{"gene":"RECK","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2003,"finding":"RECK was identified as a membrane-anchored GPI-anchored glycoprotein that negatively regulates MMP-2, MMP-9, and MT1-MMP activities. Mice lacking RECK die in utero with elevated MMP activity and reduced collagen type I; this lethal phenotype is partially rescued by MMP-2 null mutation, demonstrating functional interaction between RECK and MMP-2 in vivo.","method":"Gene knockout mouse model, genetic epistasis (Reck-null × MMP-2-null double mutant), in vitro MMP activity assays","journal":"Cancer metastasis reviews","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vivo genetic epistasis with double-knockout rescue, replicated across multiple model systems","pmids":["12784995"],"is_preprint":false},{"year":2003,"finding":"HDAC inhibitor trichostatin A (TSA) up-regulates RECK transcriptionally in human lung cancer cells, increases cell-surface RECK protein, attenuates MMP-2 activity, and suppresses invasion. siRNA knockdown of RECK abolishes the TSA-mediated inhibition of MMP-2 activation, establishing RECK as the mediating effector.","method":"siRNA knockdown, flow cytometry, gelatin zymography, invasion assay, transcriptional activation assay","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA rescue experiment with multiple orthogonal readouts (zymography + invasion), single lab","pmids":["12810630"],"is_preprint":false},{"year":2003,"finding":"EBV latent membrane protein 1 (LMP1) represses RECK expression via the ERK/Sp1 signaling pathway, acting through an Sp1 site in the RECK promoter. This RECK suppression is required for LMP1-induced release of active MMP-9 and increased tumor cell invasiveness; re-expression of RECK or inhibition of ERK reverses these effects.","method":"Promoter reporter assay, ERK inhibitor (PD98059), siRNA, invasion assay, conditioned medium zymography","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter reporter + siRNA + functional invasion assay, single lab with multiple orthogonal methods","pmids":["14614450"],"is_preprint":false},{"year":2004,"finding":"TIMP-2 (but not TIMP-1, and including MMP-inhibitory-dead Ala+TIMP-2) inhibits endothelial cell migration by inducing RECK expression via a Rap1-signaling pathway: TIMP-2 increases Crk–C3G association, activates Rap1, and upregulates RECK, which in turn decreases cell-associated MMP activity. Anti-RECK antibody restores MMP activity and reverses TIMP-2-mediated reduction in migration. RECK-null fibroblasts fail to show TIMP-2-mediated migration inhibition despite Rap1 activation.","method":"Stable Rap1 overexpression, RECK-null cells, anti-RECK antibody, Co-IP of Crk/C3G, zymography, migration assay","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods including null-cell epistasis, genetic rescue, and antibody blockade in one study","pmids":["15604273"],"is_preprint":false},{"year":2005,"finding":"RECK protein is N-glycosylated at Asn86, Asn200, Asn297, and Asn352 (but not Asn39) in HT1080 cells. Glycosylation at Asn297 is required for suppression of MMP-9 secretion, glycosylation at Asn352 is required for inhibition of MMP-2 activation, and glycosylation at Asn86, Asn297, and Asn352 collectively mediates RECK-dependent suppression of tumor cell invasion.","method":"Site-directed mutagenesis of N-glycosylation sites, zymography, invasion assay","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — site-directed mutagenesis with functional readouts (zymography + invasion), single lab with multiple mutant constructs","pmids":["16103099"],"is_preprint":false},{"year":2006,"finding":"TIMP-2 upregulates RECK via a signaling cascade in which TIMP-2 binding activates Csk-mediated phosphorylation of Src at Tyr-527 (inhibitory), reducing Src kinase activity and causing dephosphorylation of paxillin at Tyr-31/118, which switches signaling from the Rac1 pathway (via paxillin-Crk-DOCK180) to the Rap1 pathway (via paxillin-Crk-C3G), thereby enhancing RECK expression.","method":"Phospho-specific western blotting, Co-IP of Src/Csk and paxillin complexes, dominant-negative Rap1","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, phospho-blotting, dominant-negative epistasis, single lab with multiple orthogonal methods","pmids":["16491114"],"is_preprint":false},{"year":2009,"finding":"RECK transcriptionally suppresses MMP-9 by reducing the binding of Fra-1 and c-Jun to the TRE (AP-1) and κB sites in the MMP-9 promoter. RECK overexpression in HT1080 cells decreases MMP-9 mRNA, and siRNA-mediated RECK knockdown increases MMP-9 mRNA in RECK-expressing cells.","method":"Gene expression profiling, MMP-9 promoter reporter assay, RECK-specific siRNA, ChIP","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter reporter + siRNA knockdown + ChIP, single lab","pmids":["19208844"],"is_preprint":false},{"year":2009,"finding":"MT1-MMP and RECK exert opposing roles in hematopoietic progenitor cell (CD34+) motility. RECK expression is lower on circulating progenitors compared to bone marrow cells; G-CSF decreases RECK expression in a PI3K/Akt-dependent manner, elevating MT1-MMP activity. RECK neutralization with antibody promotes motility and egress of bone marrow CD34+ cells, while forced MT1-MMP inhibition impairs homing and mobilization.","method":"Anti-RECK neutralizing antibody, siRNA, anti-MT1-MMP antibody, in vivo mobilization in NOD/SCID chimeric mice, flow cytometry","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo mouse model + antibody/siRNA functional assays + pharmacological inhibition, multiple orthogonal methods","pmids":["19197139"],"is_preprint":false},{"year":2010,"finding":"RECK is a target of miR-15b/16, miR-21, and miR-372/373. RECK mutants lacking miRNA target sites show augmented tumor/metastasis-suppressor activities. miR-372/373 are upregulated in response to hypoxia via HIF1α and TWIST1; miR-21 is upregulated by RAS/ERK signaling, demonstrating convergence of hypoxia and RAS pathways on RECK suppression through miRNAs.","method":"3'UTR luciferase reporter, miRNA target site mutagenesis, hypoxia treatment, HIF1α/TWIST1 manipulation, tumor/metastasis suppression assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — 3'UTR reporter with mutagenesis plus pathway manipulation (HIF1α, TWIST1, RAS/ERK), multiple orthogonal methods in one study","pmids":["20154725"],"is_preprint":false},{"year":2010,"finding":"In Reck heterozygous mice (Reck+/-), tissue damage after transient cerebral ischemia is augmented, recovery of hippocampal long-term potentiation is compromised, MMP gelatinolytic activity is elevated, and laminin immunoreactivity is reduced, implicating Reck in protection of ECM integrity and neurological recovery after ischemia.","method":"Reck+/- mouse model, MMP zymography, immunohistochemistry, electrophysiological LTP recording","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic model with multiple phenotypic readouts, single lab","pmids":["20796170"],"is_preprint":false},{"year":2010,"finding":"RECK is expressed in angiogenic blood vessels during uterine and embryonic vascular remodeling. shRNA-mediated Reck knockdown disrupts formation of vessels with compact, round lumens, and similar defects are seen in Reck-deficient and conditional knockout embryos, implicating Reck in non-sprouting (intussusceptive) angiogenesis.","method":"shRNA knockdown, Reck conditional knockout mouse, immunohistochemistry, morphological analysis","journal":"BMC developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional knockout + shRNA, single lab","pmids":["20691046"],"is_preprint":false},{"year":2011,"finding":"RECK expression induces cell-cycle arrest in colon carcinoma cells by downregulating SKP2 (a ubiquitin ligase component) and upregulating its substrate p27(KIP1). RECK-induced growth suppression is at least partially dependent on p27, and RECK and type I collagen share similar effects on the SKP2-p27 pathway.","method":"Acute RECK expression, cell cycle analysis, western blotting of SKP2 and p27, p27-dependent rescue experiments","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function with pathway analysis and epistasis through p27 dependence, single lab","pmids":["22158033"],"is_preprint":false},{"year":2012,"finding":"In zebrafish, Reck is expressed in neural crest cells and is required cell-autonomously for dorsal root ganglia (DRG) formation. Loss of reck function causes failure of sensory neuron precursors to migrate to the DRG position; four independent alleles of reck all lack DRG, and wild-type reck expression rescues the phenotype.","method":"Forward genetic screen, identification of four reck alleles, rescue experiment, cell-autonomous mosaic analysis","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple independent loss-of-function alleles, rescue experiment, cell-autonomy demonstrated","pmids":["22296847"],"is_preprint":false},{"year":2013,"finding":"STAT3 upregulates miR-92a, which post-transcriptionally suppresses RECK via its 3'UTR, leading to increased MMP activity and enhanced lung cancer cell invasion and migration. Anti-miR-92a restores RECK levels and reverses STAT3-induced invasiveness.","method":"3'UTR luciferase reporter, STAT3 overexpression/inhibitor (S3I-201), pre-miR-92a and anti-miR-92a transfection, gelatin zymography, transwell assay","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — 3'UTR reporter + pathway manipulation + functional assays, single lab","pmids":["23820254"],"is_preprint":false},{"year":2015,"finding":"Reck and Gpr124 function as integral components of a Wnt7a/Wnt7b-specific signaling complex required for brain angiogenesis (CNS vessel invasion) and DRG neurogenesis in zebrafish. Mosaic restoration of single wild-type tip cells in Wnt/β-catenin-deficient vessels is sufficient to initiate CNS vascular invasion, demonstrating that this pathway selectively controls tip cell function.","method":"Zebrafish genetic analysis, mosaic single-cell rescue, endothelial-specific expression, live imaging","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic model with single-cell mosaic analysis and live imaging, multiple orthogonal approaches","pmids":["26051822"],"is_preprint":false},{"year":2015,"finding":"Forward genetic screen in zebrafish identified Reck as essential for intracerebral central artery (CtA) formation via canonical Wnt/β-catenin signaling in endothelial cells. reck mutants lack most intracerebral arteries; Reck promotes BBB molecular marker expression. In cultured endothelial cells, Reck also impacts the VEGF cascade.","method":"Forward genetic screen, zebrafish Reck loss-of-function, Wnt reporter assay in endothelial cells","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — forward genetic screen with functional validation in vivo and in cultured endothelial cells, multiple readouts","pmids":["26657775"],"is_preprint":false},{"year":2015,"finding":"In glioblastoma cells, forced RECK expression inhibits invasion and migration through rearrangement of actin filaments, promoting stress fibers and mature focal adhesions with phospho-FAK, and reducing lamellipodia. RECK protein localizes predominantly at the leading edge of migrating cells, associated with membrane ruffles.","method":"RECK overexpression, transwell and wound assays, immunofluorescence, confocal microscopy for actin/FAK localization","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — gain-of-function with multiple cytoskeletal readouts and direct localization, single lab","pmids":["20127710"],"is_preprint":false},{"year":2015,"finding":"RECK knockdown in human mesenchymal stem cells (hMSCs) promotes migration, reduces osteogenic differentiation, increases adipogenesis, and attenuates Wnt/β-catenin signaling (reduced β-catenin stability and reduced transcription of DKK1, AXIN2, RUNX2). RECK also suppresses TIMP-2 transcription but does not affect MMP-2, MMP-9, MT1-MMP, or TIMP-1 in these cells.","method":"siRNA knockdown, β-catenin reporter (BAR) luciferase assay, differentiation assays, scratch wound/chemotaxis assays","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with multiple orthogonal readouts (differentiation + Wnt signaling + migration), single lab","pmids":["26459448"],"is_preprint":false},{"year":2017,"finding":"Vascular endothelial cell-specific reduction of Reck impairs CNS angiogenesis, and postnatal EC-specific loss of Reck combined with loss of Norrin impairs blood-brain barrier maintenance. The N-terminal CC1 domain of Reck binds the LRR and Ig domains of Gpr124; targeted mutagenesis weakening this interaction (Reck CC1 mutations) reduces Reck/Gpr124 stimulation of Wnt7a signaling in cell culture and impairs CNS angiogenesis in vivo. Soluble Gpr124(LRR-Ig) binds cells expressing Frizzled + Wnt7a/7b + Reck, and soluble Reck(CC1-5) binds cells expressing Frizzled + Wnt7a/7b + Gpr124, demonstrating a tripartite cell-surface complex.","method":"Conditional EC-specific knockout, targeted domain mutagenesis, cell-binding assays with soluble probes, cell culture Wnt reporter assay","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — conditional KO in vivo + mutagenesis + cell-binding assays establishing complex composition, multiple orthogonal methods","pmids":["28803732"],"is_preprint":false},{"year":2018,"finding":"RECK directly binds WNT7A and WNT7B (but not WNT3A) with 1:1 stoichiometry as determined by chemical cross-linking and binding assays with purified recombinant soluble RECK. RECK binding stabilizes monomeric, hydrophilic-active WNT7A and prevents its aggregation into inactive hydrophilic aggregates. GPR124 is the predominant binding partner of RECK in rat brain blood vessels in situ, and the GPR124 ectodomain (not transmembrane/intracellular domains) mediates RECK/WNT7-induced canonical Wnt signaling.","method":"Direct binding assay with purified recombinant proteins, chemical cross-linking, stoichiometry determination, in situ binding (rat brain vessels), Wnt reporter assay with truncated GPR124 constructs","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted direct binding with purified proteins + stoichiometry by cross-linking + in situ validation, multiple orthogonal methods","pmids":["30304675"],"is_preprint":false},{"year":2019,"finding":"Among amino acids distinguishing Wnt7a/7b from other Wnts, two clusters (one at the N-terminus, one in a protruding loop) are essential for Reck- and Gpr124-dependent signaling. Within Reck, substitutions P256A and W261A in the fourth CC domain (CC4) eliminate Wnt7a stimulation without changing protein abundance or surface localization. Mouse embryos carrying these CC4 mutations have severe forebrain angiogenesis defects.","method":"Site-directed mutagenesis of Reck CC4 domain and Wnt7a residues, Wnt reporter assay, surface localization analysis, mouse embryo phenotyping","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — mutagenesis of both ligand and receptor with in vitro reporter + in vivo mouse validation","pmids":["31225798"],"is_preprint":false},{"year":2018,"finding":"A shorter RECK isoform (generated by alternative splicing and alternative polyadenylation) promotes cell migration, opposing the canonical RECK isoform. The short RECK protein competes with MMP9 for binding to the Kazal motifs of canonical RECK, thereby liberating MMP9 from inactivating interaction with canonical RECK. Knockdown of the short isoform reduces fibroblast migration, whereas knockdown of canonical RECK increases migration.","method":"Isoform-specific siRNA knockdown, Matrigel invasion/migration assay, competitive binding assay between short RECK and MMP9 on canonical RECK Kazal motifs","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isoform-specific KD + competitive binding mechanistic assay, single lab","pmids":["29874120"],"is_preprint":false},{"year":2021,"finding":"GDE2 (glycerophosphodiester phosphodiesterase 2) stimulates ADAM10 α-secretase cleavage of APP by shedding and inactivating membrane-tethered RECK, a GPI-anchored inhibitor of ADAM10. In Alzheimer's disease, RECK is highly elevated on the membrane and GDE2 is abnormally sequestered inside neurons. Genetic ablation of GDE2 phenocopies elevated membrane RECK and causes reduced sAPPα, increased Aβ, and synaptic protein loss; RECK reduction restores APP processing balance.","method":"Genetic ablation (GDE2 KO mice), RECK reduction rescue experiment, biochemical fractionation, sAPPα/Aβ measurement, synaptic protein analysis","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with biochemical readouts, genetic rescue, and in vivo disease model with multiple orthogonal methods","pmids":["33731436"],"is_preprint":false},{"year":2022,"finding":"The WNT7A/WNT7B/GPR124/RECK signaling module is required for mammalian limb development. Using combinations of conditional loss-of-function alleles for Wnt7a, Wnt7b, Gpr124, and Reck (including a Reck allele specifically defective in WNT7A/WNT7B signaling), these factors synergize in limb bone growth and patterning (Lmx1b expression, nail structure formation), establishing RECK as part of this signaling unit in a non-CNS context.","method":"Conditional knockout combinations, WNT7A/WNT7B-signaling-defective Reck knock-in allele, limb phenotyping","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — combinatorial conditional knockouts with allele-specific signaling-defective mutation in vivo","pmids":["35552394"],"is_preprint":false},{"year":2013,"finding":"FXR agonist substantially increases hepatic RECK mRNA and protein expression in vivo and in vitro. FXR directly binds an FXR response element within intron 1 of the mouse RECK gene to regulate RECK transcription. FXR agonist reverses the downregulation of RECK in livers from mice fed a methionine- and choline-deficient diet.","method":"FXR agonist treatment (in vivo and in vitro), ChIP/DNA binding assay for FXR response element, qRT-PCR and western blot","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FXR binding to RECK intronic element demonstrated + in vivo validation, single lab","pmids":["24291500"],"is_preprint":false},{"year":2017,"finding":"RECK modulates ER stress by binding to and sequestering GRP78 (glucose-regulated protein 78), thereby releasing the transmembrane sensors (e.g., PERK), which activates eIF2α phosphorylation and enhances ER stress.","method":"RECK/GRP78 binding assay, PERK/eIF2α phosphorylation measurement (described in review context citing experimental results)","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — described in a review-style article without primary experimental detail in the abstract; single indirect mention","pmids":["28134767"],"is_preprint":false},{"year":2023,"finding":"Pancreatic Reck deletion in a PDAC mouse model dramatically augments spontaneous PDAC development with a mesenchymal phenotype, increased liver metastases, and EMT (with tumor cells giving rise to inflammatory CAF-like cells by lineage tracing). RECK re-expression in Reck-null PDAC cells markedly reduces liver metastases, shifts tumor phenotype to epithelial, downregulates MMP2 and MMP3, increases E-cadherin, and decreases EMT transcription factors. An MMP inhibitor recapitulates RECK effects on E-cadherin and EMT factors.","method":"Pancreatic conditional Reck knockout, lineage tracing, splenic transplantation model, RECK re-expression, MMP inhibitor treatment, western blotting","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — conditional KO + rescue re-expression + MMP inhibitor epistasis + lineage tracing, multiple orthogonal methods in one study","pmids":["37712427"],"is_preprint":false},{"year":2010,"finding":"RECK is upregulated in osteoarthritic (OA) cartilage chondrocytes. siRNA knockdown of RECK reduces chondrocyte spreading and focal adhesions and increases migration (in an MMP activity-dependent manner), while RECK overexpression inhibits migration and promotes proliferation via maintained phospho-FAK and phospho-ERK levels.","method":"siRNA knockdown, RECK overexpression, monolayer wound assay, MMP activity-dependent pharmacological rescue, immunohistochemistry, western blotting for FAK and ERK phosphorylation","journal":"The American journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional genetic manipulation (KD and OE) with multiple readouts and MMP activity dependence, single lab","pmids":["20395433"],"is_preprint":false},{"year":2015,"finding":"RECK expression impedes DNA repair in breast cancer cells by inhibiting erbB signaling and attenuating downstream JAB1 and RAD51 expression, leading to activation of ATM/ATR pathways and γ-H2AX foci formation. Ectopic expression of JAB1 counteracts RECK-induced RAD51 reduction and drug sensitization; EGF or HER-2 overexpression reverses RECK inhibitory effects.","method":"RECK overexpression, γ-H2AX foci formation, ATM/ATR pathway activation assay, erbB signaling inhibition, JAB1 rescue expression, HER-2/EGF reversal","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function with epistasis through JAB1 rescue and upstream receptor manipulation, single lab","pmids":["26396917"],"is_preprint":false},{"year":2016,"finding":"Adgra2 (Gpr124) and Reck traffic to the plasma membrane independently of each other: Adgra2 trafficking depends on precise LRR domain composition but occurs in a Reck-independent manner (CRISPR/Cas9 Adgra2-null cells), and Reck reaches the plasma membrane irrespective of Adgra2 expression, suggesting they meet at the plasma membrane after independent intracellular trafficking.","method":"CRISPR/Cas9 gene editing of Adgra2, subcellular localization assays, characterization of zebrafish ouchless allele (LRR domain deletion)","journal":"Biology open","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO cells with direct localization assays, single lab","pmids":["27979830"],"is_preprint":false},{"year":2022,"finding":"Mycoplasma pneumoniae infection decreases RECK expression in bronchial epithelial cells by inducing Sp1 phosphorylation. RECK overexpression significantly impairs M. pneumoniae-triggered MMP-9 enzymatic activity (without affecting MMP-9 protein level), establishing RECK as a post-translational regulator of MMP-9 activity in this context.","method":"RECK overexpression, MMP-9 activity assay, Sp1 phosphorylation analysis, specific pathway inhibitors and chromatin co-precipitation","journal":"Virulence","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RECK gain-of-function with MMP-9 activity readout separating protein level from activity, single lab","pmids":["35892136"],"is_preprint":false}],"current_model":"RECK is a GPI-anchored membrane glycoprotein that functions as a multi-target inhibitor of extracellular proteolysis (MMP-2, MMP-9, MT1-MMP, ADAM10) and as a Wnt7a/Wnt7b-selective co-receptor/stabilizer: it directly binds WNT7A/7B with 1:1 stoichiometry to stabilize active ligand, assembles with GPR124 (via its CC1 domain) and Frizzled/LRP at the endothelial cell surface to transduce CNS-specific Wnt/β-catenin signaling required for brain angiogenesis and BBB formation, while on the tumor-suppressor side it limits invasion/metastasis by blocking MMP-mediated ECM degradation (regulated by N-glycosylation at specific Asn residues), suppressing MMP-9 transcription via the AP-1/κB pathway, activating the SKP2–p27 cell cycle brake, and inhibiting ADAM10-dependent APP cleavage (controlled by GDE2-mediated RECK shedding); its expression is transcriptionally repressed by oncogenic RAS/ERK–Sp1 and post-transcriptionally by multiple miRNAs (miR-21, miR-15b/16, miR-372/373, miR-92a/b, miR-96, miR-221/222, and others), and is induced by TIMP-2 through a Rap1 signaling cascade and by HDAC inhibitors through Sp1 site deacetylation."},"narrative":{"mechanistic_narrative":"RECK is a GPI-anchored membrane glycoprotein with two distinct biological roles: it is a multi-target inhibitor of pericellular proteolysis and a Wnt7a/Wnt7b-selective co-receptor that transduces CNS-specific Wnt/β-catenin signaling [PMID:12784995, PMID:28803732, PMID:30304675]. As a protease regulator, RECK negatively controls MMP-2, MMP-9, and MT1-MMP activity, and its loss is embryonic-lethal with elevated MMP activity and ECM (collagen) deficits that are partially rescued by concurrent MMP-2 ablation, establishing a functional RECK–MMP-2 axis in vivo [PMID:12784995]. RECK acts on MMPs at multiple levels — direct inhibition of MMP-2 activation and MMP-9 secretion through site-specific N-glycosylation (Asn297, Asn352) [PMID:16103099], post-translational suppression of MMP-9 enzymatic activity [PMID:35892136], and transcriptional repression of MMP-9 by reducing Fra-1/c-Jun occupancy of the AP-1/κB sites in its promoter [PMID:19208844]. Through this proteolytic control RECK restrains tumor cell invasion and metastasis: pancreatic Reck deletion drives mesenchymal PDAC with EMT and liver metastasis, while re-expression downregulates MMP2/MMP3, restores E-cadherin, and is phenocopied by MMP inhibition [PMID:37712427]. RECK additionally enforces a cell-cycle brake by downregulating SKP2 and stabilizing p27(KIP1) [PMID:22158033]. In its second role, RECK directly binds WNT7A and WNT7B (not WNT3A) at 1:1 stoichiometry, stabilizing the active monomeric ligand, and assembles with GPR124 — via its N-terminal CC1 domain binding the GPR124 LRR/Ig ectodomain — together with Frizzled to form a tripartite cell-surface complex that drives canonical Wnt signaling for brain angiogenesis and blood-brain barrier formation [PMID:28803732, PMID:30304675, PMID:26051822, PMID:26657775]. Discrete CC4 residues (P256, W261) are required for WNT7A stimulation, and this WNT7/GPR124/RECK module also operates outside the CNS in limb development [PMID:31225798, PMID:35552394]. RECK shedding by GDE2 relieves its inhibition of ADAM10-dependent APP cleavage, linking elevated membrane RECK to impaired α-secretase processing in Alzheimer's disease [PMID:33731436]. RECK is transcriptionally repressed by oncogenic ERK/Sp1 signaling [PMID:14614450] and by multiple miRNAs (miR-15b/16, miR-21, miR-372/373, miR-92a) downstream of hypoxia, RAS, and STAT3 [PMID:20154725, PMID:23820254], and is induced by TIMP-2 through a Rap1 cascade and by HDAC inhibition [PMID:15604273, PMID:12810630].","teleology":[{"year":2003,"claim":"Established RECK as a physiologically essential, membrane-anchored MMP inhibitor rather than an in vitro curiosity, by showing its loss is lethal through unleashed proteolysis.","evidence":"Reck-null mice with genetic epistasis against MMP-2-null and in vitro MMP activity assays","pmids":["12784995"],"confidence":"High","gaps":["Did not resolve which MMP interactions are direct enzymatic inhibition versus indirect","Mechanism of ECM/collagen protection not separated from MMP activity"]},{"year":2003,"claim":"Defined how RECK is silenced in cancer and how it can be pharmacologically restored, linking ERK/Sp1 promoter repression and HDAC-inhibitor induction to invasive phenotypes.","evidence":"TSA induction and siRNA rescue in lung cancer; LMP1/ERK/Sp1 promoter reporter and invasion assays","pmids":["12810630","14614450"],"confidence":"Medium","gaps":["Single-lab transcriptional studies","Direct Sp1 occupancy versus indirect effects not fully dissected"]},{"year":2004,"claim":"Identified an inducible, MMP-inhibition-independent signaling route (TIMP-2→Rap1) that upregulates RECK to suppress endothelial migration, defining RECK as a downstream effector of TIMP-2.","evidence":"Rap1 overexpression, RECK-null cells, anti-RECK antibody, Crk/C3G Co-IP, migration assays; later refined to a Src/Csk/paxillin switch","pmids":["15604273","16491114"],"confidence":"High","gaps":["How Rap1 signaling reaches the RECK promoter not defined","Src/paxillin switch model is single-lab Co-IP based"]},{"year":2005,"claim":"Mapped the post-translational requirement for RECK function by showing specific N-glycosylation sites are differentially required to block MMP-2 versus MMP-9.","evidence":"Site-directed mutagenesis of Asn residues with zymography and invasion assays in HT1080","pmids":["16103099"],"confidence":"High","gaps":["No structural basis for how glycans confer protease selectivity","Single cell-line context"]},{"year":2009,"claim":"Extended RECK's repertoire beyond direct protease inhibition to transcriptional MMP-9 repression and revealed opposing RECK/MT1-MMP roles in progenitor motility in vivo.","evidence":"MMP-9 promoter reporter, ChIP and siRNA; anti-RECK/anti-MT1-MMP antibody and NOD/SCID mobilization model","pmids":["19208844","19197139"],"confidence":"Medium","gaps":["Mechanism linking surface RECK to nuclear AP-1 occupancy unresolved","G-CSF/PI3K control of RECK shown only in progenitor context"]},{"year":2010,"claim":"Showed convergent post-transcriptional silencing of RECK by oncogenic and hypoxic pathways through specific miRNAs, explaining loss of RECK in tumors without promoter mutation.","evidence":"3'UTR luciferase reporters with target-site mutagenesis, HIF1α/TWIST1/RAS manipulation, tumor-suppression assays","pmids":["20154725"],"confidence":"High","gaps":["Relative contribution of each miRNA in vivo not quantified","Did not address whether de-repression alone restores tumor suppression"]},{"year":2010,"claim":"Connected RECK to non-tumor physiology — ischemic ECM protection, vascular lumen morphogenesis, and OA chondrocyte adhesion — broadening its role to tissue integrity and cell shape.","evidence":"Reck+/- ischemia model with LTP/zymography; conditional KO/shRNA angiogenesis; chondrocyte KD/OE with FAK/ERK readouts","pmids":["20796170","20691046","20395433"],"confidence":"Medium","gaps":["Whether vascular and ECM phenotypes are purely MMP-mediated unclear","Single-lab phenotypic studies"]},{"year":2011,"claim":"Identified a proteolysis-independent growth-suppressive arm of RECK acting through the SKP2–p27 cell-cycle axis.","evidence":"Acute RECK expression, cell-cycle analysis, SKP2/p27 westerns and p27-dependence rescue in colon carcinoma","pmids":["22158033"],"confidence":"Medium","gaps":["How surface RECK signals to SKP2 not defined","p27-independent component not characterized"]},{"year":2012,"claim":"Revealed a developmental, signaling role for Reck in neural crest by showing cell-autonomous requirement for sensory neuron migration to the DRG.","evidence":"Zebrafish forward screen, four independent reck alleles, rescue and mosaic cell-autonomy analysis","pmids":["22296847"],"confidence":"High","gaps":["Molecular pathway downstream of Reck in neural crest not yet linked to Wnt at this stage"]},{"year":2015,"claim":"Repositioned RECK as a core component of a Wnt7a/7b-GPR124 signaling complex selectively driving CNS angiogenesis, BBB formation, and tip-cell function.","evidence":"Zebrafish forward genetics, endothelial Wnt reporters, mosaic single-cell rescue and live imaging","pmids":["26051822","26657775"],"confidence":"High","gaps":["Biochemical composition of the receptor complex not yet defined at this stage","VEGF cascade involvement only correlative in culture"]},{"year":2017,"claim":"Defined the architecture of the Wnt7 signaling complex by mapping the RECK CC1–GPR124 ectodomain interaction and demonstrating a tripartite Frizzled/Wnt7/RECK/GPR124 surface assembly required for CNS vasculature.","evidence":"EC-specific conditional KO, CC1 domain mutagenesis, soluble-probe cell-binding assays, Wnt reporters","pmids":["28803732"],"confidence":"High","gaps":["Stoichiometry of the full complex not resolved here","How the complex couples to β-catenin not detailed"]},{"year":2018,"claim":"Demonstrated direct, selective biochemistry — RECK binds WNT7A/7B at 1:1 to stabilize the active ligand — and identified GPR124 as RECK's predominant in situ vascular partner.","evidence":"Purified recombinant binding assays, chemical cross-linking stoichiometry, in situ rat brain vessel binding, truncated GPR124 reporters","pmids":["30304675"],"confidence":"High","gaps":["Structure of the RECK–WNT7 interface not solved","How ligand stabilization is handed to Frizzled mechanistically unclear"]},{"year":2018,"claim":"Uncovered a regulatory short RECK isoform that antagonizes canonical RECK by competing MMP9 off its Kazal motifs, revealing isoform-level tuning of protease inhibition.","evidence":"Isoform-specific siRNA, migration assays, competitive MMP9-binding assay on canonical RECK Kazal motifs","pmids":["29874120"],"confidence":"Medium","gaps":["Physiological regulation of isoform ratio unknown","Single-lab competitive binding model"]},{"year":2019,"claim":"Pinpointed the ligand- and receptor-side determinants of Wnt7 selectivity, identifying RECK CC4 residues (P256, W261) essential for signaling and CNS angiogenesis without affecting trafficking.","evidence":"Mutagenesis of Reck CC4 and Wnt7a residues, Wnt reporters, surface localization, mouse embryo phenotyping","pmids":["31225798"],"confidence":"High","gaps":["How CC1 (GPR124 binding) and CC4 (Wnt7 function) cooperate not structurally resolved"]},{"year":2021,"claim":"Linked RECK shedding to neurodegeneration by showing GDE2-mediated release of GPI-anchored RECK is required to permit ADAM10 α-secretase cleavage of APP.","evidence":"GDE2 KO mice, RECK-reduction rescue, sAPPα/Aβ and synaptic protein measurements, biochemical fractionation","pmids":["33731436"],"confidence":"High","gaps":["Direct RECK–ADAM10 inhibition kinetics not quantified","Why RECK is elevated in human AD mechanistically unclear"]},{"year":2022,"claim":"Generalized the WNT7/GPR124/RECK module beyond the CNS by showing it is required for mammalian limb bone growth and patterning.","evidence":"Combinatorial conditional KOs and a Wnt7-signaling-defective Reck knock-in allele with limb phenotyping","pmids":["35552394"],"confidence":"High","gaps":["Tissue source of Wnt7 ligands and complex partners in limb not fully mapped"]},{"year":2023,"claim":"Provided definitive in vivo evidence that RECK loss promotes EMT, mesenchymal PDAC, and metastasis through MMP-dependent ECM remodeling, with re-expression rescuing the epithelial state.","evidence":"Pancreatic conditional Reck KO, lineage tracing, splenic transplant metastasis model, RECK re-expression, MMP-inhibitor epistasis","pmids":["37712427"],"confidence":"High","gaps":["Whether the Wnt7 signaling arm contributes to the PDAC phenotype not addressed","Identity of all relevant MMP substrates not defined"]},{"year":null,"claim":"A unified structural and mechanistic account of how one GPI-anchored protein both inhibits diverse proteases (MMPs, ADAM10) and serves as a Wnt7-selective co-receptor — including whether these functions are spatially or isoform-segregated — remains unresolved.","evidence":"No single study reconciles the protease-inhibitory and Wnt-signaling roles structurally","pmids":[],"confidence":"Medium","gaps":["No atomic structure of RECK or its complexes","Functional crosstalk between MMP-inhibition and Wnt-signaling domains untested","GRP78/ER-stress role rests on a single low-confidence report (#25)"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,4,21,30]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[18,19,14,15]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,4,22]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,18,29,16]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[0,4,26]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[18,19,15]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[14,23,12]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[26,22]}],"complexes":["WNT7A/7B–GPR124–Frizzled–RECK signaling complex"],"partners":["WNT7A","WNT7B","GPR124","MMP9","MMP2","ADAM10","TIMP2","GDE2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O95980","full_name":"Reversion-inducing cysteine-rich protein with Kazal motifs","aliases":["Suppressor of tumorigenicity 15 protein"],"length_aa":971,"mass_kda":106.5,"function":"Functions together with ADGRA2 to enable brain endothelial cells to selectively respond to Wnt7 signals (WNT7A or WNT7B) (PubMed:28289266, PubMed:30026314). Plays a key role in Wnt7-specific responses: required for central nervous system (CNS) angiogenesis and blood-brain barrier regulation (By similarity). Acts as a Wnt7-specific coactivator of canonical Wnt signaling by decoding Wnt ligands: acts by interacting specifically with the disordered linker region of Wnt7, thereby conferring ligand selectivity for Wnt7 (PubMed:30026314). ADGRA2 is then required to deliver RECK-bound Wnt7 to frizzled by assembling a higher-order RECK-ADGRA2-Fzd-LRP5-LRP6 complex (PubMed:30026314). Also acts as a serine protease inhibitor: negatively regulates matrix metalloproteinase-9 (MMP9) by suppressing MMP9 secretion and by direct inhibition of its enzymatic activity (PubMed:18194466, PubMed:9789069). 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FHIP2A","url":"https://www.omim.org/entry/617312"},{"mim_id":"611731","title":"APC REGULATOR OF WNT SIGNALING PATHWAY; APC","url":"https://www.omim.org/entry/611731"},{"mim_id":"610586","title":"RHO GTPase-ACTIVATING PROTEIN 24; ARHGAP24","url":"https://www.omim.org/entry/610586"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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radiotherapy.","date":"2019","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/31866421","citation_count":29,"is_preprint":false},{"pmid":"16791855","id":"PMC_16791855","title":"Downregulation of the RECK-tumor and metastasis suppressor gene in glioma invasiveness.","date":"2006","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16791855","citation_count":26,"is_preprint":false},{"pmid":"29510387","id":"PMC_29510387","title":"Suppression of Non-Small Cell Lung Cancer Growth and Metastasis by a Novel Small Molecular Activator of RECK.","date":"2018","source":"Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/29510387","citation_count":26,"is_preprint":false},{"pmid":"33028683","id":"PMC_33028683","title":"Clinical and Molecular Description of a High-Copy IncQ1 KPC-2 Plasmid Harbored by the International ST15 Klebsiella 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International Association for the Study of the Liver","url":"https://pubmed.ncbi.nlm.nih.gov/37904642","citation_count":21,"is_preprint":false},{"pmid":"26463982","id":"PMC_26463982","title":"A Hypothesis for the Role of RECK in Angiogenesis.","date":"2016","source":"Current vascular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/26463982","citation_count":21,"is_preprint":false},{"pmid":"26459448","id":"PMC_26459448","title":"RECK (reversion-inducing cysteine-rich protein with Kazal motifs) regulates migration, differentiation and Wnt/β-catenin signaling in human mesenchymal stem cells.","date":"2015","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/26459448","citation_count":21,"is_preprint":false},{"pmid":"20973064","id":"PMC_20973064","title":"Expression of matrix metalloproteinase regulator, RECK, and its clinical significance in osteosarcoma.","date":"2010","source":"Journal of orthopaedic research : official publication of the Orthopaedic Research Society","url":"https://pubmed.ncbi.nlm.nih.gov/20973064","citation_count":21,"is_preprint":false},{"pmid":"33959615","id":"PMC_33959615","title":"Reck-Notch1 Signaling Mediates miR-221/222 Regulation of Lung Cancer Stem Cells in NSCLC.","date":"2021","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/33959615","citation_count":21,"is_preprint":false},{"pmid":"22753763","id":"PMC_22753763","title":"The potential of RECK inducers as antitumor agents for glioma.","date":"2012","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/22753763","citation_count":20,"is_preprint":false},{"pmid":"30841433","id":"PMC_30841433","title":"Curcumin suppresses wilms' tumor metastasis by inhibiting RECK methylation.","date":"2019","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/30841433","citation_count":20,"is_preprint":false},{"pmid":"37712427","id":"PMC_37712427","title":"Pancreatic RECK inactivation promotes cancer formation, epithelial-mesenchymal transition, and metastasis.","date":"2023","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/37712427","citation_count":19,"is_preprint":false},{"pmid":"21842347","id":"PMC_21842347","title":"MT1-MMP and RECK: opposite and essential roles in hematopoietic stem and progenitor cell retention and migration.","date":"2011","source":"Journal of molecular medicine (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/21842347","citation_count":19,"is_preprint":false},{"pmid":"29599320","id":"PMC_29599320","title":"MicroRNA-96 Promotes Tumor Invasion in Colorectal Cancer via RECK.","date":"2018","source":"Anticancer 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open","url":"https://pubmed.ncbi.nlm.nih.gov/27979830","citation_count":18,"is_preprint":false},{"pmid":"20796170","id":"PMC_20796170","title":"The Reck tumor suppressor protein alleviates tissue damage and promotes functional recovery after transient cerebral ischemia in mice.","date":"2010","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20796170","citation_count":18,"is_preprint":false},{"pmid":"22183444","id":"PMC_22183444","title":"Expression of RECK in endothelial cells of glioma: comparison with CD34 and VEGF expressions.","date":"2011","source":"Journal of neuro-oncology","url":"https://pubmed.ncbi.nlm.nih.gov/22183444","citation_count":18,"is_preprint":false},{"pmid":"33674428","id":"PMC_33674428","title":"Vegetable-Derived Carbapenemase-Producing High-Risk Klebsiella pneumoniae ST15 and Acinetobacter baumannii ST2 Clones in Japan: Coexistence of blaNDM-1, blaOXA-66, blaOXA-72, and an AbaR4-Like Resistance Island in the Same Sample.","date":"2021","source":"Applied and environmental microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/33674428","citation_count":17,"is_preprint":false},{"pmid":"33941323","id":"PMC_33941323","title":"Dihydroartemisinin regulates apoptosis, migration, and invasion of ovarian cancer cells via mediating RECK.","date":"2021","source":"Journal of pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33941323","citation_count":16,"is_preprint":false},{"pmid":"16463672","id":"PMC_16463672","title":"Expression of RECK gene and MMP-9 in hilar cholangiocarcinoma and its clinical significance.","date":"2005","source":"Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban","url":"https://pubmed.ncbi.nlm.nih.gov/16463672","citation_count":16,"is_preprint":false},{"pmid":"20395433","id":"PMC_20395433","title":"RECK is up-regulated and involved in chondrocyte cloning in human osteoarthritic cartilage.","date":"2010","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/20395433","citation_count":16,"is_preprint":false},{"pmid":"31933974","id":"PMC_31933974","title":"MiR-92a promotes the invasion and migration of colorectal cancer by targeting RECK.","date":"2019","source":"International journal of clinical and experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/31933974","citation_count":16,"is_preprint":false},{"pmid":"35552394","id":"PMC_35552394","title":"The WNT7A/WNT7B/GPR124/RECK signaling module plays an essential role in mammalian limb development.","date":"2022","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/35552394","citation_count":15,"is_preprint":false},{"pmid":"26431549","id":"PMC_26431549","title":"Isolation and characterization of novel RECK tumor suppressor gene splice variants.","date":"2015","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26431549","citation_count":15,"is_preprint":false},{"pmid":"36895489","id":"PMC_36895489","title":"The BAP31/miR-181a-5p/RECK axis promotes angiogenesis in colorectal cancer via fibroblast activation.","date":"2023","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/36895489","citation_count":15,"is_preprint":false},{"pmid":"36374086","id":"PMC_36374086","title":"Identification of KPC-112 from an ST15 Klebsiella pneumoniae Strain Conferring Resistance to Ceftazidime-Avibactam.","date":"2022","source":"mSphere","url":"https://pubmed.ncbi.nlm.nih.gov/36374086","citation_count":15,"is_preprint":false},{"pmid":"35892136","id":"PMC_35892136","title":"Mycoplasma pneumoniae downregulates RECK to promote matrix metalloproteinase-9 secretion by bronchial epithelial cells.","date":"2022","source":"Virulence","url":"https://pubmed.ncbi.nlm.nih.gov/35892136","citation_count":15,"is_preprint":false},{"pmid":"26396917","id":"PMC_26396917","title":"RECK impedes DNA repair by inhibiting the erbB/JAB1/Rad51 signaling axis and enhances chemosensitivity of breast cancer cells.","date":"2015","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/26396917","citation_count":15,"is_preprint":false},{"pmid":"24291500","id":"PMC_24291500","title":"Activation of farnesoid X receptor induces RECK expression in mouse liver.","date":"2013","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/24291500","citation_count":15,"is_preprint":false},{"pmid":"29108633","id":"PMC_29108633","title":"Preeclampsia associates with RECK-dependent decrease in human trophoblasts migration and invasion.","date":"2017","source":"Placenta","url":"https://pubmed.ncbi.nlm.nih.gov/29108633","citation_count":15,"is_preprint":false},{"pmid":"38612895","id":"PMC_38612895","title":"MiR-21 Regulates Growth and Migration of Cervical Cancer Cells by RECK Signaling Pathway.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38612895","citation_count":14,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51466,"output_tokens":8305,"usd":0.139487,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":17869,"output_tokens":5576,"usd":0.114373,"stage2_stop_reason":"end_turn"},"total_usd":0.25386,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"RECK was identified as a membrane-anchored GPI-anchored glycoprotein that negatively regulates MMP-2, MMP-9, and MT1-MMP activities. Mice lacking RECK die in utero with elevated MMP activity and reduced collagen type I; this lethal phenotype is partially rescued by MMP-2 null mutation, demonstrating functional interaction between RECK and MMP-2 in vivo.\",\n      \"method\": \"Gene knockout mouse model, genetic epistasis (Reck-null × MMP-2-null double mutant), in vitro MMP activity assays\",\n      \"journal\": \"Cancer metastasis reviews\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vivo genetic epistasis with double-knockout rescue, replicated across multiple model systems\",\n      \"pmids\": [\"12784995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"HDAC inhibitor trichostatin A (TSA) up-regulates RECK transcriptionally in human lung cancer cells, increases cell-surface RECK protein, attenuates MMP-2 activity, and suppresses invasion. siRNA knockdown of RECK abolishes the TSA-mediated inhibition of MMP-2 activation, establishing RECK as the mediating effector.\",\n      \"method\": \"siRNA knockdown, flow cytometry, gelatin zymography, invasion assay, transcriptional activation assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA rescue experiment with multiple orthogonal readouts (zymography + invasion), single lab\",\n      \"pmids\": [\"12810630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"EBV latent membrane protein 1 (LMP1) represses RECK expression via the ERK/Sp1 signaling pathway, acting through an Sp1 site in the RECK promoter. This RECK suppression is required for LMP1-induced release of active MMP-9 and increased tumor cell invasiveness; re-expression of RECK or inhibition of ERK reverses these effects.\",\n      \"method\": \"Promoter reporter assay, ERK inhibitor (PD98059), siRNA, invasion assay, conditioned medium zymography\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter reporter + siRNA + functional invasion assay, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"14614450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"TIMP-2 (but not TIMP-1, and including MMP-inhibitory-dead Ala+TIMP-2) inhibits endothelial cell migration by inducing RECK expression via a Rap1-signaling pathway: TIMP-2 increases Crk–C3G association, activates Rap1, and upregulates RECK, which in turn decreases cell-associated MMP activity. Anti-RECK antibody restores MMP activity and reverses TIMP-2-mediated reduction in migration. RECK-null fibroblasts fail to show TIMP-2-mediated migration inhibition despite Rap1 activation.\",\n      \"method\": \"Stable Rap1 overexpression, RECK-null cells, anti-RECK antibody, Co-IP of Crk/C3G, zymography, migration assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods including null-cell epistasis, genetic rescue, and antibody blockade in one study\",\n      \"pmids\": [\"15604273\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"RECK protein is N-glycosylated at Asn86, Asn200, Asn297, and Asn352 (but not Asn39) in HT1080 cells. Glycosylation at Asn297 is required for suppression of MMP-9 secretion, glycosylation at Asn352 is required for inhibition of MMP-2 activation, and glycosylation at Asn86, Asn297, and Asn352 collectively mediates RECK-dependent suppression of tumor cell invasion.\",\n      \"method\": \"Site-directed mutagenesis of N-glycosylation sites, zymography, invasion assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — site-directed mutagenesis with functional readouts (zymography + invasion), single lab with multiple mutant constructs\",\n      \"pmids\": [\"16103099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"TIMP-2 upregulates RECK via a signaling cascade in which TIMP-2 binding activates Csk-mediated phosphorylation of Src at Tyr-527 (inhibitory), reducing Src kinase activity and causing dephosphorylation of paxillin at Tyr-31/118, which switches signaling from the Rac1 pathway (via paxillin-Crk-DOCK180) to the Rap1 pathway (via paxillin-Crk-C3G), thereby enhancing RECK expression.\",\n      \"method\": \"Phospho-specific western blotting, Co-IP of Src/Csk and paxillin complexes, dominant-negative Rap1\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, phospho-blotting, dominant-negative epistasis, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"16491114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"RECK transcriptionally suppresses MMP-9 by reducing the binding of Fra-1 and c-Jun to the TRE (AP-1) and κB sites in the MMP-9 promoter. RECK overexpression in HT1080 cells decreases MMP-9 mRNA, and siRNA-mediated RECK knockdown increases MMP-9 mRNA in RECK-expressing cells.\",\n      \"method\": \"Gene expression profiling, MMP-9 promoter reporter assay, RECK-specific siRNA, ChIP\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter reporter + siRNA knockdown + ChIP, single lab\",\n      \"pmids\": [\"19208844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"MT1-MMP and RECK exert opposing roles in hematopoietic progenitor cell (CD34+) motility. RECK expression is lower on circulating progenitors compared to bone marrow cells; G-CSF decreases RECK expression in a PI3K/Akt-dependent manner, elevating MT1-MMP activity. RECK neutralization with antibody promotes motility and egress of bone marrow CD34+ cells, while forced MT1-MMP inhibition impairs homing and mobilization.\",\n      \"method\": \"Anti-RECK neutralizing antibody, siRNA, anti-MT1-MMP antibody, in vivo mobilization in NOD/SCID chimeric mice, flow cytometry\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo mouse model + antibody/siRNA functional assays + pharmacological inhibition, multiple orthogonal methods\",\n      \"pmids\": [\"19197139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"RECK is a target of miR-15b/16, miR-21, and miR-372/373. RECK mutants lacking miRNA target sites show augmented tumor/metastasis-suppressor activities. miR-372/373 are upregulated in response to hypoxia via HIF1α and TWIST1; miR-21 is upregulated by RAS/ERK signaling, demonstrating convergence of hypoxia and RAS pathways on RECK suppression through miRNAs.\",\n      \"method\": \"3'UTR luciferase reporter, miRNA target site mutagenesis, hypoxia treatment, HIF1α/TWIST1 manipulation, tumor/metastasis suppression assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — 3'UTR reporter with mutagenesis plus pathway manipulation (HIF1α, TWIST1, RAS/ERK), multiple orthogonal methods in one study\",\n      \"pmids\": [\"20154725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In Reck heterozygous mice (Reck+/-), tissue damage after transient cerebral ischemia is augmented, recovery of hippocampal long-term potentiation is compromised, MMP gelatinolytic activity is elevated, and laminin immunoreactivity is reduced, implicating Reck in protection of ECM integrity and neurological recovery after ischemia.\",\n      \"method\": \"Reck+/- mouse model, MMP zymography, immunohistochemistry, electrophysiological LTP recording\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic model with multiple phenotypic readouts, single lab\",\n      \"pmids\": [\"20796170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"RECK is expressed in angiogenic blood vessels during uterine and embryonic vascular remodeling. shRNA-mediated Reck knockdown disrupts formation of vessels with compact, round lumens, and similar defects are seen in Reck-deficient and conditional knockout embryos, implicating Reck in non-sprouting (intussusceptive) angiogenesis.\",\n      \"method\": \"shRNA knockdown, Reck conditional knockout mouse, immunohistochemistry, morphological analysis\",\n      \"journal\": \"BMC developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional knockout + shRNA, single lab\",\n      \"pmids\": [\"20691046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"RECK expression induces cell-cycle arrest in colon carcinoma cells by downregulating SKP2 (a ubiquitin ligase component) and upregulating its substrate p27(KIP1). RECK-induced growth suppression is at least partially dependent on p27, and RECK and type I collagen share similar effects on the SKP2-p27 pathway.\",\n      \"method\": \"Acute RECK expression, cell cycle analysis, western blotting of SKP2 and p27, p27-dependent rescue experiments\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function with pathway analysis and epistasis through p27 dependence, single lab\",\n      \"pmids\": [\"22158033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In zebrafish, Reck is expressed in neural crest cells and is required cell-autonomously for dorsal root ganglia (DRG) formation. Loss of reck function causes failure of sensory neuron precursors to migrate to the DRG position; four independent alleles of reck all lack DRG, and wild-type reck expression rescues the phenotype.\",\n      \"method\": \"Forward genetic screen, identification of four reck alleles, rescue experiment, cell-autonomous mosaic analysis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple independent loss-of-function alleles, rescue experiment, cell-autonomy demonstrated\",\n      \"pmids\": [\"22296847\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"STAT3 upregulates miR-92a, which post-transcriptionally suppresses RECK via its 3'UTR, leading to increased MMP activity and enhanced lung cancer cell invasion and migration. Anti-miR-92a restores RECK levels and reverses STAT3-induced invasiveness.\",\n      \"method\": \"3'UTR luciferase reporter, STAT3 overexpression/inhibitor (S3I-201), pre-miR-92a and anti-miR-92a transfection, gelatin zymography, transwell assay\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — 3'UTR reporter + pathway manipulation + functional assays, single lab\",\n      \"pmids\": [\"23820254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Reck and Gpr124 function as integral components of a Wnt7a/Wnt7b-specific signaling complex required for brain angiogenesis (CNS vessel invasion) and DRG neurogenesis in zebrafish. Mosaic restoration of single wild-type tip cells in Wnt/β-catenin-deficient vessels is sufficient to initiate CNS vascular invasion, demonstrating that this pathway selectively controls tip cell function.\",\n      \"method\": \"Zebrafish genetic analysis, mosaic single-cell rescue, endothelial-specific expression, live imaging\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic model with single-cell mosaic analysis and live imaging, multiple orthogonal approaches\",\n      \"pmids\": [\"26051822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Forward genetic screen in zebrafish identified Reck as essential for intracerebral central artery (CtA) formation via canonical Wnt/β-catenin signaling in endothelial cells. reck mutants lack most intracerebral arteries; Reck promotes BBB molecular marker expression. In cultured endothelial cells, Reck also impacts the VEGF cascade.\",\n      \"method\": \"Forward genetic screen, zebrafish Reck loss-of-function, Wnt reporter assay in endothelial cells\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — forward genetic screen with functional validation in vivo and in cultured endothelial cells, multiple readouts\",\n      \"pmids\": [\"26657775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In glioblastoma cells, forced RECK expression inhibits invasion and migration through rearrangement of actin filaments, promoting stress fibers and mature focal adhesions with phospho-FAK, and reducing lamellipodia. RECK protein localizes predominantly at the leading edge of migrating cells, associated with membrane ruffles.\",\n      \"method\": \"RECK overexpression, transwell and wound assays, immunofluorescence, confocal microscopy for actin/FAK localization\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — gain-of-function with multiple cytoskeletal readouts and direct localization, single lab\",\n      \"pmids\": [\"20127710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RECK knockdown in human mesenchymal stem cells (hMSCs) promotes migration, reduces osteogenic differentiation, increases adipogenesis, and attenuates Wnt/β-catenin signaling (reduced β-catenin stability and reduced transcription of DKK1, AXIN2, RUNX2). RECK also suppresses TIMP-2 transcription but does not affect MMP-2, MMP-9, MT1-MMP, or TIMP-1 in these cells.\",\n      \"method\": \"siRNA knockdown, β-catenin reporter (BAR) luciferase assay, differentiation assays, scratch wound/chemotaxis assays\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with multiple orthogonal readouts (differentiation + Wnt signaling + migration), single lab\",\n      \"pmids\": [\"26459448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Vascular endothelial cell-specific reduction of Reck impairs CNS angiogenesis, and postnatal EC-specific loss of Reck combined with loss of Norrin impairs blood-brain barrier maintenance. The N-terminal CC1 domain of Reck binds the LRR and Ig domains of Gpr124; targeted mutagenesis weakening this interaction (Reck CC1 mutations) reduces Reck/Gpr124 stimulation of Wnt7a signaling in cell culture and impairs CNS angiogenesis in vivo. Soluble Gpr124(LRR-Ig) binds cells expressing Frizzled + Wnt7a/7b + Reck, and soluble Reck(CC1-5) binds cells expressing Frizzled + Wnt7a/7b + Gpr124, demonstrating a tripartite cell-surface complex.\",\n      \"method\": \"Conditional EC-specific knockout, targeted domain mutagenesis, cell-binding assays with soluble probes, cell culture Wnt reporter assay\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — conditional KO in vivo + mutagenesis + cell-binding assays establishing complex composition, multiple orthogonal methods\",\n      \"pmids\": [\"28803732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RECK directly binds WNT7A and WNT7B (but not WNT3A) with 1:1 stoichiometry as determined by chemical cross-linking and binding assays with purified recombinant soluble RECK. RECK binding stabilizes monomeric, hydrophilic-active WNT7A and prevents its aggregation into inactive hydrophilic aggregates. GPR124 is the predominant binding partner of RECK in rat brain blood vessels in situ, and the GPR124 ectodomain (not transmembrane/intracellular domains) mediates RECK/WNT7-induced canonical Wnt signaling.\",\n      \"method\": \"Direct binding assay with purified recombinant proteins, chemical cross-linking, stoichiometry determination, in situ binding (rat brain vessels), Wnt reporter assay with truncated GPR124 constructs\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted direct binding with purified proteins + stoichiometry by cross-linking + in situ validation, multiple orthogonal methods\",\n      \"pmids\": [\"30304675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Among amino acids distinguishing Wnt7a/7b from other Wnts, two clusters (one at the N-terminus, one in a protruding loop) are essential for Reck- and Gpr124-dependent signaling. Within Reck, substitutions P256A and W261A in the fourth CC domain (CC4) eliminate Wnt7a stimulation without changing protein abundance or surface localization. Mouse embryos carrying these CC4 mutations have severe forebrain angiogenesis defects.\",\n      \"method\": \"Site-directed mutagenesis of Reck CC4 domain and Wnt7a residues, Wnt reporter assay, surface localization analysis, mouse embryo phenotyping\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — mutagenesis of both ligand and receptor with in vitro reporter + in vivo mouse validation\",\n      \"pmids\": [\"31225798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"A shorter RECK isoform (generated by alternative splicing and alternative polyadenylation) promotes cell migration, opposing the canonical RECK isoform. The short RECK protein competes with MMP9 for binding to the Kazal motifs of canonical RECK, thereby liberating MMP9 from inactivating interaction with canonical RECK. Knockdown of the short isoform reduces fibroblast migration, whereas knockdown of canonical RECK increases migration.\",\n      \"method\": \"Isoform-specific siRNA knockdown, Matrigel invasion/migration assay, competitive binding assay between short RECK and MMP9 on canonical RECK Kazal motifs\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isoform-specific KD + competitive binding mechanistic assay, single lab\",\n      \"pmids\": [\"29874120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GDE2 (glycerophosphodiester phosphodiesterase 2) stimulates ADAM10 α-secretase cleavage of APP by shedding and inactivating membrane-tethered RECK, a GPI-anchored inhibitor of ADAM10. In Alzheimer's disease, RECK is highly elevated on the membrane and GDE2 is abnormally sequestered inside neurons. Genetic ablation of GDE2 phenocopies elevated membrane RECK and causes reduced sAPPα, increased Aβ, and synaptic protein loss; RECK reduction restores APP processing balance.\",\n      \"method\": \"Genetic ablation (GDE2 KO mice), RECK reduction rescue experiment, biochemical fractionation, sAPPα/Aβ measurement, synaptic protein analysis\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with biochemical readouts, genetic rescue, and in vivo disease model with multiple orthogonal methods\",\n      \"pmids\": [\"33731436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The WNT7A/WNT7B/GPR124/RECK signaling module is required for mammalian limb development. Using combinations of conditional loss-of-function alleles for Wnt7a, Wnt7b, Gpr124, and Reck (including a Reck allele specifically defective in WNT7A/WNT7B signaling), these factors synergize in limb bone growth and patterning (Lmx1b expression, nail structure formation), establishing RECK as part of this signaling unit in a non-CNS context.\",\n      \"method\": \"Conditional knockout combinations, WNT7A/WNT7B-signaling-defective Reck knock-in allele, limb phenotyping\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — combinatorial conditional knockouts with allele-specific signaling-defective mutation in vivo\",\n      \"pmids\": [\"35552394\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"FXR agonist substantially increases hepatic RECK mRNA and protein expression in vivo and in vitro. FXR directly binds an FXR response element within intron 1 of the mouse RECK gene to regulate RECK transcription. FXR agonist reverses the downregulation of RECK in livers from mice fed a methionine- and choline-deficient diet.\",\n      \"method\": \"FXR agonist treatment (in vivo and in vitro), ChIP/DNA binding assay for FXR response element, qRT-PCR and western blot\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FXR binding to RECK intronic element demonstrated + in vivo validation, single lab\",\n      \"pmids\": [\"24291500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RECK modulates ER stress by binding to and sequestering GRP78 (glucose-regulated protein 78), thereby releasing the transmembrane sensors (e.g., PERK), which activates eIF2α phosphorylation and enhances ER stress.\",\n      \"method\": \"RECK/GRP78 binding assay, PERK/eIF2α phosphorylation measurement (described in review context citing experimental results)\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — described in a review-style article without primary experimental detail in the abstract; single indirect mention\",\n      \"pmids\": [\"28134767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Pancreatic Reck deletion in a PDAC mouse model dramatically augments spontaneous PDAC development with a mesenchymal phenotype, increased liver metastases, and EMT (with tumor cells giving rise to inflammatory CAF-like cells by lineage tracing). RECK re-expression in Reck-null PDAC cells markedly reduces liver metastases, shifts tumor phenotype to epithelial, downregulates MMP2 and MMP3, increases E-cadherin, and decreases EMT transcription factors. An MMP inhibitor recapitulates RECK effects on E-cadherin and EMT factors.\",\n      \"method\": \"Pancreatic conditional Reck knockout, lineage tracing, splenic transplantation model, RECK re-expression, MMP inhibitor treatment, western blotting\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — conditional KO + rescue re-expression + MMP inhibitor epistasis + lineage tracing, multiple orthogonal methods in one study\",\n      \"pmids\": [\"37712427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"RECK is upregulated in osteoarthritic (OA) cartilage chondrocytes. siRNA knockdown of RECK reduces chondrocyte spreading and focal adhesions and increases migration (in an MMP activity-dependent manner), while RECK overexpression inhibits migration and promotes proliferation via maintained phospho-FAK and phospho-ERK levels.\",\n      \"method\": \"siRNA knockdown, RECK overexpression, monolayer wound assay, MMP activity-dependent pharmacological rescue, immunohistochemistry, western blotting for FAK and ERK phosphorylation\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional genetic manipulation (KD and OE) with multiple readouts and MMP activity dependence, single lab\",\n      \"pmids\": [\"20395433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RECK expression impedes DNA repair in breast cancer cells by inhibiting erbB signaling and attenuating downstream JAB1 and RAD51 expression, leading to activation of ATM/ATR pathways and γ-H2AX foci formation. Ectopic expression of JAB1 counteracts RECK-induced RAD51 reduction and drug sensitization; EGF or HER-2 overexpression reverses RECK inhibitory effects.\",\n      \"method\": \"RECK overexpression, γ-H2AX foci formation, ATM/ATR pathway activation assay, erbB signaling inhibition, JAB1 rescue expression, HER-2/EGF reversal\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function with epistasis through JAB1 rescue and upstream receptor manipulation, single lab\",\n      \"pmids\": [\"26396917\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Adgra2 (Gpr124) and Reck traffic to the plasma membrane independently of each other: Adgra2 trafficking depends on precise LRR domain composition but occurs in a Reck-independent manner (CRISPR/Cas9 Adgra2-null cells), and Reck reaches the plasma membrane irrespective of Adgra2 expression, suggesting they meet at the plasma membrane after independent intracellular trafficking.\",\n      \"method\": \"CRISPR/Cas9 gene editing of Adgra2, subcellular localization assays, characterization of zebrafish ouchless allele (LRR domain deletion)\",\n      \"journal\": \"Biology open\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO cells with direct localization assays, single lab\",\n      \"pmids\": [\"27979830\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Mycoplasma pneumoniae infection decreases RECK expression in bronchial epithelial cells by inducing Sp1 phosphorylation. RECK overexpression significantly impairs M. pneumoniae-triggered MMP-9 enzymatic activity (without affecting MMP-9 protein level), establishing RECK as a post-translational regulator of MMP-9 activity in this context.\",\n      \"method\": \"RECK overexpression, MMP-9 activity assay, Sp1 phosphorylation analysis, specific pathway inhibitors and chromatin co-precipitation\",\n      \"journal\": \"Virulence\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RECK gain-of-function with MMP-9 activity readout separating protein level from activity, single lab\",\n      \"pmids\": [\"35892136\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RECK is a GPI-anchored membrane glycoprotein that functions as a multi-target inhibitor of extracellular proteolysis (MMP-2, MMP-9, MT1-MMP, ADAM10) and as a Wnt7a/Wnt7b-selective co-receptor/stabilizer: it directly binds WNT7A/7B with 1:1 stoichiometry to stabilize active ligand, assembles with GPR124 (via its CC1 domain) and Frizzled/LRP at the endothelial cell surface to transduce CNS-specific Wnt/β-catenin signaling required for brain angiogenesis and BBB formation, while on the tumor-suppressor side it limits invasion/metastasis by blocking MMP-mediated ECM degradation (regulated by N-glycosylation at specific Asn residues), suppressing MMP-9 transcription via the AP-1/κB pathway, activating the SKP2–p27 cell cycle brake, and inhibiting ADAM10-dependent APP cleavage (controlled by GDE2-mediated RECK shedding); its expression is transcriptionally repressed by oncogenic RAS/ERK–Sp1 and post-transcriptionally by multiple miRNAs (miR-21, miR-15b/16, miR-372/373, miR-92a/b, miR-96, miR-221/222, and others), and is induced by TIMP-2 through a Rap1 signaling cascade and by HDAC inhibitors through Sp1 site deacetylation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RECK is a GPI-anchored membrane glycoprotein with two distinct biological roles: it is a multi-target inhibitor of pericellular proteolysis and a Wnt7a/Wnt7b-selective co-receptor that transduces CNS-specific Wnt/β-catenin signaling [#0, #18, #19]. As a protease regulator, RECK negatively controls MMP-2, MMP-9, and MT1-MMP activity, and its loss is embryonic-lethal with elevated MMP activity and ECM (collagen) deficits that are partially rescued by concurrent MMP-2 ablation, establishing a functional RECK–MMP-2 axis in vivo [#0]. RECK acts on MMPs at multiple levels — direct inhibition of MMP-2 activation and MMP-9 secretion through site-specific N-glycosylation (Asn297, Asn352) [#4], post-translational suppression of MMP-9 enzymatic activity [#30], and transcriptional repression of MMP-9 by reducing Fra-1/c-Jun occupancy of the AP-1/κB sites in its promoter [#6]. Through this proteolytic control RECK restrains tumor cell invasion and metastasis: pancreatic Reck deletion drives mesenchymal PDAC with EMT and liver metastasis, while re-expression downregulates MMP2/MMP3, restores E-cadherin, and is phenocopied by MMP inhibition [#26]. RECK additionally enforces a cell-cycle brake by downregulating SKP2 and stabilizing p27(KIP1) [#11]. In its second role, RECK directly binds WNT7A and WNT7B (not WNT3A) at 1:1 stoichiometry, stabilizing the active monomeric ligand, and assembles with GPR124 — via its N-terminal CC1 domain binding the GPR124 LRR/Ig ectodomain — together with Frizzled to form a tripartite cell-surface complex that drives canonical Wnt signaling for brain angiogenesis and blood-brain barrier formation [#18, #19, #14, #15]. Discrete CC4 residues (P256, W261) are required for WNT7A stimulation, and this WNT7/GPR124/RECK module also operates outside the CNS in limb development [#20, #23]. RECK shedding by GDE2 relieves its inhibition of ADAM10-dependent APP cleavage, linking elevated membrane RECK to impaired α-secretase processing in Alzheimer's disease [#22]. RECK is transcriptionally repressed by oncogenic ERK/Sp1 signaling [#2] and by multiple miRNAs (miR-15b/16, miR-21, miR-372/373, miR-92a) downstream of hypoxia, RAS, and STAT3 [#8, #13], and is induced by TIMP-2 through a Rap1 cascade and by HDAC inhibition [#3, #1].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established RECK as a physiologically essential, membrane-anchored MMP inhibitor rather than an in vitro curiosity, by showing its loss is lethal through unleashed proteolysis.\",\n      \"evidence\": \"Reck-null mice with genetic epistasis against MMP-2-null and in vitro MMP activity assays\",\n      \"pmids\": [\"12784995\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which MMP interactions are direct enzymatic inhibition versus indirect\", \"Mechanism of ECM/collagen protection not separated from MMP activity\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defined how RECK is silenced in cancer and how it can be pharmacologically restored, linking ERK/Sp1 promoter repression and HDAC-inhibitor induction to invasive phenotypes.\",\n      \"evidence\": \"TSA induction and siRNA rescue in lung cancer; LMP1/ERK/Sp1 promoter reporter and invasion assays\",\n      \"pmids\": [\"12810630\", \"14614450\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab transcriptional studies\", \"Direct Sp1 occupancy versus indirect effects not fully dissected\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identified an inducible, MMP-inhibition-independent signaling route (TIMP-2→Rap1) that upregulates RECK to suppress endothelial migration, defining RECK as a downstream effector of TIMP-2.\",\n      \"evidence\": \"Rap1 overexpression, RECK-null cells, anti-RECK antibody, Crk/C3G Co-IP, migration assays; later refined to a Src/Csk/paxillin switch\",\n      \"pmids\": [\"15604273\", \"16491114\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Rap1 signaling reaches the RECK promoter not defined\", \"Src/paxillin switch model is single-lab Co-IP based\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Mapped the post-translational requirement for RECK function by showing specific N-glycosylation sites are differentially required to block MMP-2 versus MMP-9.\",\n      \"evidence\": \"Site-directed mutagenesis of Asn residues with zymography and invasion assays in HT1080\",\n      \"pmids\": [\"16103099\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural basis for how glycans confer protease selectivity\", \"Single cell-line context\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Extended RECK's repertoire beyond direct protease inhibition to transcriptional MMP-9 repression and revealed opposing RECK/MT1-MMP roles in progenitor motility in vivo.\",\n      \"evidence\": \"MMP-9 promoter reporter, ChIP and siRNA; anti-RECK/anti-MT1-MMP antibody and NOD/SCID mobilization model\",\n      \"pmids\": [\"19208844\", \"19197139\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking surface RECK to nuclear AP-1 occupancy unresolved\", \"G-CSF/PI3K control of RECK shown only in progenitor context\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed convergent post-transcriptional silencing of RECK by oncogenic and hypoxic pathways through specific miRNAs, explaining loss of RECK in tumors without promoter mutation.\",\n      \"evidence\": \"3'UTR luciferase reporters with target-site mutagenesis, HIF1α/TWIST1/RAS manipulation, tumor-suppression assays\",\n      \"pmids\": [\"20154725\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of each miRNA in vivo not quantified\", \"Did not address whether de-repression alone restores tumor suppression\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Connected RECK to non-tumor physiology — ischemic ECM protection, vascular lumen morphogenesis, and OA chondrocyte adhesion — broadening its role to tissue integrity and cell shape.\",\n      \"evidence\": \"Reck+/- ischemia model with LTP/zymography; conditional KO/shRNA angiogenesis; chondrocyte KD/OE with FAK/ERK readouts\",\n      \"pmids\": [\"20796170\", \"20691046\", \"20395433\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether vascular and ECM phenotypes are purely MMP-mediated unclear\", \"Single-lab phenotypic studies\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified a proteolysis-independent growth-suppressive arm of RECK acting through the SKP2–p27 cell-cycle axis.\",\n      \"evidence\": \"Acute RECK expression, cell-cycle analysis, SKP2/p27 westerns and p27-dependence rescue in colon carcinoma\",\n      \"pmids\": [\"22158033\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How surface RECK signals to SKP2 not defined\", \"p27-independent component not characterized\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Revealed a developmental, signaling role for Reck in neural crest by showing cell-autonomous requirement for sensory neuron migration to the DRG.\",\n      \"evidence\": \"Zebrafish forward screen, four independent reck alleles, rescue and mosaic cell-autonomy analysis\",\n      \"pmids\": [\"22296847\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular pathway downstream of Reck in neural crest not yet linked to Wnt at this stage\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Repositioned RECK as a core component of a Wnt7a/7b-GPR124 signaling complex selectively driving CNS angiogenesis, BBB formation, and tip-cell function.\",\n      \"evidence\": \"Zebrafish forward genetics, endothelial Wnt reporters, mosaic single-cell rescue and live imaging\",\n      \"pmids\": [\"26051822\", \"26657775\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biochemical composition of the receptor complex not yet defined at this stage\", \"VEGF cascade involvement only correlative in culture\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined the architecture of the Wnt7 signaling complex by mapping the RECK CC1–GPR124 ectodomain interaction and demonstrating a tripartite Frizzled/Wnt7/RECK/GPR124 surface assembly required for CNS vasculature.\",\n      \"evidence\": \"EC-specific conditional KO, CC1 domain mutagenesis, soluble-probe cell-binding assays, Wnt reporters\",\n      \"pmids\": [\"28803732\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of the full complex not resolved here\", \"How the complex couples to β-catenin not detailed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated direct, selective biochemistry — RECK binds WNT7A/7B at 1:1 to stabilize the active ligand — and identified GPR124 as RECK's predominant in situ vascular partner.\",\n      \"evidence\": \"Purified recombinant binding assays, chemical cross-linking stoichiometry, in situ rat brain vessel binding, truncated GPR124 reporters\",\n      \"pmids\": [\"30304675\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the RECK–WNT7 interface not solved\", \"How ligand stabilization is handed to Frizzled mechanistically unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Uncovered a regulatory short RECK isoform that antagonizes canonical RECK by competing MMP9 off its Kazal motifs, revealing isoform-level tuning of protease inhibition.\",\n      \"evidence\": \"Isoform-specific siRNA, migration assays, competitive MMP9-binding assay on canonical RECK Kazal motifs\",\n      \"pmids\": [\"29874120\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological regulation of isoform ratio unknown\", \"Single-lab competitive binding model\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Pinpointed the ligand- and receptor-side determinants of Wnt7 selectivity, identifying RECK CC4 residues (P256, W261) essential for signaling and CNS angiogenesis without affecting trafficking.\",\n      \"evidence\": \"Mutagenesis of Reck CC4 and Wnt7a residues, Wnt reporters, surface localization, mouse embryo phenotyping\",\n      \"pmids\": [\"31225798\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CC1 (GPR124 binding) and CC4 (Wnt7 function) cooperate not structurally resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked RECK shedding to neurodegeneration by showing GDE2-mediated release of GPI-anchored RECK is required to permit ADAM10 α-secretase cleavage of APP.\",\n      \"evidence\": \"GDE2 KO mice, RECK-reduction rescue, sAPPα/Aβ and synaptic protein measurements, biochemical fractionation\",\n      \"pmids\": [\"33731436\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct RECK–ADAM10 inhibition kinetics not quantified\", \"Why RECK is elevated in human AD mechanistically unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Generalized the WNT7/GPR124/RECK module beyond the CNS by showing it is required for mammalian limb bone growth and patterning.\",\n      \"evidence\": \"Combinatorial conditional KOs and a Wnt7-signaling-defective Reck knock-in allele with limb phenotyping\",\n      \"pmids\": [\"35552394\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue source of Wnt7 ligands and complex partners in limb not fully mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Provided definitive in vivo evidence that RECK loss promotes EMT, mesenchymal PDAC, and metastasis through MMP-dependent ECM remodeling, with re-expression rescuing the epithelial state.\",\n      \"evidence\": \"Pancreatic conditional Reck KO, lineage tracing, splenic transplant metastasis model, RECK re-expression, MMP-inhibitor epistasis\",\n      \"pmids\": [\"37712427\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the Wnt7 signaling arm contributes to the PDAC phenotype not addressed\", \"Identity of all relevant MMP substrates not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A unified structural and mechanistic account of how one GPI-anchored protein both inhibits diverse proteases (MMPs, ADAM10) and serves as a Wnt7-selective co-receptor — including whether these functions are spatially or isoform-segregated — remains unresolved.\",\n      \"evidence\": \"No single study reconciles the protease-inhibitory and Wnt-signaling roles structurally\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No atomic structure of RECK or its complexes\", \"Functional crosstalk between MMP-inhibition and Wnt-signaling domains untested\", \"GRP78/ER-stress role rests on a single low-confidence report (#25)\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 4, 21, 30]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [18, 19, 14, 15]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 4, 22]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 18, 29, 16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [0, 4, 26]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [18, 19, 15]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [14, 23, 12]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [26, 22]}\n    ],\n    \"complexes\": [\n      \"WNT7A/7B–GPR124–Frizzled–RECK signaling complex\"\n    ],\n    \"partners\": [\n      \"WNT7A\",\n      \"WNT7B\",\n      \"GPR124\",\n      \"MMP9\",\n      \"MMP2\",\n      \"ADAM10\",\n      \"TIMP2\",\n      \"GDE2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}