RHO-1/RhoA with BLI-3/NADPH oxidase, stimulating ROS production that signals via p38 MAP kinase to the transcription factor SKN-1/NRF1,2,3, promoting stress resistance and longevity. Either loss of memo-1 or overexpression of BLI-3 is sufficient to increase lifespan.","method":"C. elegans genetic epistasis (memo-1 loss-of-function, bli-3 overexpression), co-immunoprecipitation (RHO-1 with BLI-3), ROS measurement, p38/SKN-1 pathway reporter assays, lifespan assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis plus Co-IP and multiple orthogonal functional assays in a well-validated model organism","pmids":["28085666"],"is_preprint":false},{"year":2018,"finding":"MEMO1 binding specificity for the ErbB2 phosphopeptide (pTyr1227) was quantitatively mapped using a fluorescence polarization assay and molecular dynamics simulations: the interaction requires phosphorylation of the tyrosine residue and is pH-dependent; mutagenesis identified residues contributing to favorable interactions at the MEMO1-peptide interface.","method":"Fluorescence polarization assay, molecular dynamics simulations, site-directed mutagenesis of MEMO1","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro binding assay with mutagenesis, single lab","pmids":["30067338"],"is_preprint":false},{"year":2018,"finding":"Renal Memo1 deletion in mice leads to elevated serum FGF23 and increased expression/protein abundance of distal renal calcium transporters TRPV5, NCX1, and calbindin-D28k. TRPV5 membrane abundance was vitamin D-dependent while NCX1 abundance was vitamin D-independent, revealing distinct Memo1-dependent and Memo1-independent regulatory mechanisms for renal calcium handling.","method":"Inducible kidney-specific Memo1 KO mouse model (Cre/lox), serum biochemistry, qPCR and Western blot for transporter expression, vitamin D-deficient diet challenge","journal":"Frontiers in physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined transport phenotype and diet rescue, single lab","pmids":["30038585"],"is_preprint":false},{"year":2018,"finding":"Memo1 deletion in mice results in severely altered trabecular bone with lower mineralization. Alkaline phosphatase (ALP) activity is decreased in serum and bone without change in ALPL expression; the bone intracellular redox state is altered and ALP dimerization is reduced in Memo cKO bone, linking Memo's redox function to ALP post-translational regulation (dimerization-dependent activity).","method":"Whole-body Cre/lox Memo cKO mice, micro-CT, ALP activity assays, detergent sensitivity assay for ALP dimerization, redox state measurements in bone","journal":"JBMR plus","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with mechanistic follow-up (redox state and ALP dimerization assay), single lab","pmids":["30038965"],"is_preprint":false},{"year":2019,"finding":"Memo1 is a critical determinant of radial glial cell (RGC) tiling during neocortical development. Memo1 deletion or knockdown causes hyperbranching of RGC basal processes, disrupted tiling, and aberrant neuronal layering. Mechanistically, Memo1 regulates microtubule stability required for RGC tiling: Memo1 deficiency disrupts MT minus-end CAMSAP2 distribution, initiates aberrant MT branching, and alters polarized trafficking of basal domain proteins such as GPR56.","method":"Conditional Memo1 KO and in utero knockdown in developing mouse cortex, live imaging, immunofluorescence for CAMSAP2 and GPR56, MT dynamics assays","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO plus multiple orthogonal imaging and molecular readouts establishing mechanism in vivo","pmids":["31277925"],"is_preprint":false},{"year":2020,"finding":"Memo1 KO mice show higher serum magnesium and decreased calcification propensity compared to Klotho/Fgf23-deficient models. Both inducible whole-body and kidney-specific Memo1 KO mice display increased expression of intestinal and renal magnesium channels and the regulator EGF, identifying MEMO1 as a regulator of magnesium homeostasis through control of magnesium channel expression.","method":"Inducible whole-body and kidney-specific Memo1 KO mouse models, serum magnesium biochemistry, qPCR for magnesium channel genes, calcification propensity assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two complementary conditional KO models with defined molecular phenotype, single lab","pmids":["32706793"],"is_preprint":false},{"year":2022,"finding":"Purified MEMO1 coordinates two reduced Cu(I) ions per protein under reducing conditions in vitro, shielding them from ROS generation. The cytoplasmic copper chaperone Atox1 can interact with and exchange Cu(I) with MEMO1 in vitro, and the two proteins show spatial proximity in breast cancer cells, suggesting MEMO1 acts as a Cu(I) chelator/shuttle toward Atox1 and the secretory pathway.","method":"Multiple biophysical methods (ITC, ICP-MS, EPR, UV-Vis spectroscopy) for Cu-binding characterization, in vitro Cu(I) exchange assay between MEMO1 and Atox1, proximity ligation assay in breast cancer cells","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal biophysical assays for Cu binding plus in vitro protein-protein Cu exchange and cellular proximity validation","pmids":["36067318"],"is_preprint":false},{"year":2022,"finding":"HPV16 E7 interacts with MEMO1 through its C-terminal E80/D81 residues and targets MEMO1 for proteasomal degradation via a Cullin2-dependent mechanism. MEMO1 overexpression decreases cell transformation and proliferation; knockdown of MEMO1 correlates with Akt activation in HPV-positive cervical cancer cells.","method":"Pulldown assay (HPV16 E7 peptide), co-immunoprecipitation, proteasome inhibitor rescue, Cullin2 knockdown, MEMO1 overexpression and knockdown with Akt Western blot","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pulldown confirmed by Co-IP, degradation mechanism tested with inhibitors and genetic knockdown, single lab","pmids":["36197110"],"is_preprint":false},{"year":2022,"finding":"Memo1 is required for renal FGF23-Klotho signaling: Memo cKO mice show impaired FGF23-driven renal ERK phosphorylation and transcriptional responses. FGF23 actions involve activation of oxidation-sensitive protein phosphotyrosyl phosphatases; redox proteomics revealed excessive reduced thiols of Rho-GDI1 in Memo cKO, and Memo's redox function interacts with oxidation at Rho-GDI1 Cys79, with disturbed small Rho-GTPase abundance in cKO kidney.","method":"Postnatally induced whole-body Memo cKO mice, FGF23 injection + ERK phosphorylation Western blot, phosphotyrosyl phosphatase activity assay, redox proteomics (thiol trapping), Rho-GDI1 Cys79 oxidation assay, Rho-GTPase activity assays","journal":"Journal of cell communication and signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods in vivo and in vitro establishing redox-dependent FGF23 signaling mechanism, single lab","pmids":["36434320"],"is_preprint":false},{"year":2023,"finding":"Copper additions to MDA-MB-231 breast cancer cells increase intracellular ROS, and this effect is further elevated when MEMO1 is silenced. MEMO1 knockdown exaggerates copper-induced cell death, supporting that MEMO1 protects cancer cells from copper-mediated redox toxicity in a cellular context.","method":"MEMO1 siRNA knockdown, copper addition to breast cancer cells, multiple commercial ROS probes, cell viability assay","journal":"Journal of inorganic biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — three orthogonal ROS probes and cell viability assay in knockdown cells, single lab","pmids":["37487298"],"is_preprint":false},{"year":2024,"finding":"Purified MEMO1 binds iron with high affinity under redox conditions mimicking the intracellular environment, and crystal structures of MEMO1 in complex with iron and copper were solved. The iron coordination mode in MEMO1 closely resembles that of iron-containing extradiol dioxygenases (sharing a similar structural fold). MEMO1 exhibits genetic interactions with iron-related proteins TFR2, mitoferrin-2 (SLC25A28), and IRP1/ACO1 in cancer cells and is involved in ferroptosis and iron supply to mitochondria.","method":"X-ray crystallography (MEMO1-iron and MEMO1-copper complexes), in vitro iron binding assays, genetic interaction analysis (cancer cell line essentiality data), co-immunoprecipitation/proximity assays for TFR2/SLC25A28/IRP1 interactions, ferroptosis assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures plus in vitro binding plus genetic interaction confirmation and cellular functional assays","pmids":["38640016"],"is_preprint":false},{"year":2021,"finding":"Phenazine-based small-molecule inhibitors of MEMO1 were identified that competitively disrupt MEMO1's interaction with its ErbB2 phosphopeptide partner (KI ~2.7 µM in fluorescence polarization assay) and slow breast cancer cell migration in a scratch assay, confirming that the MEMO1 phosphopeptide-binding interface is functionally important for cell motility.","method":"Virtual screening, competitive fluorescence polarization assay, molecular dynamics simulations, scratch/wound-healing migration assay","journal":"ChemMedChem","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — validated in vitro binding inhibition plus cell migration functional readout, single lab","pmids":["33332774"],"is_preprint":false},{"year":2023,"finding":"Conditional deletion of MEMO1 from ameloblasts results in enamel mineralization defects (reduced mineral density and tooth integrity) associated with disruption of ameloblast morphology, reduction in late-stage ameloblast markers, and disruption of cytoskeletal-associated gene expression, establishing a cell-autonomous role for MEMO1 in ameloblast maturation and enamel formation.","method":"Ameloblast-specific conditional Memo1 KO (Cre/lox), micro-CT for mineral density, histology, single-cell/molecular profiling of ameloblasts","journal":"Journal of dental research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined cellular and molecular phenotype, single lab","pmids":["37475472"],"is_preprint":false},{"year":2025,"finding":"MEMO1 knockdown in retinal microvascular endothelial cells (RMVECs) enhances VEGF-induced VEGFR2 and STAT3 phosphorylation and increases wound closure; conversely, MEMO1 overexpression suppresses VEGF-induced VEGFR2/STAT3 phosphorylation and dampens VEGF-induced wound closure. In the absence of VEGF, MEMO1 overexpression promotes proliferation via AKT phosphorylation. In vivo, endothelial-specific MEMO1 knockdown increases intravitreal neovascularization (IVNV) in a rat ROP model, identifying MEMO1 as a negative regulator of VEGF-driven pathological angiogenesis.","method":"MEMO1 siRNA knockdown and overexpression in cultured RMVECs, Western blot for VEGFR2/STAT3/AKT phosphorylation, wound closure assay, endothelial-specific in vivo MEMO1 knockdown in rat ROP model with IVNV quantification","journal":"FASEB bioAdvances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal gain/loss-of-function with signaling readouts and in vivo validation, single lab","pmids":["40936746"],"is_preprint":false},{"year":2025,"finding":"MEMO1 KO in MDA-MB-231 breast cancer cells causes increased α-ketoglutarate and citrate levels regardless of iron availability, and elevated fumarate, malate, and glutamate specifically under low iron conditions, indicating MEMO1 regulates TCA cycle metabolite flux in an iron-dependent manner. ACO2 and OGDH knockdowns inhibit MDA-MB-231 proliferation, confirming TCA cycle essentiality.","method":"ShRNA MEMO1 knockdown and KO, LC-MS/MS quantification of TCA cycle metabolites under varying iron conditions, ACO2/OGDH knockdown proliferation assays","journal":"Metabolites","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — metabolomics with multiple iron conditions and genetic controls, single lab","pmids":["40278406"],"is_preprint":false}],"current_model":"MEMO1 is a structurally conserved iron- and copper-binding redox protein whose vestigial dioxygenase active site directly binds ErbB2 phospho-Tyr1227 peptides; it mediates receptor tyrosine kinase (ErbB2, FGFR, IGF-IR)-driven cell motility by relaying signals to the microtubule cytoskeleton via a RhoA-mDia1 axis, regulating actin dynamics through cofilin interaction, and sustaining NOX1-dependent ROS production; it additionally participates in S1P signaling, extranuclear ERα signaling via c-Src, copper and iron homeostasis (including TCA cycle regulation), and developmental processes including radial glial tiling, endochondral ossification, enamel mineralization, and vascular development."},"narrative":{"mechanistic_narrative":"MEMO1 is a structurally conserved, metal-binding signaling adaptor that couples receptor tyrosine kinase signaling to the cytoskeleton and to cellular redox and metal homeostasis [PMID:15156151, PMID:24917593, PMID:38640016]. It was first defined as a relay downstream of ErbB2: through its vestigial class III nonheme-dioxygenase active site it directly binds the ErbB2 phospho-Tyr1227 motif, constituting a novel phosphotyrosine-recognition fold distinct from SH2 and PTB modules [PMID:18045866, PMID:21840311]. Acting downstream of this and other receptors, MEMO1 controls directional cell migration by governing microtubule dynamics and leading-edge actin organization, mediated through proper localization of RhoA and its effector mDia1 and through direct binding to cofilin, whose F-actin-severing activity it enhances [PMID:18955552, PMID:19223396]. This cytoskeletal role extends in vivo to radial glial process tiling in the developing neocortex, where MEMO1 stabilizes microtubules and directs CAMSAP2 minus-end distribution and polarized GPR56 trafficking [PMID:31277925]. MEMO1 also functions as a metal-binding redox protein: it coordinates Cu(I) ions and exchanges them with the chaperone Atox1, binds iron in a mode resembling extradiol dioxygenases, and sustains NOX1-dependent ROS production required for tumor cell migration and metastasis [PMID:24917593, PMID:36067318, PMID:38640016]. Its iron-binding activity feeds into ferroptosis sensitivity, mitochondrial iron supply, and iron-dependent control of TCA cycle metabolite flux [PMID:38640016, PMID:40278406]. Beyond cancer, MEMO1 broadly tunes growth factor signaling—FGFR/FGF23-Klotho, IGF-IR/IRS1-PI3K/Akt, S1P, and VEGFR2—and is required for organismal mineral homeostasis, governing renal calcium, magnesium and vitamin D handling and skeletal and enamel mineralization [PMID:22824790, PMID:24056085, PMID:24714781, PMID:30038585, PMID:32706793, PMID:36434320, PMID:37475472, PMID:40936746]. In C. elegans the orthologue inhibits BLI-3/NADPH oxidase via RHO-1, linking MEMO1 to ROS-dependent stress resistance and longevity [PMID:28085666].","teleology":[{"year":2004,"claim":"Established MEMO1's founding identity by asking how ErbB2 chemotactic signals reach the cytoskeleton; it answered that MEMO is a required relay between ErbB2 and microtubule extension.","evidence":"ErbB2 phosphopeptide co-precipitation and knockdown migration/microtubule imaging in cells","pmids":["15156151"],"confidence":"High","gaps":["Direct vs Shc-mediated binding to ErbB2 not resolved","Molecular mechanism linking MEMO to microtubules not yet defined"]},{"year":2007,"claim":"Resolved how MEMO1 recognizes phosphotyrosine; the crystal structure revealed a dioxygenase-like fold lacking enzymatic activity that binds the ErbB2 pTyr1227 peptide through its vestigial active site, defining a new phosphotyrosine-binding class.","evidence":"X-ray crystallography at 2.1 Å plus in vitro phosphopeptide binding","pmids":["18045866"],"confidence":"High","gaps":["No metal or catalytic activity detected at this stage","Physiological relevance of the dioxygenase-like fold unexplained"]},{"year":2008,"claim":"Defined the downstream cytoskeletal mechanism by showing MEMO controls microtubule growth/shortening transitions via RhoA-mDia1 localization at the leading edge.","evidence":"siRNA knockdown, live microtubule imaging, RhoA/mDia1 immunofluorescence in migrating cells","pmids":["18955552"],"confidence":"High","gaps":["Direct biochemical link between MEMO and RhoA not established","How MEMO positions RhoA/mDia1 to the membrane unknown"]},{"year":2009,"claim":"Identified a direct actin-regulatory partner, placing MEMO upstream of cofilin and PLCγ1 in ErbB2-driven chemotaxis.","evidence":"Yeast two-hybrid, recombinant pulldown, Co-IP, in vitro F-actin depolymerization assay, knockdown migration tracking","pmids":["19223396"],"confidence":"High","gaps":["Structural basis of MEMO-cofilin interaction unknown","How cofilin and RhoA-mDia1 arms are coordinated unclear"]},{"year":2011,"claim":"Refined the phosphopeptide recognition by mapping the minimal ErbB2 sequence and a novel pTyr motif distinct from SH2/PTB.","evidence":"NMR/docking structural modeling and peptide-variant binding assays","pmids":["21840311"],"confidence":"Medium","gaps":["Docking model not validated by co-crystal structure","Single-lab characterization"]},{"year":2012,"claim":"Extended MEMO1 beyond ErbB2 by linking it to IGF-IR signaling, showing it binds IRS1 and drives PI3K/Akt-Snail1 EMT.","evidence":"Co-IP, Western blots for Akt/Snail1, EMT marker and overexpression/knockdown assays in mammary epithelial cells","pmids":["22824790"],"confidence":"Medium","gaps":["Direct vs indirect IRS1 binding not resolved","Single-lab finding"]},{"year":2013,"claim":"Connected MEMO1 to nuclear-receptor and FGFR signaling, showing it mediates extranuclear ERα function and is required for FGFR-dependent vitamin D/calcium homeostasis in vivo.","evidence":"Multiple Co-IPs (ERα, IGF1R, ERBB2, FGFR), signaling Western blots, ERα reporter, xenografts, and conditional KO mouse phenotyping","pmids":["23861392","24056085"],"confidence":"Medium","gaps":["Whether ERα and FGFR effects share a common molecular mechanism unknown","Single-lab studies"]},{"year":2014,"claim":"Reframed MEMO1 as a copper-dependent redox protein required for NOX1-driven ROS, migration, and metastasis, and as a regulator of S1P signaling and vascular development.","evidence":"Biochemical redox/ROS assays, NOX1 activity, knockdown/overexpression, xenograft metastasis; separate MEF and HUVEC S1P rescue plus endothelial KO embryos","pmids":["24917593","24714781"],"confidence":"High","gaps":["Direct enzymatic redox mechanism of MEMO1 not biochemically defined","Relationship between redox role and phosphopeptide-binding role unclear"]},{"year":2015,"claim":"Established cell-autonomous developmental roles in endochondral ossification through neural crest-specific deletion affecting cranial base mineralization and vascular invasion.","evidence":"ENU mutant mapping, neural crest conditional KO, histology, gene expression, micro-CT","pmids":["26746790"],"confidence":"Medium","gaps":["Molecular target driving ossification defect not identified","Non-autonomous palate role unexplained"]},{"year":2016,"claim":"Detailed the ERα-c-Src axis and uncovered transcriptional control of MEMO1 itself by HER2 via AhR/ARNT.","evidence":"Co-IP, ERα Y537 phosphorylation Western, fractionation; ChIP and luciferase reporter on MEMO1 promoter with migration/invasion assays","pmids":["27472465","27941874"],"confidence":"Medium","gaps":["Direct MEMO1-c-Src binding interface unknown","Single-lab transcriptional and signaling mechanisms"]},{"year":2017,"claim":"Demonstrated an evolutionarily conserved redox-signaling function: the C. elegans orthologue inhibits NADPH oxidase via RhoA, controlling ROS, p38-SKN-1 stress signaling, and longevity.","evidence":"C. elegans genetic epistasis, RHO-1/BLI-3 Co-IP, ROS measurement, pathway reporters, lifespan assays","pmids":["28085666"],"confidence":"High","gaps":["Whether mammalian MEMO1 inhibits or sustains NOX is context-dependent and unreconciled","Direct biochemical mechanism of NOX regulation unknown"]},{"year":2018,"claim":"Linked MEMO1's redox function to mineral homeostasis and skeletal biology, showing it regulates renal calcium transporters, magnesium channels, and redox-dependent alkaline phosphatase dimerization in bone.","evidence":"Kidney-specific and whole-body conditional KO mice, serum biochemistry, transporter qPCR/Western, ALP activity and dimerization assays, redox measurements","pmids":["30038585","30038965","32706793"],"confidence":"Medium","gaps":["Direct molecular substrate of MEMO1's redox effect on transporters/ALP not defined","Single-lab in vivo models"]},{"year":2019,"claim":"Provided the clearest in vivo cytoskeletal mechanism, showing MEMO1 stabilizes microtubules to govern radial glial tiling via CAMSAP2 minus-end organization and polarized trafficking.","evidence":"Conditional KO and in utero knockdown, live imaging, CAMSAP2/GPR56 immunofluorescence, microtubule dynamics assays","pmids":["31277925"],"confidence":"High","gaps":["How MEMO1 biochemically controls CAMSAP2 distribution unknown","Link to the metal/redox functions not addressed"]},{"year":2022,"claim":"Defined MEMO1 as a Cu(I) coordinator that shields copper from ROS and exchanges it with Atox1, and identified its proteasomal regulation by HPV16 E7.","evidence":"ITC/ICP-MS/EPR/UV-Vis Cu binding, in vitro Cu(I) exchange with Atox1, proximity ligation; E7 pulldown, Co-IP, Cullin2-dependent degradation assays","pmids":["36067318","36434320","36197110"],"confidence":"High","gaps":["Whether copper shuttling explains the migration/redox phenotypes not shown","Physiological copper cargo destination beyond Atox1 unclear"]},{"year":2024,"claim":"Established MEMO1 as an iron-binding protein with a dioxygenase-like coordination mode, connecting it to ferroptosis, mitochondrial iron supply, and iron-dependent TCA cycle flux.","evidence":"Crystal structures of MEMO1-iron and MEMO1-copper, in vitro iron binding, genetic interactions with TFR2/SLC25A28/IRP1, ferroptosis and metabolomics assays","pmids":["38640016","40278406"],"confidence":"High","gaps":["Whether iron binding is catalytic or carrier-like unresolved","Mechanism linking iron handling to TCA flux not defined"]},{"year":2025,"claim":"Identified MEMO1 as a negative regulator of VEGF-driven pathological angiogenesis, dampening VEGFR2/STAT3 signaling in retinal endothelium.","evidence":"Reciprocal knockdown/overexpression in RMVECs, phospho-Western, wound closure, endothelial-specific knockdown in rat ROP model","pmids":["40936746"],"confidence":"Medium","gaps":["Direct molecular target on the VEGFR2 pathway unknown","Reconciliation with pro-migratory roles in cancer unclear"]},{"year":null,"claim":"How MEMO1's single dioxygenase-like fold integrates its phosphotyrosine-binding, copper/iron coordination, and redox-signaling activities into one mechanism across such diverse tissues remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying biochemical model connecting metal binding to signaling output","No co-crystal structure of MEMO1 with a full-length partner","Tissue-specific substrate/effector selection mechanism unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[1,4,14]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[3]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[19,23]},{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[8,21,23]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,2]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2,19]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[2,17]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,7,26]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[8,13,22]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[19,23,27]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[10,17,25,9]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[23]}],"complexes":["FGFR signalosome"],"partners":["ERBB2","COFILIN","RHOA","IRS1","ESR1","C-SRC","ATOX1","IGF1R"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y316","full_name":"Protein MEMO1","aliases":["C21orf19-like protein","Hepatitis C virus NS5A-transactivated protein 7","HCV NS5A-transactivated protein 7","Mediator of ErbB2-driven cell motility 1","Mediator of cell motility 1","Memo-1"],"length_aa":297,"mass_kda":33.7,"function":"May control cell migration by relaying extracellular chemotactic signals to the microtubule cytoskeleton. Mediator of ERBB2 signaling. The MEMO1-RHOA-DIAPH1 signaling pathway plays an important role in ERBB2-dependent stabilization of microtubules at the cell cortex. It controls the localization of APC and CLASP2 to the cell membrane, via the regulation of GSK3B activity. In turn, membrane-bound APC allows the localization of the MACF1 to the cell membrane, which is required for microtubule capture and stabilization. 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HLA","url":"https://www.omim.org/entry/601201"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MEMO1"},"hgnc":{"alias_symbol":["CGI-27","MEMO"],"prev_symbol":["C2orf4"]},"alphafold":{"accession":"Q9Y316","domains":[{"cath_id":"3.40.830.10","chopping":"40-295","consensus_level":"high","plddt":98.2764,"start":40,"end":295}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y316","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y316-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y316-F1-predicted_aligned_error_v6.png","plddt_mean":97.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MEMO1","jax_strain_url":"https://www.jax.org/strain/search?query=MEMO1"},"sequence":{"accession":"Q9Y316","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y316.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y316/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y316"}},"corpus_meta":[{"pmid":"24917593","id":"PMC_24917593","title":"Memo is a 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letters","url":"https://pubmed.ncbi.nlm.nih.gov/21840311","citation_count":6,"is_preprint":false},{"pmid":"36434320","id":"PMC_36434320","title":"Renal FGF23 signaling depends on redox protein Memo1 and promotes orthovanadate-sensitive protein phosphotyrosyl phosphatase activity.","date":"2022","source":"Journal of cell communication and signaling","url":"https://pubmed.ncbi.nlm.nih.gov/36434320","citation_count":4,"is_preprint":false},{"pmid":"32069395","id":"PMC_32069395","title":"MEMO: A Method for Computing Metabolic Modules for Cell-Free Production Systems.","date":"2020","source":"ACS synthetic biology","url":"https://pubmed.ncbi.nlm.nih.gov/32069395","citation_count":4,"is_preprint":false},{"pmid":"34257807","id":"PMC_34257807","title":"Physiological Dose of EGCG Attenuates the Health Defects of High Dose by Regulating MEMO-1 in Caenorhabditis elegans.","date":"2021","source":"Oxidative medicine and cellular longevity","url":"https://pubmed.ncbi.nlm.nih.gov/34257807","citation_count":4,"is_preprint":false},{"pmid":"31388689","id":"PMC_31388689","title":"Finding MEMo: minimum sets of elementary flux modes.","date":"2019","source":"Journal of mathematical biology","url":"https://pubmed.ncbi.nlm.nih.gov/31388689","citation_count":4,"is_preprint":false},{"pmid":"29125034","id":"PMC_29125034","title":"The Memo Slide: An explorative study into a novel mechanical follow-the-leader mechanism.","date":"2017","source":"Proceedings of the Institution of Mechanical Engineers. Part H, Journal of engineering in medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29125034","citation_count":4,"is_preprint":false},{"pmid":"36967231","id":"PMC_36967231","title":"FGFR regulator Memo1 is dispensable for FGF23 expression by osteoblasts during folic acid-driven kidney injury.","date":"2023","source":"Physiological reports","url":"https://pubmed.ncbi.nlm.nih.gov/36967231","citation_count":2,"is_preprint":false},{"pmid":"37475472","id":"PMC_37475472","title":"MEMO1 Is Required for Ameloblast Maturation and Functional Enamel Formation.","date":"2023","source":"Journal of dental research","url":"https://pubmed.ncbi.nlm.nih.gov/37475472","citation_count":2,"is_preprint":false},{"pmid":"40513293","id":"PMC_40513293","title":"MEMO: A micro memo sensor detecting microRNA-RISC using an accurate cell-free expression platform.","date":"2025","source":"Biosensors & bioelectronics","url":"https://pubmed.ncbi.nlm.nih.gov/40513293","citation_count":2,"is_preprint":false},{"pmid":"25384962","id":"PMC_25384962","title":"Mutant Enrichment with 3'-Modified Oligonucleotides (MEMO)-Quantitative PCR for Detection of NPM1 Mutations in Acute Myeloid Leukemia.","date":"2014","source":"Journal of clinical laboratory analysis","url":"https://pubmed.ncbi.nlm.nih.gov/25384962","citation_count":2,"is_preprint":false},{"pmid":"37561333","id":"PMC_37561333","title":"MiR-485-3p/MiR-543/MiR-337-3p is Required for the Oncogenic Potential of the Hsa_circ_0007385-MEMO1 Axis in Colorectal Cancer.","date":"2023","source":"Biochemical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/37561333","citation_count":1,"is_preprint":false},{"pmid":"41596744","id":"PMC_41596744","title":"Molecular Landscape of Advanced Endometrial Cancer: Exploratory Analyses at Modena Cancer Center (MEMO).","date":"2026","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41596744","citation_count":1,"is_preprint":false},{"pmid":"40936746","id":"PMC_40936746","title":"Endothelial MEMO1 Regulates Angiogenic Signaling in a Model of Retinopathy of Prematurity.","date":"2025","source":"FASEB bioAdvances","url":"https://pubmed.ncbi.nlm.nih.gov/40936746","citation_count":0,"is_preprint":false},{"pmid":"40278406","id":"PMC_40278406","title":"Metabolic Effects of the Cancer Metastasis Modulator MEMO1.","date":"2025","source":"Metabolites","url":"https://pubmed.ncbi.nlm.nih.gov/40278406","citation_count":0,"is_preprint":false},{"pmid":"31487522","id":"PMC_31487522","title":"Memo1 Tiles the Radial Glial Cell Grid.","date":"2019","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/31487522","citation_count":0,"is_preprint":false},{"pmid":"41021316","id":"PMC_41021316","title":"MEMO-Stab2: Multi-View Sequence-Based Deep Learning Framework for Predicting Mutation-Induced Stability Changes in Transmembrane Proteins.","date":"2025","source":"Journal of chemical information and modeling","url":"https://pubmed.ncbi.nlm.nih.gov/41021316","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.05.18.654712","title":"Memo-Patho: Bridging Local-Global Transmembrane Protein Contexts with Contrastive Pretraining for Alignment-Free Pathogenicity Prediction","date":"2025-05-23","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.18.654712","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.06.25.24309498","title":"<i>Instead of seeing it as a health care issue, you see it as you:</i>Reasons for alcohol use, consequences of use, and barriers to help seeking among fathers in Kenya","date":"2024-06-27","source":"bioRxiv","url":"https://doi.org/10.1101/2024.06.25.24309498","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":31096,"output_tokens":7549,"usd":0.103262,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":17063,"output_tokens":5326,"usd":0.109232,"stage2_stop_reason":"end_turn"},"total_usd":0.212494,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"MEMO1 (Memo) was identified as a novel protein that interacts with a phospho-Tyr1227-containing peptide of ErbB2/Neu, most probably through the Shc adaptor protein. In Memo-defective cells, ErbB2-driven lamellipodia form normally but microtubule extension toward the cell cortex fails, establishing Memo as a relay between ErbB2 chemotactic signals and the microtubule cytoskeleton.\",\n      \"method\": \"Co-precipitation with ErbB2 phosphopeptide, dominant-negative/knockdown cell migration assays, live imaging of lamellipodia and microtubule dynamics\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-precipitation, functional knockdown with specific cytoskeletal phenotype, replicated in subsequent studies\",\n      \"pmids\": [\"15156151\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Crystal structure of human MEMO1 at 2.1 Å resolution revealed it is homologous to class III nonheme iron-dependent dioxygenases. No metal binding or classical enzymatic (dioxygenase) activity was detected, but MEMO1 directly binds an ErbB2-derived phosphopeptide encompassing Tyr-1227 via its vestigial enzymatic active site, defining it as a new class of phosphotyrosine-binding protein.\",\n      \"method\": \"X-ray crystallography (2.1 Å), in vitro phosphopeptide binding assay, active-site structural comparison\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus direct binding assay with mutagenesis-level structural comparison; foundational mechanistic paper\",\n      \"pmids\": [\"18045866\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Memo controls ErbB2-regulated microtubule dynamics by altering the transition frequency between MT growth and shortening phases. Memo is required for proper localization of RhoA GTPase and its effector mDia1 to the plasma membrane; Memo-RhoA-mDia1 signaling coordinates lamellipodial actin network organization, adhesion site formation, and microtubule outgrowth at the leading edge during cell migration.\",\n      \"method\": \"Memo siRNA knockdown, live MT dynamics imaging, immunofluorescence of RhoA/mDia1 localization, adhesion site quantification\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (live imaging, IF localization, genetic knockdown with defined cytoskeletal phenotypes), replicated in a dedicated mechanistic study\",\n      \"pmids\": [\"18955552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Memo interacts directly with cofilin (identified by yeast two-hybrid and confirmed by in vitro pulldown with recombinant proteins and co-immunoprecipitation). Memo enhances cofilin F-actin depolymerizing and severing activity in vitro. In Memo-knockdown cells, HRG-induced PLCγ1 phosphorylation is reduced and GFP-cofilin recruitment to lamellipodia is impaired, placing Memo upstream of both PLCγ1 and cofilin in ErbB2-driven chemotaxis.\",\n      \"method\": \"Yeast two-hybrid, recombinant protein pulldown, co-immunoprecipitation, in vitro F-actin binding and depolymerization assay, Memo/PLCγ1 knockdown with live cell migration directionality tracking\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — yeast two-hybrid confirmed by in vitro reconstitution and Co-IP, plus in vitro functional actin assay and genetic epistasis\",\n      \"pmids\": [\"19223396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Structural and functional analysis defined the minimum ErbB2 phosphopeptide sequence required for MEMO1 recognition. The interaction is pH-dependent and requires phosphorylation of Tyr-1227; a docking-based structural model of the MEMO1/phosphopeptide complex was generated and compared to SH2 and PTB phosphotyrosine motifs, identifying a novel phosphotyrosine recognition motif.\",\n      \"method\": \"NMR/docking structural modeling, peptide binding assays, mutagenesis of phosphopeptide variants\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — structural model plus binding validation with peptide variants, single lab\",\n      \"pmids\": [\"21840311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MEMO1 binds to insulin receptor substrate 1 (IRS1), activates the downstream PI3K/Akt signaling pathway, upregulates Snail1, and thereby triggers the epithelial-mesenchymal transition (EMT) program in mammary epithelial cells downstream of IGF-IR signaling.\",\n      \"method\": \"Co-immunoprecipitation (MEMO1-IRS1 interaction), Western blot for PI3K/Akt activation and Snail1, EMT marker analysis, overexpression/knockdown functional assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus downstream signaling readouts, single lab, multiple functional assays\",\n      \"pmids\": [\"22824790\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MEMO1 physically interacts with estrogen receptor α (ERα) and, through its interactions with growth factor receptors IGF1R and ERBB2, mediates extranuclear ER functions including activation of MAPK and AKT. This leads to ERα phosphorylation and regulation of estrogen-responsive gene expression; MEMO1 is required for estrogen-induced breast tumor growth in vivo.\",\n      \"method\": \"Co-immunoprecipitation (MEMO-ERα, MEMO-IGF1R, MEMO-ERBB2), Western blot for MAPK/AKT activation and ERα phosphorylation, ERα reporter assay, xenograft tumor growth\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple Co-IPs, downstream signaling assays, and in vivo data, single lab\",\n      \"pmids\": [\"23861392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Memo associates with the FGFR signalosome and is necessary for optimal activation of downstream FGF signaling. Loss of Memo in mouse embryonic fibroblasts reduces FGF-induced signaling responses. Memo conditional-knockout mice show reduced lifespan, premature aging phenotypes, elevated serum 1,25(OH)2D and calcium, identifying Memo as a novel regulator of FGFR signaling that controls vitamin D and calcium homeostasis.\",\n      \"method\": \"Co-immunoprecipitation (Memo-FGFR complex), Memo KO MEFs signaling assays, conditional knockout mouse model with phenotypic analysis\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and KO MEF signaling assays, plus in vivo KO phenotype, single lab\",\n      \"pmids\": [\"24056085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Memo is a copper-dependent redox enzyme: biochemical assays showed Memo promotes a more oxidized intracellular milieu and stimulates ROS production in cellular structures involved in migration. Memo is required for sustained production of superoxide (O2−) by NADPH oxidase 1 (NOX1) in breast cancer cells. Memo is required for migration/invasion in vitro and spontaneous lung metastasis in vivo.\",\n      \"method\": \"Biochemical redox assays, ROS measurement (intracellular oxidation probes), NOX1 activity assays, Memo knockdown/overexpression, in vivo xenograft metastasis\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal biochemical and cell-based assays plus in vivo metastasis data\",\n      \"pmids\": [\"24917593\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Memo null MEFs are impaired in PDGF-induced migration due to a defect in sphingosine-1-phosphate (S1P) cell-autonomous signaling. In endothelial cells (HUVECs), Memo knockdown reduces junctional VE-cadherin and increases sprouting; these phenotypes are rescued by exogenous S1P, placing Memo in the cell-autonomous S1PR signaling pathway. Endothelial-specific Memo KO embryos show vascular defects from E13.5, mimicking S1PR-deficient phenotypes.\",\n      \"method\": \"Memo KO MEF migration assays with S1P rescue, HUVEC knockdown with VE-cadherin immunofluorescence and sprouting assays, conventional and endothelial-specific conditional Memo KO mice\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple cell-based rescue experiments and in vivo KO phenotype, single lab\",\n      \"pmids\": [\"24714781\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Neural crest cell-specific deletion of Memo1 causes failure of anterior cranial base ossification (cell-autonomous role), while palate formation is largely normal in these conditional mutants (suggesting a non-autonomous role for MEMO1 in palatal closure). Memo1 mutants show increased hypertrophic chondrocyte zones, reduced vascular invasion and mineralization, and reduced expression of matrix metalloproteinases and osteoblast lineage markers in the cranial base.\",\n      \"method\": \"ENU-induced recessive mutant mouse, non-complementation mapping to Memo1, neural crest-specific conditional Memo1 KO (Cre/lox), histology, gene expression analysis, micro-CT\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with cell-type-specific rescue experiment, cell-autonomous function established\",\n      \"pmids\": [\"26746790\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Memo interacts with c-Src and facilitates ERα–c-Src interaction, ERα Y537 phosphorylation, and ERα extra-nuclear localization downstream of heregulin and estrogen in breast cancer cells.\",\n      \"method\": \"Co-immunoprecipitation (Memo-c-Src, ERα-c-Src), Western blot for ERα Y537 phosphorylation, sub-cellular fractionation/immunofluorescence of ERα localization, Memo knockdown\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, phosphorylation assay, and subcellular localization with functional link, single lab\",\n      \"pmids\": [\"27472465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"HER2 activation drives MEMO1 expression in colorectal cancer cells through AhR/ARNT transcriptional complex recruitment to the MEMO1 gene promoter (established by reporter assays and chromatin IP). MEMO1 depletion negatively affects the cellular actin network and is required for HER2-mediated migration and invasion.\",\n      \"method\": \"Chromatin immunoprecipitation (AhR/ARNT on MEMO1 promoter), luciferase reporter assay, MEMO1 siRNA knockdown with actin immunofluorescence and migration/invasion assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assay confirm transcriptional mechanism; functional knockdown assays, single lab\",\n      \"pmids\": [\"27941874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In C. elegans, MEMO-1 (the orthologue of mammalian MEMO1) inhibits BLI-3/NADPH oxidase. Loss of memo-1 results in enhanced interaction of RHO-1/RhoA with BLI-3/NADPH oxidase, stimulating ROS production that signals via p38 MAP kinase to the transcription factor SKN-1/NRF1,2,3, promoting stress resistance and longevity. Either loss of memo-1 or overexpression of BLI-3 is sufficient to increase lifespan.\",\n      \"method\": \"C. elegans genetic epistasis (memo-1 loss-of-function, bli-3 overexpression), co-immunoprecipitation (RHO-1 with BLI-3), ROS measurement, p38/SKN-1 pathway reporter assays, lifespan assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis plus Co-IP and multiple orthogonal functional assays in a well-validated model organism\",\n      \"pmids\": [\"28085666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MEMO1 binding specificity for the ErbB2 phosphopeptide (pTyr1227) was quantitatively mapped using a fluorescence polarization assay and molecular dynamics simulations: the interaction requires phosphorylation of the tyrosine residue and is pH-dependent; mutagenesis identified residues contributing to favorable interactions at the MEMO1-peptide interface.\",\n      \"method\": \"Fluorescence polarization assay, molecular dynamics simulations, site-directed mutagenesis of MEMO1\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro binding assay with mutagenesis, single lab\",\n      \"pmids\": [\"30067338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Renal Memo1 deletion in mice leads to elevated serum FGF23 and increased expression/protein abundance of distal renal calcium transporters TRPV5, NCX1, and calbindin-D28k. TRPV5 membrane abundance was vitamin D-dependent while NCX1 abundance was vitamin D-independent, revealing distinct Memo1-dependent and Memo1-independent regulatory mechanisms for renal calcium handling.\",\n      \"method\": \"Inducible kidney-specific Memo1 KO mouse model (Cre/lox), serum biochemistry, qPCR and Western blot for transporter expression, vitamin D-deficient diet challenge\",\n      \"journal\": \"Frontiers in physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined transport phenotype and diet rescue, single lab\",\n      \"pmids\": [\"30038585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Memo1 deletion in mice results in severely altered trabecular bone with lower mineralization. Alkaline phosphatase (ALP) activity is decreased in serum and bone without change in ALPL expression; the bone intracellular redox state is altered and ALP dimerization is reduced in Memo cKO bone, linking Memo's redox function to ALP post-translational regulation (dimerization-dependent activity).\",\n      \"method\": \"Whole-body Cre/lox Memo cKO mice, micro-CT, ALP activity assays, detergent sensitivity assay for ALP dimerization, redox state measurements in bone\",\n      \"journal\": \"JBMR plus\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with mechanistic follow-up (redox state and ALP dimerization assay), single lab\",\n      \"pmids\": [\"30038965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Memo1 is a critical determinant of radial glial cell (RGC) tiling during neocortical development. Memo1 deletion or knockdown causes hyperbranching of RGC basal processes, disrupted tiling, and aberrant neuronal layering. Mechanistically, Memo1 regulates microtubule stability required for RGC tiling: Memo1 deficiency disrupts MT minus-end CAMSAP2 distribution, initiates aberrant MT branching, and alters polarized trafficking of basal domain proteins such as GPR56.\",\n      \"method\": \"Conditional Memo1 KO and in utero knockdown in developing mouse cortex, live imaging, immunofluorescence for CAMSAP2 and GPR56, MT dynamics assays\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO plus multiple orthogonal imaging and molecular readouts establishing mechanism in vivo\",\n      \"pmids\": [\"31277925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Memo1 KO mice show higher serum magnesium and decreased calcification propensity compared to Klotho/Fgf23-deficient models. Both inducible whole-body and kidney-specific Memo1 KO mice display increased expression of intestinal and renal magnesium channels and the regulator EGF, identifying MEMO1 as a regulator of magnesium homeostasis through control of magnesium channel expression.\",\n      \"method\": \"Inducible whole-body and kidney-specific Memo1 KO mouse models, serum magnesium biochemistry, qPCR for magnesium channel genes, calcification propensity assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two complementary conditional KO models with defined molecular phenotype, single lab\",\n      \"pmids\": [\"32706793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Purified MEMO1 coordinates two reduced Cu(I) ions per protein under reducing conditions in vitro, shielding them from ROS generation. The cytoplasmic copper chaperone Atox1 can interact with and exchange Cu(I) with MEMO1 in vitro, and the two proteins show spatial proximity in breast cancer cells, suggesting MEMO1 acts as a Cu(I) chelator/shuttle toward Atox1 and the secretory pathway.\",\n      \"method\": \"Multiple biophysical methods (ITC, ICP-MS, EPR, UV-Vis spectroscopy) for Cu-binding characterization, in vitro Cu(I) exchange assay between MEMO1 and Atox1, proximity ligation assay in breast cancer cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal biophysical assays for Cu binding plus in vitro protein-protein Cu exchange and cellular proximity validation\",\n      \"pmids\": [\"36067318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HPV16 E7 interacts with MEMO1 through its C-terminal E80/D81 residues and targets MEMO1 for proteasomal degradation via a Cullin2-dependent mechanism. MEMO1 overexpression decreases cell transformation and proliferation; knockdown of MEMO1 correlates with Akt activation in HPV-positive cervical cancer cells.\",\n      \"method\": \"Pulldown assay (HPV16 E7 peptide), co-immunoprecipitation, proteasome inhibitor rescue, Cullin2 knockdown, MEMO1 overexpression and knockdown with Akt Western blot\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pulldown confirmed by Co-IP, degradation mechanism tested with inhibitors and genetic knockdown, single lab\",\n      \"pmids\": [\"36197110\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Memo1 is required for renal FGF23-Klotho signaling: Memo cKO mice show impaired FGF23-driven renal ERK phosphorylation and transcriptional responses. FGF23 actions involve activation of oxidation-sensitive protein phosphotyrosyl phosphatases; redox proteomics revealed excessive reduced thiols of Rho-GDI1 in Memo cKO, and Memo's redox function interacts with oxidation at Rho-GDI1 Cys79, with disturbed small Rho-GTPase abundance in cKO kidney.\",\n      \"method\": \"Postnatally induced whole-body Memo cKO mice, FGF23 injection + ERK phosphorylation Western blot, phosphotyrosyl phosphatase activity assay, redox proteomics (thiol trapping), Rho-GDI1 Cys79 oxidation assay, Rho-GTPase activity assays\",\n      \"journal\": \"Journal of cell communication and signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods in vivo and in vitro establishing redox-dependent FGF23 signaling mechanism, single lab\",\n      \"pmids\": [\"36434320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Copper additions to MDA-MB-231 breast cancer cells increase intracellular ROS, and this effect is further elevated when MEMO1 is silenced. MEMO1 knockdown exaggerates copper-induced cell death, supporting that MEMO1 protects cancer cells from copper-mediated redox toxicity in a cellular context.\",\n      \"method\": \"MEMO1 siRNA knockdown, copper addition to breast cancer cells, multiple commercial ROS probes, cell viability assay\",\n      \"journal\": \"Journal of inorganic biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — three orthogonal ROS probes and cell viability assay in knockdown cells, single lab\",\n      \"pmids\": [\"37487298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Purified MEMO1 binds iron with high affinity under redox conditions mimicking the intracellular environment, and crystal structures of MEMO1 in complex with iron and copper were solved. The iron coordination mode in MEMO1 closely resembles that of iron-containing extradiol dioxygenases (sharing a similar structural fold). MEMO1 exhibits genetic interactions with iron-related proteins TFR2, mitoferrin-2 (SLC25A28), and IRP1/ACO1 in cancer cells and is involved in ferroptosis and iron supply to mitochondria.\",\n      \"method\": \"X-ray crystallography (MEMO1-iron and MEMO1-copper complexes), in vitro iron binding assays, genetic interaction analysis (cancer cell line essentiality data), co-immunoprecipitation/proximity assays for TFR2/SLC25A28/IRP1 interactions, ferroptosis assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures plus in vitro binding plus genetic interaction confirmation and cellular functional assays\",\n      \"pmids\": [\"38640016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Phenazine-based small-molecule inhibitors of MEMO1 were identified that competitively disrupt MEMO1's interaction with its ErbB2 phosphopeptide partner (KI ~2.7 µM in fluorescence polarization assay) and slow breast cancer cell migration in a scratch assay, confirming that the MEMO1 phosphopeptide-binding interface is functionally important for cell motility.\",\n      \"method\": \"Virtual screening, competitive fluorescence polarization assay, molecular dynamics simulations, scratch/wound-healing migration assay\",\n      \"journal\": \"ChemMedChem\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — validated in vitro binding inhibition plus cell migration functional readout, single lab\",\n      \"pmids\": [\"33332774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Conditional deletion of MEMO1 from ameloblasts results in enamel mineralization defects (reduced mineral density and tooth integrity) associated with disruption of ameloblast morphology, reduction in late-stage ameloblast markers, and disruption of cytoskeletal-associated gene expression, establishing a cell-autonomous role for MEMO1 in ameloblast maturation and enamel formation.\",\n      \"method\": \"Ameloblast-specific conditional Memo1 KO (Cre/lox), micro-CT for mineral density, histology, single-cell/molecular profiling of ameloblasts\",\n      \"journal\": \"Journal of dental research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined cellular and molecular phenotype, single lab\",\n      \"pmids\": [\"37475472\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MEMO1 knockdown in retinal microvascular endothelial cells (RMVECs) enhances VEGF-induced VEGFR2 and STAT3 phosphorylation and increases wound closure; conversely, MEMO1 overexpression suppresses VEGF-induced VEGFR2/STAT3 phosphorylation and dampens VEGF-induced wound closure. In the absence of VEGF, MEMO1 overexpression promotes proliferation via AKT phosphorylation. In vivo, endothelial-specific MEMO1 knockdown increases intravitreal neovascularization (IVNV) in a rat ROP model, identifying MEMO1 as a negative regulator of VEGF-driven pathological angiogenesis.\",\n      \"method\": \"MEMO1 siRNA knockdown and overexpression in cultured RMVECs, Western blot for VEGFR2/STAT3/AKT phosphorylation, wound closure assay, endothelial-specific in vivo MEMO1 knockdown in rat ROP model with IVNV quantification\",\n      \"journal\": \"FASEB bioAdvances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal gain/loss-of-function with signaling readouts and in vivo validation, single lab\",\n      \"pmids\": [\"40936746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MEMO1 KO in MDA-MB-231 breast cancer cells causes increased α-ketoglutarate and citrate levels regardless of iron availability, and elevated fumarate, malate, and glutamate specifically under low iron conditions, indicating MEMO1 regulates TCA cycle metabolite flux in an iron-dependent manner. ACO2 and OGDH knockdowns inhibit MDA-MB-231 proliferation, confirming TCA cycle essentiality.\",\n      \"method\": \"ShRNA MEMO1 knockdown and KO, LC-MS/MS quantification of TCA cycle metabolites under varying iron conditions, ACO2/OGDH knockdown proliferation assays\",\n      \"journal\": \"Metabolites\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — metabolomics with multiple iron conditions and genetic controls, single lab\",\n      \"pmids\": [\"40278406\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MEMO1 is a structurally conserved iron- and copper-binding redox protein whose vestigial dioxygenase active site directly binds ErbB2 phospho-Tyr1227 peptides; it mediates receptor tyrosine kinase (ErbB2, FGFR, IGF-IR)-driven cell motility by relaying signals to the microtubule cytoskeleton via a RhoA-mDia1 axis, regulating actin dynamics through cofilin interaction, and sustaining NOX1-dependent ROS production; it additionally participates in S1P signaling, extranuclear ERα signaling via c-Src, copper and iron homeostasis (including TCA cycle regulation), and developmental processes including radial glial tiling, endochondral ossification, enamel mineralization, and vascular development.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MEMO1 is a structurally conserved, metal-binding signaling adaptor that couples receptor tyrosine kinase signaling to the cytoskeleton and to cellular redox and metal homeostasis [#0, #8, #23]. It was first defined as a relay downstream of ErbB2: through its vestigial class III nonheme-dioxygenase active site it directly binds the ErbB2 phospho-Tyr1227 motif, constituting a novel phosphotyrosine-recognition fold distinct from SH2 and PTB modules [#1, #4]. Acting downstream of this and other receptors, MEMO1 controls directional cell migration by governing microtubule dynamics and leading-edge actin organization, mediated through proper localization of RhoA and its effector mDia1 and through direct binding to cofilin, whose F-actin-severing activity it enhances [#2, #3]. This cytoskeletal role extends in vivo to radial glial process tiling in the developing neocortex, where MEMO1 stabilizes microtubules and directs CAMSAP2 minus-end distribution and polarized GPR56 trafficking [#17]. MEMO1 also functions as a metal-binding redox protein: it coordinates Cu(I) ions and exchanges them with the chaperone Atox1, binds iron in a mode resembling extradiol dioxygenases, and sustains NOX1-dependent ROS production required for tumor cell migration and metastasis [#8, #19, #23]. Its iron-binding activity feeds into ferroptosis sensitivity, mitochondrial iron supply, and iron-dependent control of TCA cycle metabolite flux [#23, #27]. Beyond cancer, MEMO1 broadly tunes growth factor signaling—FGFR/FGF23-Klotho, IGF-IR/IRS1-PI3K/Akt, S1P, and VEGFR2—and is required for organismal mineral homeostasis, governing renal calcium, magnesium and vitamin D handling and skeletal and enamel mineralization [#5, #7, #9, #15, #18, #21, #25, #26]. In C. elegans the orthologue inhibits BLI-3/NADPH oxidase via RHO-1, linking MEMO1 to ROS-dependent stress resistance and longevity [#13].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established MEMO1's founding identity by asking how ErbB2 chemotactic signals reach the cytoskeleton; it answered that MEMO is a required relay between ErbB2 and microtubule extension.\",\n      \"evidence\": \"ErbB2 phosphopeptide co-precipitation and knockdown migration/microtubule imaging in cells\",\n      \"pmids\": [\"15156151\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs Shc-mediated binding to ErbB2 not resolved\", \"Molecular mechanism linking MEMO to microtubules not yet defined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Resolved how MEMO1 recognizes phosphotyrosine; the crystal structure revealed a dioxygenase-like fold lacking enzymatic activity that binds the ErbB2 pTyr1227 peptide through its vestigial active site, defining a new phosphotyrosine-binding class.\",\n      \"evidence\": \"X-ray crystallography at 2.1 Å plus in vitro phosphopeptide binding\",\n      \"pmids\": [\"18045866\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No metal or catalytic activity detected at this stage\", \"Physiological relevance of the dioxygenase-like fold unexplained\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined the downstream cytoskeletal mechanism by showing MEMO controls microtubule growth/shortening transitions via RhoA-mDia1 localization at the leading edge.\",\n      \"evidence\": \"siRNA knockdown, live microtubule imaging, RhoA/mDia1 immunofluorescence in migrating cells\",\n      \"pmids\": [\"18955552\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical link between MEMO and RhoA not established\", \"How MEMO positions RhoA/mDia1 to the membrane unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified a direct actin-regulatory partner, placing MEMO upstream of cofilin and PLCγ1 in ErbB2-driven chemotaxis.\",\n      \"evidence\": \"Yeast two-hybrid, recombinant pulldown, Co-IP, in vitro F-actin depolymerization assay, knockdown migration tracking\",\n      \"pmids\": [\"19223396\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of MEMO-cofilin interaction unknown\", \"How cofilin and RhoA-mDia1 arms are coordinated unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Refined the phosphopeptide recognition by mapping the minimal ErbB2 sequence and a novel pTyr motif distinct from SH2/PTB.\",\n      \"evidence\": \"NMR/docking structural modeling and peptide-variant binding assays\",\n      \"pmids\": [\"21840311\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Docking model not validated by co-crystal structure\", \"Single-lab characterization\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extended MEMO1 beyond ErbB2 by linking it to IGF-IR signaling, showing it binds IRS1 and drives PI3K/Akt-Snail1 EMT.\",\n      \"evidence\": \"Co-IP, Western blots for Akt/Snail1, EMT marker and overexpression/knockdown assays in mammary epithelial cells\",\n      \"pmids\": [\"22824790\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect IRS1 binding not resolved\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connected MEMO1 to nuclear-receptor and FGFR signaling, showing it mediates extranuclear ERα function and is required for FGFR-dependent vitamin D/calcium homeostasis in vivo.\",\n      \"evidence\": \"Multiple Co-IPs (ERα, IGF1R, ERBB2, FGFR), signaling Western blots, ERα reporter, xenografts, and conditional KO mouse phenotyping\",\n      \"pmids\": [\"23861392\", \"24056085\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ERα and FGFR effects share a common molecular mechanism unknown\", \"Single-lab studies\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Reframed MEMO1 as a copper-dependent redox protein required for NOX1-driven ROS, migration, and metastasis, and as a regulator of S1P signaling and vascular development.\",\n      \"evidence\": \"Biochemical redox/ROS assays, NOX1 activity, knockdown/overexpression, xenograft metastasis; separate MEF and HUVEC S1P rescue plus endothelial KO embryos\",\n      \"pmids\": [\"24917593\", \"24714781\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct enzymatic redox mechanism of MEMO1 not biochemically defined\", \"Relationship between redox role and phosphopeptide-binding role unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established cell-autonomous developmental roles in endochondral ossification through neural crest-specific deletion affecting cranial base mineralization and vascular invasion.\",\n      \"evidence\": \"ENU mutant mapping, neural crest conditional KO, histology, gene expression, micro-CT\",\n      \"pmids\": [\"26746790\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular target driving ossification defect not identified\", \"Non-autonomous palate role unexplained\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Detailed the ERα-c-Src axis and uncovered transcriptional control of MEMO1 itself by HER2 via AhR/ARNT.\",\n      \"evidence\": \"Co-IP, ERα Y537 phosphorylation Western, fractionation; ChIP and luciferase reporter on MEMO1 promoter with migration/invasion assays\",\n      \"pmids\": [\"27472465\", \"27941874\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct MEMO1-c-Src binding interface unknown\", \"Single-lab transcriptional and signaling mechanisms\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated an evolutionarily conserved redox-signaling function: the C. elegans orthologue inhibits NADPH oxidase via RhoA, controlling ROS, p38-SKN-1 stress signaling, and longevity.\",\n      \"evidence\": \"C. elegans genetic epistasis, RHO-1/BLI-3 Co-IP, ROS measurement, pathway reporters, lifespan assays\",\n      \"pmids\": [\"28085666\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether mammalian MEMO1 inhibits or sustains NOX is context-dependent and unreconciled\", \"Direct biochemical mechanism of NOX regulation unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linked MEMO1's redox function to mineral homeostasis and skeletal biology, showing it regulates renal calcium transporters, magnesium channels, and redox-dependent alkaline phosphatase dimerization in bone.\",\n      \"evidence\": \"Kidney-specific and whole-body conditional KO mice, serum biochemistry, transporter qPCR/Western, ALP activity and dimerization assays, redox measurements\",\n      \"pmids\": [\"30038585\", \"30038965\", \"32706793\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular substrate of MEMO1's redox effect on transporters/ALP not defined\", \"Single-lab in vivo models\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Provided the clearest in vivo cytoskeletal mechanism, showing MEMO1 stabilizes microtubules to govern radial glial tiling via CAMSAP2 minus-end organization and polarized trafficking.\",\n      \"evidence\": \"Conditional KO and in utero knockdown, live imaging, CAMSAP2/GPR56 immunofluorescence, microtubule dynamics assays\",\n      \"pmids\": [\"31277925\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How MEMO1 biochemically controls CAMSAP2 distribution unknown\", \"Link to the metal/redox functions not addressed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined MEMO1 as a Cu(I) coordinator that shields copper from ROS and exchanges it with Atox1, and identified its proteasomal regulation by HPV16 E7.\",\n      \"evidence\": \"ITC/ICP-MS/EPR/UV-Vis Cu binding, in vitro Cu(I) exchange with Atox1, proximity ligation; E7 pulldown, Co-IP, Cullin2-dependent degradation assays\",\n      \"pmids\": [\"36067318\", \"36434320\", \"36197110\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether copper shuttling explains the migration/redox phenotypes not shown\", \"Physiological copper cargo destination beyond Atox1 unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established MEMO1 as an iron-binding protein with a dioxygenase-like coordination mode, connecting it to ferroptosis, mitochondrial iron supply, and iron-dependent TCA cycle flux.\",\n      \"evidence\": \"Crystal structures of MEMO1-iron and MEMO1-copper, in vitro iron binding, genetic interactions with TFR2/SLC25A28/IRP1, ferroptosis and metabolomics assays\",\n      \"pmids\": [\"38640016\", \"40278406\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether iron binding is catalytic or carrier-like unresolved\", \"Mechanism linking iron handling to TCA flux not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified MEMO1 as a negative regulator of VEGF-driven pathological angiogenesis, dampening VEGFR2/STAT3 signaling in retinal endothelium.\",\n      \"evidence\": \"Reciprocal knockdown/overexpression in RMVECs, phospho-Western, wound closure, endothelial-specific knockdown in rat ROP model\",\n      \"pmids\": [\"40936746\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular target on the VEGFR2 pathway unknown\", \"Reconciliation with pro-migratory roles in cancer unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MEMO1's single dioxygenase-like fold integrates its phosphotyrosine-binding, copper/iron coordination, and redox-signaling activities into one mechanism across such diverse tissues remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying biochemical model connecting metal binding to signaling output\", \"No co-crystal structure of MEMO1 with a full-length partner\", \"Tissue-specific substrate/effector selection mechanism unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [1, 4, 14]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [19, 23]},\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [8, 21, 23]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 19]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [2, 17]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 7, 26]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [8, 13, 22]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [19, 23, 27]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [10, 17, 25, 9]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [23]}\n    ],\n    \"complexes\": [\"FGFR signalosome\"],\n    \"partners\": [\"ERBB2\", \"cofilin\", \"RhoA\", \"IRS1\", \"ESR1\", \"c-Src\", \"Atox1\", \"IGF1R\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}