{"gene":"GAS7","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":1998,"finding":"GAS7 inhibition in terminally differentiating cerebellar cultures impedes neurite outgrowth from maturing Purkinje cells, and GAS7 overexpression in undifferentiated neuroblastoma cells promotes neurite-like outgrowth, establishing a direct role for GAS7 in neuronal morphological differentiation.","method":"In situ hybridization, immunocytochemistry, antisense inhibition in primary cerebellar cultures, overexpression in neuroblastoma cells","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function (antisense) with defined cellular phenotype and gain-of-function overexpression, single lab, two orthogonal approaches","pmids":["9736752"],"is_preprint":false},{"year":1999,"finding":"The Gas7 gene encodes two protein isoforms (Gas7 and Gas7-cb) by alternative splicing from distinct 5' exons; Gas7 is predominant in cerebrum and growth-arrested fibroblasts, while Gas7-cb is predominant in cerebellum, with unique N-terminal sequences.","method":"RNase protection assay, Western blot, genomic BAC characterization, cDNA cloning","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal molecular methods in single lab establishing isoform structure and differential expression","pmids":["10552931"],"is_preprint":false},{"year":2002,"finding":"GAS7 directly binds F-actin via its C-terminal domain, localizes near the plasma membrane in membrane ruffles via its C-terminal domain, promotes actin assembly and crosslinking of actin filaments, and induces membrane outgrowth requiring actin polymerization.","method":"F-actin affinity chromatography, purified His-Gas7 direct binding assay, cytochalasin D treatment, electron microscopy, ectopic overexpression with domain deletion mutants","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified protein, direct binding assay, domain mutagenesis, EM, and functional inhibitor experiment across multiple orthogonal methods","pmids":["11795944"],"is_preprint":false},{"year":2003,"finding":"MLL-GAS7 fusion protein transforms multipotent hematopoietic progenitors and impairs their differentiation while enhancing in vitro growth, and induces mixed lineage leukemias in mice, acting through a dimerization-dependent mechanism.","method":"Retroviral transduction/transplantation assay in mice, in vitro colony-forming assays, immunophenotyping","journal":"Cancer cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — retroviral transduction plus in vivo transplantation with defined leukemia phenotypes, single lab, multiple readouts","pmids":["12620410"],"is_preprint":false},{"year":2003,"finding":"GAS7 overexpression in PC12 cells induces expanded cell morphology and spike-like processes resembling early neurite formation; endogenous rat Gas7 is transiently elevated prior to NGF-promoted neurite outgrowth; antisense inhibition of Gas7 reduces NGF-promoted neurite outgrowths, establishing Gas7 as an early-stage intermediary in NGF-induced neuronal differentiation.","method":"Overexpression in PC12 cells, antisense oligonucleotide knockdown, NGF stimulation assay, RT-PCR","journal":"Journal of neuroscience research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function experiments with defined morphological phenotype, single lab, two orthogonal approaches","pmids":["14515354"],"is_preprint":false},{"year":2003,"finding":"Hoxa7 and Hoxa9 contribute to MLL-GAS7-mediated leukemogenesis as downstream targets; Hoxa7/9 deficiency does not abolish transformation by MLL-GAS7 but increases disease latency and reduces penetrance, placing these Hox genes downstream of MLL-GAS7 in the leukemogenic pathway.","method":"Retroviral transduction/transplantation in Hoxa7- and Hoxa9-knockout mice, in vitro colony-forming assays, epistasis analysis","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis using knockout mice with defined disease phenotype endpoints, single lab","pmids":["15070702"],"is_preprint":false},{"year":2005,"finding":"Human GAS7 isoforms hGas7-a (FCH domain only) and hGas7-b (WW + FCH domains) differentially induce neurite-like processes: hGas7-a preferentially elicits lamellipodia, while hGas7-b elicits filopodia, implicating the WW domain in filopodia and the FCH domain in lamellipodia formation.","method":"Transfection of Neuro-2a and SH-SY5Y cells with isoform-specific constructs, quantitative PCR, protein expression analysis","journal":"Journal of neuroscience research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — isoform overexpression with morphological phenotype scoring, single lab, two cell lines used","pmids":["15948147"],"is_preprint":false},{"year":2008,"finding":"GAS7b expression is transiently upregulated during chondrogenic differentiation of human MSCs downstream of ERK1/2 and SOX9 signaling; antisense inhibition of hGas7b impairs chondrogenesis, but Gas7b inhibition does not affect the p-ERK/SOX9 pathway, placing Gas7b downstream of ERK1/2 and SOX9.","method":"Antisense oligonucleotides, siRNA knockdown of SOX9, ERK inhibitor PD98059, aggregate culture chondrogenesis assay, Western blot, RT-PCR","journal":"Osteoarthritis and cartilage","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic/chemical epistasis with multiple inhibitors and loss-of-function, defined phenotypic readouts, single lab","pmids":["18455446"],"is_preprint":false},{"year":2009,"finding":"Gas7 stabilizes tubulin sheet intermediates during microtubule polymerization, promoting microtubule elongation without catastrophe; in the absence of Gas7, sheet-like structures were rarely observed and were fragile, demonstrating that Gas7 enhances microtubule polymerization by stabilizing sheet intermediates.","method":"Dark-field microscopy real-time observation, electron microscopy, in vitro microtubule polymerization assay with and without Gas7","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified components, real-time optical microscopy and electron microscopy, multiple orthogonal methods","pmids":["19580814"],"is_preprint":false},{"year":2010,"finding":"Gas7 co-localizes and physically interacts with N-WASP via WW-Pro domain interaction (not SH3-Pro) in growth cones of hippocampal neurons and recruits the Arp2/3 complex in a Cdc42-independent manner to promote membrane protrusions and neurite outgrowth.","method":"Co-immunoprecipitation, co-localization in Neuro-2a cells and hippocampal neurons, domain mutant analysis, Arp2/3 recruitment assay, Cdc42 dominant-negative experiment, siRNA knockdown","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, domain mapping, loss-of-function siRNA with defined neurite phenotype, Cdc42-independence established, multiple orthogonal methods","pmids":["20150425"],"is_preprint":false},{"year":2012,"finding":"Gas7-deficient mice show age-dependent motor activity defects associated with decreased spinal motor neuron numbers, reduced muscle strength, altered muscle fiber composition (fewer fast fibers in soleus), and reduced nerve terminal sprouting at neuromuscular junctions.","method":"Gas7-deficient mouse genetic model, motor function testing, histomorphometry, MHC I/II immunostaining, NMJ analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockout mouse with multiple defined cellular and morphological phenotypes, single lab","pmids":["22662195"],"is_preprint":false},{"year":2013,"finding":"Gas7 knockdown using shRNA decreases Runx2 expression and its target genes (alkaline phosphatase, type I collagen, osteocalcin, osteopontin) and reduces mineralization; ectopic Gas7 expression induces Runx2-dependent transcriptional activity and osteoblast differentiation, establishing Gas7 as a regulator of osteogenesis upstream of Runx2.","method":"shRNA knockdown, ectopic overexpression, Runx2 transcriptional reporter assay, gene expression analysis, mineralization assay in MSC cultures","journal":"Stem cells international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with defined transcriptional and differentiation phenotypes, single lab","pmids":["23840221"],"is_preprint":false},{"year":2018,"finding":"p53 directly regulates GAS7 gene expression; GAS7 associates with CYFIP1 and the WAVE2 complex to suppress breast cancer metastasis by blocking CYFIP1–Rac1 interaction, actin polymerization, and β1-integrin/FAK/Src signaling.","method":"ChIP/transcriptional analysis establishing p53 regulation of GAS7, co-immunoprecipitation of GAS7 with CYFIP1/WAVE2, Rac1 interaction assay, actin polymerization assay, signaling pathway analysis by Western blot","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, signaling pathway analysis, and functional metastasis assays, single lab, multiple orthogonal methods","pmids":["29706651"],"is_preprint":false},{"year":2019,"finding":"The GAS7 F-BAR domain forms two-dimensional sheet-like assemblies on flat membranes through unique hydrophilic loops; this assembly is required for phagocytic cup formation in macrophages, and mutations of the hydrophilic loops abolish both membrane localization of GAS7 and phagocytosis.","method":"Super-resolution microscopy, cryo-EM/electron microscopy of GAS7 on liposomes, site-directed mutagenesis of hydrophilic loops, phagocytosis assay in macrophages, membrane localization assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — structural analysis by super-resolution and EM, mutagenesis of functional loops, and direct functional readout in macrophage phagocytosis assay","pmids":["31628328"],"is_preprint":false},{"year":2019,"finding":"The hGas7c SH3 domain adopts a typical β-barrel fold but exhibits a non-canonical ligand-binding mode, with chemical shift perturbations localized to the RT-loop rather than the canonical hydrophobic pockets, indicating distinctive ligand-binding specificity.","method":"Solution NMR structure determination, NMR titration with proline-rich peptide P41 and phage-display-selected peptides","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structure with ligand binding validation, single lab but multiple ligands tested","pmids":["31296381"],"is_preprint":false},{"year":2020,"finding":"Gas7 localizes to mitochondria in neurons; Gas7 knockout leads to mitochondrial elongation and perinuclear clustering, increased mitochondrial fusion proteins, increased PKA-dependent phosphorylation of Drp-1, and reduced PINK1 expression and PINK1-mediated phosphorylation of Mfn-2, Parkin, and ubiquitin; ectopic Gas7 expression restores normal mitochondrial morphology and PINK1 levels.","method":"Gas7-knockout mouse, subcellular fractionation, immunofluorescence colocalization, Western blot for fusion/fission proteins and phospho-targets, ectopic Gas7 rescue in null neurons","journal":"FASEB bioAdvances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockout mouse with rescue, subcellular fractionation, multiple molecular readouts, single lab","pmids":["32161906"],"is_preprint":false},{"year":2021,"finding":"GAS7 deficiency accelerates metastasis in MYCN-driven neuroblastoma by downregulating genes involved in cell-cell interaction and disrupting contact among tumor cells, and is associated with increased MYCN protein levels; GAS7 expression is suppressed by MYCN amplification.","method":"Zebrafish and mammalian GAS7-deficient neuroblastoma models with MYCN overexpression/amplification, expression profiling, ultrastructural analysis, in vivo metastasis assay","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two model organisms (zebrafish and mammalian), genetic loss-of-function with defined metastasis phenotype, expression analysis, single lab","pmids":["33602789"],"is_preprint":false},{"year":2023,"finding":"Gas7 acts as a novel dendritic spine initiation factor; upon neuronal activation, Gas7 clusters at spine initiation hotspots in a PI3K-dependent manner requiring an intact F-BAR domain, recruits N-WASP and actin via Arp2/3 complex, and promotes new dendritic spine formation; Gas7 overexpression increases and knockdown decreases spine density in hippocampal neurons.","method":"Bicuculline activation of organotypic hippocampal slices, live imaging, PI3K inhibitor experiments, F-BAR domain mutants, N-WASP and actin colocalization, Arp2/3 inhibition, gain- and loss-of-function spine density quantification","journal":"eNeuro","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function in primary neurons with multiple orthogonal methods, domain mutants, chemical inhibitors, single lab","pmids":["36963834"],"is_preprint":false},{"year":2023,"finding":"GAS7 inhibits HCC cell proliferation and migration, induces cell cycle arrest, apoptosis, and autophagy, and enhances oxaliplatin sensitivity by inhibiting the PI3K/Akt signaling pathway; transcription factor Sp1 is responsible for inhibiting Gas7 expression in HCC.","method":"Functional cell assays (proliferation, migration, apoptosis, autophagy), Western blot for PI3K/Akt pathway, Sp1 transcription factor analysis, oxaliplatin sensitivity assay","journal":"Cellular signalling","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, standard functional assays without reconstitution or structural validation of the PI3K/Akt mechanism","pmids":["37769891"],"is_preprint":false},{"year":2026,"finding":"PHF20 interacts with GAS7 and promotes its ubiquitin-mediated degradation; loss of PHF20 stabilizes GAS7, which is associated with increased nuclear F-actin assembly and impaired DNA damage repair, sensitizing cutaneous squamous cell carcinoma cells to chemotherapy.","method":"Co-immunoprecipitation, ubiquitination assay, PHF20 knockdown and GAS7 stabilization measurement, nuclear F-actin imaging, DNA damage assay, in vivo tumor xenograft","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, in vitro and in vivo functional readouts, single lab, multiple methods","pmids":["42215448"],"is_preprint":false}],"current_model":"GAS7 is an F-BAR/FCH domain-containing cytoskeletal regulator that directly binds F-actin via its C-terminal domain to promote actin polymerization and crosslinking, forms two-dimensional sheet-like assemblies on flat membranes through unique hydrophilic loops to drive phagocytic cup formation in macrophages, interacts with N-WASP via WW-Pro domains to recruit the Arp2/3 complex (Cdc42-independently) for neurite outgrowth and dendritic spine initiation in neurons, stabilizes tubulin sheet intermediates to promote microtubule polymerization, localizes to mitochondria and controls mitochondrial dynamics via the PINK1/Drp-1/Mfn-2 axis, associates with CYFIP1/WAVE2 to suppress Rac1-driven actin polymerization and metastasis, is subject to ubiquitin-mediated degradation by PHF20, and is transcriptionally regulated by p53 and Sp1."},"narrative":{"mechanistic_narrative":"GAS7 is an F-BAR/FCH domain-containing cytoskeletal regulator that couples membrane remodeling to actin and microtubule dynamics during cellular morphogenesis [PMID:11795944, PMID:31628328]. It binds F-actin directly through its C-terminal domain, localizes to membrane ruffles, and promotes actin assembly and filament crosslinking to drive membrane outgrowth [PMID:11795944], while its F-BAR domain forms two-dimensional sheet-like assemblies on flat membranes via unique hydrophilic loops that are required for phagocytic cup formation in macrophages [PMID:31628328]. GAS7 also stabilizes tubulin sheet intermediates to promote processive microtubule elongation [PMID:19580814]. In neurons, GAS7 physically interacts with N-WASP through its WW-Pro module and recruits the Arp2/3 complex in a Cdc42-independent manner to generate membrane protrusions, neurite outgrowth, and activity-dependent dendritic spine initiation, the latter requiring an intact F-BAR domain and PI3K signaling [PMID:20150425, PMID:36963834]. These activities underlie its established role in neuronal morphological differentiation, including NGF-promoted neurite outgrowth [PMID:9736752, PMID:14515354], and Gas7-deficient mice display motor neuron loss and neuromuscular defects [PMID:22662195]. Distinct isoforms with different domain content (FCH-only versus WW+FCH) elicit lamellipodia versus filopodia [PMID:15948147]. GAS7 additionally localizes to mitochondria and controls mitochondrial morphology through the PINK1/Drp-1/Mfn-2 axis [PMID:32161906], and in cancer it acts as a metastasis suppressor by associating with CYFIP1/WAVE2 to block CYFIP1–Rac1 interaction and integrin/FAK/Src signaling [PMID:29706651, PMID:33602789]. GAS7 expression and stability are tuned by p53 [PMID:29706651], Sp1 [PMID:37769891], MYCN [PMID:33602789], and PHF20-mediated ubiquitin degradation [PMID:42215448]. The MLL-GAS7 fusion transforms hematopoietic progenitors to cause mixed-lineage leukemia through a dimerization-dependent mechanism acting upstream of Hoxa7/Hoxa9 [PMID:12620410, PMID:15070702].","teleology":[{"year":1998,"claim":"Established that GAS7 has a direct cellular role in neuronal morphogenesis rather than being a passive growth-arrest marker.","evidence":"Antisense inhibition in primary cerebellar cultures and overexpression in neuroblastoma cells","pmids":["9736752"],"confidence":"Medium","gaps":["No molecular mechanism for how GAS7 promotes neurite outgrowth identified","No binding partners or cytoskeletal substrate defined"]},{"year":1999,"claim":"Resolved the gene architecture, defining tissue-specific isoforms with distinct N-termini that would later explain functional divergence.","evidence":"RNase protection, genomic BAC characterization, and cDNA cloning","pmids":["10552931"],"confidence":"Medium","gaps":["Functional differences between isoforms not yet tested","Domain-level activities undefined"]},{"year":2002,"claim":"Identified the molecular basis of GAS7's morphogenic activity by showing direct F-actin binding and actin assembly/crosslinking driving membrane outgrowth.","evidence":"F-actin affinity chromatography, purified protein binding assay, cytochalasin D, EM, and domain-deletion overexpression","pmids":["11795944"],"confidence":"High","gaps":["Did not connect actin activity to a defined nucleation machinery","Membrane-shaping role of F-BAR domain not yet established"]},{"year":2003,"claim":"Placed GAS7 within NGF-induced neuronal differentiation as an early intermediary, linking external trophic signaling to morphological change.","evidence":"Overexpression and antisense knockdown in PC12 cells with NGF stimulation","pmids":["14515354"],"confidence":"Medium","gaps":["Upstream signaling connecting NGF to GAS7 not mapped","No effector identified downstream of GAS7"]},{"year":2003,"claim":"Demonstrated that GAS7 contributes oncogenic potential as an MLL fusion partner, transforming hematopoietic progenitors via dimerization.","evidence":"Retroviral transduction/transplantation in mice and colony-forming assays","pmids":["12620410"],"confidence":"Medium","gaps":["Role of native GAS7 sequence versus dimerization motif not dissected","Relationship to normal GAS7 cytoskeletal function unclear"]},{"year":2004,"claim":"Positioned Hoxa7/Hoxa9 as downstream effectors of MLL-GAS7 leukemogenesis through genetic epistasis.","evidence":"Retroviral transduction/transplantation in Hoxa7/Hoxa9 knockout mice","pmids":["15070702"],"confidence":"Medium","gaps":["Hox loss only modulated latency/penetrance, not abolishing transformation","Additional downstream targets not defined"]},{"year":2005,"claim":"Linked specific GAS7 domains to distinct protrusion morphologies, indicating modular control of cytoskeletal output.","evidence":"Isoform-specific construct transfection in Neuro-2a and SH-SY5Y cells","pmids":["15948147"],"confidence":"Medium","gaps":["Molecular partners of WW versus FCH domains not identified here","Mechanism converting domain identity to filopodia/lamellipodia unresolved"]},{"year":2008,"claim":"Extended GAS7 function to mesenchymal lineage commitment, placing Gas7b downstream of ERK1/2 and SOX9 in chondrogenesis.","evidence":"Antisense/siRNA knockdown, ERK inhibitor PD98059, and aggregate chondrogenesis assays in human MSCs","pmids":["18455446"],"confidence":"Medium","gaps":["Direct GAS7 effectors in chondrocytes not identified","Cytoskeletal mechanism in this context not tested"]},{"year":2009,"claim":"Revealed a second cytoskeletal activity—stabilization of tubulin sheet intermediates—broadening GAS7 from an actin to a dual cytoskeletal regulator.","evidence":"In vitro microtubule polymerization with purified Gas7, dark-field and electron microscopy","pmids":["19580814"],"confidence":"High","gaps":["Domain responsible for tubulin binding not mapped","In vivo relevance of microtubule activity not established"]},{"year":2010,"claim":"Defined the actin-nucleation mechanism by showing GAS7 binds N-WASP via WW-Pro and recruits Arp2/3 independently of Cdc42.","evidence":"Reciprocal Co-IP, domain mutants, Arp2/3 recruitment, Cdc42 dominant-negative, and siRNA in hippocampal neurons","pmids":["20150425"],"confidence":"High","gaps":["How GAS7 activates N-WASP biochemically not resolved","Spatial trigger for the interaction in neurons not defined"]},{"year":2012,"claim":"Provided organismal validation that GAS7 is required for motor neuron maintenance and neuromuscular function.","evidence":"Gas7-deficient mouse motor testing, histomorphometry, and NMJ analysis","pmids":["22662195"],"confidence":"Medium","gaps":["Cell-autonomous versus systemic basis of motor defect unclear","Molecular pathway linking GAS7 loss to neuron loss not defined"]},{"year":2013,"claim":"Showed GAS7 drives osteoblast differentiation upstream of Runx2, extending its lineage-specification role.","evidence":"shRNA knockdown and overexpression with Runx2 reporter and mineralization assays in MSCs","pmids":["23840221"],"confidence":"Medium","gaps":["Mechanism connecting cytoskeletal GAS7 to Runx2 transcription unknown","Direct molecular intermediates not identified"]},{"year":2018,"claim":"Established GAS7 as a p53-regulated metastasis suppressor acting through CYFIP1/WAVE2 to restrain Rac1-driven actin and integrin signaling.","evidence":"Transcriptional analysis of p53 regulation, Co-IP with CYFIP1/WAVE2, Rac1 interaction and actin polymerization assays in breast cancer","pmids":["29706651"],"confidence":"Medium","gaps":["Structural basis for blocking CYFIP1–Rac1 not defined","Reconciliation with GAS7's pro-actin activities elsewhere unresolved"]},{"year":2019,"claim":"Defined the membrane-shaping mechanism: F-BAR sheet-like assembly on flat membranes via hydrophilic loops drives macrophage phagocytic cup formation.","evidence":"Super-resolution and cryo-EM on liposomes, hydrophilic-loop mutagenesis, and phagocytosis assays","pmids":["31628328"],"confidence":"High","gaps":["How sheet assembly coordinates with actin machinery at the cup not fully mapped","Regulation of loop-mediated membrane binding unknown"]},{"year":2019,"claim":"Structurally characterized the GAS7 SH3 domain, revealing a non-canonical RT-loop ligand-binding mode distinct from typical SH3 pockets.","evidence":"Solution NMR structure with proline-rich and phage-display peptide titrations","pmids":["31296381"],"confidence":"High","gaps":["Physiological SH3 ligands not identified","Functional role of the SH3 domain in cells untested"]},{"year":2020,"claim":"Uncovered a non-cytoskeletal role: GAS7 controls mitochondrial morphology through the PINK1/Drp-1/Mfn-2 axis in neurons.","evidence":"Gas7-knockout mouse with fractionation, phospho-protein Western blots, and ectopic rescue in null neurons","pmids":["32161906"],"confidence":"Medium","gaps":["Whether GAS7 acts directly on mitochondrial machinery or indirectly unknown","Link between cytoskeletal and mitochondrial functions unresolved"]},{"year":2021,"claim":"Showed GAS7 suppresses metastasis in MYCN-driven neuroblastoma by maintaining cell-cell contact, and is repressed by MYCN.","evidence":"Zebrafish and mammalian GAS7-deficient neuroblastoma models with expression profiling and in vivo metastasis assays","pmids":["33602789"],"confidence":"Medium","gaps":["Direct cell-contact genes mediating the effect not pinpointed","Mechanism of MYCN repression of GAS7 not defined"]},{"year":2023,"claim":"Identified GAS7 as an activity-dependent dendritic spine initiation factor requiring PI3K signaling and an intact F-BAR domain.","evidence":"Bicuculline activation of hippocampal slices, live imaging, PI3K inhibition, F-BAR mutants, and spine density quantification","pmids":["36963834"],"confidence":"Medium","gaps":["How PI3K triggers GAS7 clustering biochemically not defined","Link between spine initiation and synaptic function not measured"]},{"year":2023,"claim":"Reported GAS7 as a tumor suppressor in HCC acting via PI3K/Akt inhibition and repressed by Sp1.","evidence":"Functional proliferation/migration/apoptosis/autophagy assays and Sp1 analysis in HCC cells","pmids":["37769891"],"confidence":"Low","gaps":["PI3K/Akt mechanism not validated by reconstitution or structure","Direct versus indirect effect of GAS7 on the pathway unresolved"]},{"year":2026,"claim":"Defined post-translational control of GAS7 by PHF20-mediated ubiquitin degradation, linking GAS7 stability to nuclear F-actin and DNA damage repair.","evidence":"Co-IP, ubiquitination assay, PHF20 knockdown, nuclear F-actin imaging, DNA damage assay, and xenografts in cutaneous SCC","pmids":["42215448"],"confidence":"Medium","gaps":["E3 ligase machinery directing GAS7 ubiquitination not identified","Mechanism by which nuclear GAS7 F-actin impairs repair unresolved"]},{"year":null,"claim":"How GAS7's distinct activities—actin assembly, microtubule stabilization, F-BAR membrane shaping, mitochondrial control, and nuclear F-actin—are integrated and switched in a context-dependent manner remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model linking cytoplasmic cytoskeletal and nuclear/mitochondrial roles","Domain-level determinants of context selection not mapped","Regulatory switches controlling pro- versus anti-actin behavior unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[2,9]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[9,12]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[13]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,13]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[2,8]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[15]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,9,17]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[13]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,12,16]}],"complexes":["WAVE2 complex (CYFIP1/WAVE2)"],"partners":["WASL","ACTR2/ACTR3 (ARP2/3)","CYFIP1","WAVE2","PHF20","TUBB"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O60861","full_name":"Growth arrest-specific protein 7","aliases":[],"length_aa":476,"mass_kda":54.4,"function":"May play a role in promoting maturation and morphological differentiation of cerebellar neurons","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/O60861/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GAS7","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/GAS7","total_profiled":1310},"omim":[{"mim_id":"603127","title":"GROWTH ARREST-SPECIFIC 7; GAS7","url":"https://www.omim.org/entry/603127"},{"mim_id":"601665","title":"OBESITY","url":"https://www.omim.org/entry/601665"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Actin filaments","reliability":"Additional"},{"location":"Focal adhesion sites","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":176.2}],"url":"https://www.proteinatlas.org/search/GAS7"},"hgnc":{"alias_symbol":["KIAA0394","MGC1348"],"prev_symbol":[]},"alphafold":{"accession":"O60861","domains":[{"cath_id":"2.30.30.40","chopping":"3-59","consensus_level":"high","plddt":87.0254,"start":3,"end":59},{"cath_id":"-","chopping":"174-219","consensus_level":"medium","plddt":89.9589,"start":174,"end":219},{"cath_id":"1.20.1270.60","chopping":"224-266_287-443","consensus_level":"high","plddt":96.8982,"start":224,"end":443}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O60861","model_url":"https://alphafold.ebi.ac.uk/files/AF-O60861-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O60861-F1-predicted_aligned_error_v6.png","plddt_mean":83.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GAS7","jax_strain_url":"https://www.jax.org/strain/search?query=GAS7"},"sequence":{"accession":"O60861","fasta_url":"https://rest.uniprot.org/uniprotkb/O60861.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O60861/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O60861"}},"corpus_meta":[{"pmid":"12620410","id":"PMC_12620410","title":"MLL-GAS7 transforms multipotent hematopoietic progenitors and induces mixed lineage leukemias in mice.","date":"2003","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/12620410","citation_count":160,"is_preprint":false},{"pmid":"15070702","id":"PMC_15070702","title":"Leukemic transformation of hematopoietic progenitors by MLL-GAS7 in the absence of Hoxa7 or Hoxa9.","date":"2003","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/15070702","citation_count":133,"is_preprint":false},{"pmid":"9736752","id":"PMC_9736752","title":"gas7: A gene expressed preferentially in growth-arrested fibroblasts and terminally differentiated Purkinje neurons affects neurite formation.","date":"1998","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/9736752","citation_count":85,"is_preprint":false},{"pmid":"10706619","id":"PMC_10706619","title":"Detection of leukemia-associated MLL-GAS7 translocation early during chemotherapy with DNA topoisomerase II inhibitors.","date":"2000","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/10706619","citation_count":85,"is_preprint":false},{"pmid":"11795944","id":"PMC_11795944","title":"Association of the growth-arrest-specific protein Gas7 with F-actin induces reorganization of microfilaments and promotes membrane outgrowth.","date":"2002","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/11795944","citation_count":59,"is_preprint":false},{"pmid":"20150425","id":"PMC_20150425","title":"Gas7 functions with N-WASP to regulate the neurite outgrowth of hippocampal neurons.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20150425","citation_count":48,"is_preprint":false},{"pmid":"29706651","id":"PMC_29706651","title":"Wild-type p53 upregulates an early onset breast cancer-associated gene GAS7 to suppress 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expressed in brain and regulated following kainate-induced neuronal injury.","date":"2005","source":"Journal of neuroscience research","url":"https://pubmed.ncbi.nlm.nih.gov/15657892","citation_count":11,"is_preprint":false},{"pmid":"36963834","id":"PMC_36963834","title":"Gas7 Is a Novel Dendritic Spine Initiation Factor.","date":"2023","source":"eNeuro","url":"https://pubmed.ncbi.nlm.nih.gov/36963834","citation_count":10,"is_preprint":false},{"pmid":"38955306","id":"PMC_38955306","title":"Exosomal miR-4516 derived from ovarian cancer stem cells enhanced cisplatin tolerance in ovarian cancer by inhibiting GAS7.","date":"2024","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/38955306","citation_count":10,"is_preprint":false},{"pmid":"29022762","id":"PMC_29022762","title":"Polymorphism rs11656696 in GAS7 Is Not Associated with Primary Open Angle Glaucoma in a Saudi Cohort.","date":"2017","source":"Genetic testing and molecular biomarkers","url":"https://pubmed.ncbi.nlm.nih.gov/29022762","citation_count":10,"is_preprint":false},{"pmid":"35400990","id":"PMC_35400990","title":"Association of ABCA1 (rs2472493) and GAS7 (rs9913911) gene variants with primary open-angle glaucoma in a Brazilian population.","date":"2022","source":"Molecular vision","url":"https://pubmed.ncbi.nlm.nih.gov/35400990","citation_count":7,"is_preprint":false},{"pmid":"23086717","id":"PMC_23086717","title":"Identification and functional characterization of zebrafish Gas7 gene in early development.","date":"2012","source":"Journal of neuroscience research","url":"https://pubmed.ncbi.nlm.nih.gov/23086717","citation_count":7,"is_preprint":false},{"pmid":"37769891","id":"PMC_37769891","title":"Gas7 attenuates hepatocellular carcinoma progression and chemoresistance through the PI3K/Akt signaling pathway.","date":"2023","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/37769891","citation_count":6,"is_preprint":false},{"pmid":"31269845","id":"PMC_31269845","title":"Association of polymorphism rs11656696 in GAS7 with primary open-Angle Glaucoma in a Chinese Population.","date":"2019","source":"Ophthalmic genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31269845","citation_count":6,"is_preprint":false},{"pmid":"30687465","id":"PMC_30687465","title":"Neuronal localization of GAS7 within human brain tissue: Implications for schizophrenia research.","date":"2018","source":"Neurology international","url":"https://pubmed.ncbi.nlm.nih.gov/30687465","citation_count":6,"is_preprint":false},{"pmid":"34914337","id":"PMC_34914337","title":"Predicting the possible effect of miR-203a-3p and miR-29a-3p on DNMT3B and GAS7 genes expression.","date":"2021","source":"Journal of integrative bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/34914337","citation_count":4,"is_preprint":false},{"pmid":"16078223","id":"PMC_16078223","title":"Expression of GAS7 in childhood CNS tumors.","date":"2006","source":"Pediatric blood & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/16078223","citation_count":4,"is_preprint":false},{"pmid":"34087781","id":"PMC_34087781","title":"Loss of Gas7 Is a Key Metastatic Switch in Neuroblastoma.","date":"2021","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/34087781","citation_count":4,"is_preprint":false},{"pmid":"38429909","id":"PMC_38429909","title":"Adipose stem cell-derived exosomes promote wound healing by regulating the let-7i-5p/GAS7 axis.","date":"2024","source":"Journal of cosmetic dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/38429909","citation_count":3,"is_preprint":false},{"pmid":"31935346","id":"PMC_31935346","title":"Immunolocalization of Gas7 in the Subgranular Zone of Mice 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Analysis.","date":"2022","source":"Cureus","url":"https://pubmed.ncbi.nlm.nih.gov/35411287","citation_count":2,"is_preprint":false},{"pmid":"31724358","id":"PMC_31724358","title":"[Effect of electroacupuncture on expressions of Gas7 and NGF in arcular nucleus of rats with focal cerebral ischemia].","date":"2019","source":"Zhongguo zhen jiu = Chinese acupuncture & moxibustion","url":"https://pubmed.ncbi.nlm.nih.gov/31724358","citation_count":1,"is_preprint":false},{"pmid":"38240248","id":"PMC_38240248","title":"Single-nucleotide polymorphisms of TLR4 and GAS7 linked to primary open-angle glaucoma among patients of Shenyang, China.","date":"2024","source":"Experimental biology and medicine (Maywood, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/38240248","citation_count":0,"is_preprint":false},{"pmid":"42136960","id":"PMC_42136960","title":"Role of Macrophage-Related Genes GAS7 and ZEB2 in Acute Myocardial Infarction Pathogenesis.","date":"2026","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/42136960","citation_count":0,"is_preprint":false},{"pmid":"41086893","id":"PMC_41086893","title":"A novel long non-coding RNA, Lnc-GAS7, modulates myosin heavy chain isoform switching via AMPK signaling in ovine muscle.","date":"2025","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/41086893","citation_count":0,"is_preprint":false},{"pmid":"31296381","id":"PMC_31296381","title":"Solution NMR structure and ligand identification of human Gas7 SH3 domain reveal a typical SH3 fold but a non-canonical ligand-binding mode.","date":"2019","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/31296381","citation_count":0,"is_preprint":false},{"pmid":"42215448","id":"PMC_42215448","title":"PHF20 stabilizes the GAS7-F-actin axis to drive DNA damage repair and chemoresistance in cutaneous squamous cell carcinoma.","date":"2026","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/42215448","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":23657,"output_tokens":4929,"usd":0.072453,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13264,"output_tokens":5553,"usd":0.102572,"stage2_stop_reason":"end_turn"},"total_usd":0.175025,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"GAS7 inhibition in terminally differentiating cerebellar cultures impedes neurite outgrowth from maturing Purkinje cells, and GAS7 overexpression in undifferentiated neuroblastoma cells promotes neurite-like outgrowth, establishing a direct role for GAS7 in neuronal morphological differentiation.\",\n      \"method\": \"In situ hybridization, immunocytochemistry, antisense inhibition in primary cerebellar cultures, overexpression in neuroblastoma cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function (antisense) with defined cellular phenotype and gain-of-function overexpression, single lab, two orthogonal approaches\",\n      \"pmids\": [\"9736752\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The Gas7 gene encodes two protein isoforms (Gas7 and Gas7-cb) by alternative splicing from distinct 5' exons; Gas7 is predominant in cerebrum and growth-arrested fibroblasts, while Gas7-cb is predominant in cerebellum, with unique N-terminal sequences.\",\n      \"method\": \"RNase protection assay, Western blot, genomic BAC characterization, cDNA cloning\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal molecular methods in single lab establishing isoform structure and differential expression\",\n      \"pmids\": [\"10552931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"GAS7 directly binds F-actin via its C-terminal domain, localizes near the plasma membrane in membrane ruffles via its C-terminal domain, promotes actin assembly and crosslinking of actin filaments, and induces membrane outgrowth requiring actin polymerization.\",\n      \"method\": \"F-actin affinity chromatography, purified His-Gas7 direct binding assay, cytochalasin D treatment, electron microscopy, ectopic overexpression with domain deletion mutants\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with purified protein, direct binding assay, domain mutagenesis, EM, and functional inhibitor experiment across multiple orthogonal methods\",\n      \"pmids\": [\"11795944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"MLL-GAS7 fusion protein transforms multipotent hematopoietic progenitors and impairs their differentiation while enhancing in vitro growth, and induces mixed lineage leukemias in mice, acting through a dimerization-dependent mechanism.\",\n      \"method\": \"Retroviral transduction/transplantation assay in mice, in vitro colony-forming assays, immunophenotyping\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — retroviral transduction plus in vivo transplantation with defined leukemia phenotypes, single lab, multiple readouts\",\n      \"pmids\": [\"12620410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"GAS7 overexpression in PC12 cells induces expanded cell morphology and spike-like processes resembling early neurite formation; endogenous rat Gas7 is transiently elevated prior to NGF-promoted neurite outgrowth; antisense inhibition of Gas7 reduces NGF-promoted neurite outgrowths, establishing Gas7 as an early-stage intermediary in NGF-induced neuronal differentiation.\",\n      \"method\": \"Overexpression in PC12 cells, antisense oligonucleotide knockdown, NGF stimulation assay, RT-PCR\",\n      \"journal\": \"Journal of neuroscience research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function experiments with defined morphological phenotype, single lab, two orthogonal approaches\",\n      \"pmids\": [\"14515354\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Hoxa7 and Hoxa9 contribute to MLL-GAS7-mediated leukemogenesis as downstream targets; Hoxa7/9 deficiency does not abolish transformation by MLL-GAS7 but increases disease latency and reduces penetrance, placing these Hox genes downstream of MLL-GAS7 in the leukemogenic pathway.\",\n      \"method\": \"Retroviral transduction/transplantation in Hoxa7- and Hoxa9-knockout mice, in vitro colony-forming assays, epistasis analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis using knockout mice with defined disease phenotype endpoints, single lab\",\n      \"pmids\": [\"15070702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Human GAS7 isoforms hGas7-a (FCH domain only) and hGas7-b (WW + FCH domains) differentially induce neurite-like processes: hGas7-a preferentially elicits lamellipodia, while hGas7-b elicits filopodia, implicating the WW domain in filopodia and the FCH domain in lamellipodia formation.\",\n      \"method\": \"Transfection of Neuro-2a and SH-SY5Y cells with isoform-specific constructs, quantitative PCR, protein expression analysis\",\n      \"journal\": \"Journal of neuroscience research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — isoform overexpression with morphological phenotype scoring, single lab, two cell lines used\",\n      \"pmids\": [\"15948147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"GAS7b expression is transiently upregulated during chondrogenic differentiation of human MSCs downstream of ERK1/2 and SOX9 signaling; antisense inhibition of hGas7b impairs chondrogenesis, but Gas7b inhibition does not affect the p-ERK/SOX9 pathway, placing Gas7b downstream of ERK1/2 and SOX9.\",\n      \"method\": \"Antisense oligonucleotides, siRNA knockdown of SOX9, ERK inhibitor PD98059, aggregate culture chondrogenesis assay, Western blot, RT-PCR\",\n      \"journal\": \"Osteoarthritis and cartilage\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic/chemical epistasis with multiple inhibitors and loss-of-function, defined phenotypic readouts, single lab\",\n      \"pmids\": [\"18455446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Gas7 stabilizes tubulin sheet intermediates during microtubule polymerization, promoting microtubule elongation without catastrophe; in the absence of Gas7, sheet-like structures were rarely observed and were fragile, demonstrating that Gas7 enhances microtubule polymerization by stabilizing sheet intermediates.\",\n      \"method\": \"Dark-field microscopy real-time observation, electron microscopy, in vitro microtubule polymerization assay with and without Gas7\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with purified components, real-time optical microscopy and electron microscopy, multiple orthogonal methods\",\n      \"pmids\": [\"19580814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Gas7 co-localizes and physically interacts with N-WASP via WW-Pro domain interaction (not SH3-Pro) in growth cones of hippocampal neurons and recruits the Arp2/3 complex in a Cdc42-independent manner to promote membrane protrusions and neurite outgrowth.\",\n      \"method\": \"Co-immunoprecipitation, co-localization in Neuro-2a cells and hippocampal neurons, domain mutant analysis, Arp2/3 recruitment assay, Cdc42 dominant-negative experiment, siRNA knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, domain mapping, loss-of-function siRNA with defined neurite phenotype, Cdc42-independence established, multiple orthogonal methods\",\n      \"pmids\": [\"20150425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Gas7-deficient mice show age-dependent motor activity defects associated with decreased spinal motor neuron numbers, reduced muscle strength, altered muscle fiber composition (fewer fast fibers in soleus), and reduced nerve terminal sprouting at neuromuscular junctions.\",\n      \"method\": \"Gas7-deficient mouse genetic model, motor function testing, histomorphometry, MHC I/II immunostaining, NMJ analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout mouse with multiple defined cellular and morphological phenotypes, single lab\",\n      \"pmids\": [\"22662195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Gas7 knockdown using shRNA decreases Runx2 expression and its target genes (alkaline phosphatase, type I collagen, osteocalcin, osteopontin) and reduces mineralization; ectopic Gas7 expression induces Runx2-dependent transcriptional activity and osteoblast differentiation, establishing Gas7 as a regulator of osteogenesis upstream of Runx2.\",\n      \"method\": \"shRNA knockdown, ectopic overexpression, Runx2 transcriptional reporter assay, gene expression analysis, mineralization assay in MSC cultures\",\n      \"journal\": \"Stem cells international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with defined transcriptional and differentiation phenotypes, single lab\",\n      \"pmids\": [\"23840221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"p53 directly regulates GAS7 gene expression; GAS7 associates with CYFIP1 and the WAVE2 complex to suppress breast cancer metastasis by blocking CYFIP1–Rac1 interaction, actin polymerization, and β1-integrin/FAK/Src signaling.\",\n      \"method\": \"ChIP/transcriptional analysis establishing p53 regulation of GAS7, co-immunoprecipitation of GAS7 with CYFIP1/WAVE2, Rac1 interaction assay, actin polymerization assay, signaling pathway analysis by Western blot\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, signaling pathway analysis, and functional metastasis assays, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"29706651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The GAS7 F-BAR domain forms two-dimensional sheet-like assemblies on flat membranes through unique hydrophilic loops; this assembly is required for phagocytic cup formation in macrophages, and mutations of the hydrophilic loops abolish both membrane localization of GAS7 and phagocytosis.\",\n      \"method\": \"Super-resolution microscopy, cryo-EM/electron microscopy of GAS7 on liposomes, site-directed mutagenesis of hydrophilic loops, phagocytosis assay in macrophages, membrane localization assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structural analysis by super-resolution and EM, mutagenesis of functional loops, and direct functional readout in macrophage phagocytosis assay\",\n      \"pmids\": [\"31628328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The hGas7c SH3 domain adopts a typical β-barrel fold but exhibits a non-canonical ligand-binding mode, with chemical shift perturbations localized to the RT-loop rather than the canonical hydrophobic pockets, indicating distinctive ligand-binding specificity.\",\n      \"method\": \"Solution NMR structure determination, NMR titration with proline-rich peptide P41 and phage-display-selected peptides\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure with ligand binding validation, single lab but multiple ligands tested\",\n      \"pmids\": [\"31296381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Gas7 localizes to mitochondria in neurons; Gas7 knockout leads to mitochondrial elongation and perinuclear clustering, increased mitochondrial fusion proteins, increased PKA-dependent phosphorylation of Drp-1, and reduced PINK1 expression and PINK1-mediated phosphorylation of Mfn-2, Parkin, and ubiquitin; ectopic Gas7 expression restores normal mitochondrial morphology and PINK1 levels.\",\n      \"method\": \"Gas7-knockout mouse, subcellular fractionation, immunofluorescence colocalization, Western blot for fusion/fission proteins and phospho-targets, ectopic Gas7 rescue in null neurons\",\n      \"journal\": \"FASEB bioAdvances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout mouse with rescue, subcellular fractionation, multiple molecular readouts, single lab\",\n      \"pmids\": [\"32161906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GAS7 deficiency accelerates metastasis in MYCN-driven neuroblastoma by downregulating genes involved in cell-cell interaction and disrupting contact among tumor cells, and is associated with increased MYCN protein levels; GAS7 expression is suppressed by MYCN amplification.\",\n      \"method\": \"Zebrafish and mammalian GAS7-deficient neuroblastoma models with MYCN overexpression/amplification, expression profiling, ultrastructural analysis, in vivo metastasis assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two model organisms (zebrafish and mammalian), genetic loss-of-function with defined metastasis phenotype, expression analysis, single lab\",\n      \"pmids\": [\"33602789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Gas7 acts as a novel dendritic spine initiation factor; upon neuronal activation, Gas7 clusters at spine initiation hotspots in a PI3K-dependent manner requiring an intact F-BAR domain, recruits N-WASP and actin via Arp2/3 complex, and promotes new dendritic spine formation; Gas7 overexpression increases and knockdown decreases spine density in hippocampal neurons.\",\n      \"method\": \"Bicuculline activation of organotypic hippocampal slices, live imaging, PI3K inhibitor experiments, F-BAR domain mutants, N-WASP and actin colocalization, Arp2/3 inhibition, gain- and loss-of-function spine density quantification\",\n      \"journal\": \"eNeuro\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function in primary neurons with multiple orthogonal methods, domain mutants, chemical inhibitors, single lab\",\n      \"pmids\": [\"36963834\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"GAS7 inhibits HCC cell proliferation and migration, induces cell cycle arrest, apoptosis, and autophagy, and enhances oxaliplatin sensitivity by inhibiting the PI3K/Akt signaling pathway; transcription factor Sp1 is responsible for inhibiting Gas7 expression in HCC.\",\n      \"method\": \"Functional cell assays (proliferation, migration, apoptosis, autophagy), Western blot for PI3K/Akt pathway, Sp1 transcription factor analysis, oxaliplatin sensitivity assay\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, standard functional assays without reconstitution or structural validation of the PI3K/Akt mechanism\",\n      \"pmids\": [\"37769891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"PHF20 interacts with GAS7 and promotes its ubiquitin-mediated degradation; loss of PHF20 stabilizes GAS7, which is associated with increased nuclear F-actin assembly and impaired DNA damage repair, sensitizing cutaneous squamous cell carcinoma cells to chemotherapy.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, PHF20 knockdown and GAS7 stabilization measurement, nuclear F-actin imaging, DNA damage assay, in vivo tumor xenograft\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, in vitro and in vivo functional readouts, single lab, multiple methods\",\n      \"pmids\": [\"42215448\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GAS7 is an F-BAR/FCH domain-containing cytoskeletal regulator that directly binds F-actin via its C-terminal domain to promote actin polymerization and crosslinking, forms two-dimensional sheet-like assemblies on flat membranes through unique hydrophilic loops to drive phagocytic cup formation in macrophages, interacts with N-WASP via WW-Pro domains to recruit the Arp2/3 complex (Cdc42-independently) for neurite outgrowth and dendritic spine initiation in neurons, stabilizes tubulin sheet intermediates to promote microtubule polymerization, localizes to mitochondria and controls mitochondrial dynamics via the PINK1/Drp-1/Mfn-2 axis, associates with CYFIP1/WAVE2 to suppress Rac1-driven actin polymerization and metastasis, is subject to ubiquitin-mediated degradation by PHF20, and is transcriptionally regulated by p53 and Sp1.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"GAS7 is an F-BAR/FCH domain-containing cytoskeletal regulator that couples membrane remodeling to actin and microtubule dynamics during cellular morphogenesis [#2, #13]. It binds F-actin directly through its C-terminal domain, localizes to membrane ruffles, and promotes actin assembly and filament crosslinking to drive membrane outgrowth [#2], while its F-BAR domain forms two-dimensional sheet-like assemblies on flat membranes via unique hydrophilic loops that are required for phagocytic cup formation in macrophages [#13]. GAS7 also stabilizes tubulin sheet intermediates to promote processive microtubule elongation [#8]. In neurons, GAS7 physically interacts with N-WASP through its WW-Pro module and recruits the Arp2/3 complex in a Cdc42-independent manner to generate membrane protrusions, neurite outgrowth, and activity-dependent dendritic spine initiation, the latter requiring an intact F-BAR domain and PI3K signaling [#9, #17]. These activities underlie its established role in neuronal morphological differentiation, including NGF-promoted neurite outgrowth [#0, #4], and Gas7-deficient mice display motor neuron loss and neuromuscular defects [#10]. Distinct isoforms with different domain content (FCH-only versus WW+FCH) elicit lamellipodia versus filopodia [#6]. GAS7 additionally localizes to mitochondria and controls mitochondrial morphology through the PINK1/Drp-1/Mfn-2 axis [#15], and in cancer it acts as a metastasis suppressor by associating with CYFIP1/WAVE2 to block CYFIP1–Rac1 interaction and integrin/FAK/Src signaling [#12, #16]. GAS7 expression and stability are tuned by p53 [#12], Sp1 [#18], MYCN [#16], and PHF20-mediated ubiquitin degradation [#19]. The MLL-GAS7 fusion transforms hematopoietic progenitors to cause mixed-lineage leukemia through a dimerization-dependent mechanism acting upstream of Hoxa7/Hoxa9 [#3, #5].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established that GAS7 has a direct cellular role in neuronal morphogenesis rather than being a passive growth-arrest marker.\",\n      \"evidence\": \"Antisense inhibition in primary cerebellar cultures and overexpression in neuroblastoma cells\",\n      \"pmids\": [\"9736752\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular mechanism for how GAS7 promotes neurite outgrowth identified\", \"No binding partners or cytoskeletal substrate defined\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Resolved the gene architecture, defining tissue-specific isoforms with distinct N-termini that would later explain functional divergence.\",\n      \"evidence\": \"RNase protection, genomic BAC characterization, and cDNA cloning\",\n      \"pmids\": [\"10552931\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional differences between isoforms not yet tested\", \"Domain-level activities undefined\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identified the molecular basis of GAS7's morphogenic activity by showing direct F-actin binding and actin assembly/crosslinking driving membrane outgrowth.\",\n      \"evidence\": \"F-actin affinity chromatography, purified protein binding assay, cytochalasin D, EM, and domain-deletion overexpression\",\n      \"pmids\": [\"11795944\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not connect actin activity to a defined nucleation machinery\", \"Membrane-shaping role of F-BAR domain not yet established\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Placed GAS7 within NGF-induced neuronal differentiation as an early intermediary, linking external trophic signaling to morphological change.\",\n      \"evidence\": \"Overexpression and antisense knockdown in PC12 cells with NGF stimulation\",\n      \"pmids\": [\"14515354\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Upstream signaling connecting NGF to GAS7 not mapped\", \"No effector identified downstream of GAS7\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Demonstrated that GAS7 contributes oncogenic potential as an MLL fusion partner, transforming hematopoietic progenitors via dimerization.\",\n      \"evidence\": \"Retroviral transduction/transplantation in mice and colony-forming assays\",\n      \"pmids\": [\"12620410\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Role of native GAS7 sequence versus dimerization motif not dissected\", \"Relationship to normal GAS7 cytoskeletal function unclear\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Positioned Hoxa7/Hoxa9 as downstream effectors of MLL-GAS7 leukemogenesis through genetic epistasis.\",\n      \"evidence\": \"Retroviral transduction/transplantation in Hoxa7/Hoxa9 knockout mice\",\n      \"pmids\": [\"15070702\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Hox loss only modulated latency/penetrance, not abolishing transformation\", \"Additional downstream targets not defined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Linked specific GAS7 domains to distinct protrusion morphologies, indicating modular control of cytoskeletal output.\",\n      \"evidence\": \"Isoform-specific construct transfection in Neuro-2a and SH-SY5Y cells\",\n      \"pmids\": [\"15948147\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular partners of WW versus FCH domains not identified here\", \"Mechanism converting domain identity to filopodia/lamellipodia unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Extended GAS7 function to mesenchymal lineage commitment, placing Gas7b downstream of ERK1/2 and SOX9 in chondrogenesis.\",\n      \"evidence\": \"Antisense/siRNA knockdown, ERK inhibitor PD98059, and aggregate chondrogenesis assays in human MSCs\",\n      \"pmids\": [\"18455446\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct GAS7 effectors in chondrocytes not identified\", \"Cytoskeletal mechanism in this context not tested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Revealed a second cytoskeletal activity—stabilization of tubulin sheet intermediates—broadening GAS7 from an actin to a dual cytoskeletal regulator.\",\n      \"evidence\": \"In vitro microtubule polymerization with purified Gas7, dark-field and electron microscopy\",\n      \"pmids\": [\"19580814\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Domain responsible for tubulin binding not mapped\", \"In vivo relevance of microtubule activity not established\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined the actin-nucleation mechanism by showing GAS7 binds N-WASP via WW-Pro and recruits Arp2/3 independently of Cdc42.\",\n      \"evidence\": \"Reciprocal Co-IP, domain mutants, Arp2/3 recruitment, Cdc42 dominant-negative, and siRNA in hippocampal neurons\",\n      \"pmids\": [\"20150425\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How GAS7 activates N-WASP biochemically not resolved\", \"Spatial trigger for the interaction in neurons not defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Provided organismal validation that GAS7 is required for motor neuron maintenance and neuromuscular function.\",\n      \"evidence\": \"Gas7-deficient mouse motor testing, histomorphometry, and NMJ analysis\",\n      \"pmids\": [\"22662195\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell-autonomous versus systemic basis of motor defect unclear\", \"Molecular pathway linking GAS7 loss to neuron loss not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed GAS7 drives osteoblast differentiation upstream of Runx2, extending its lineage-specification role.\",\n      \"evidence\": \"shRNA knockdown and overexpression with Runx2 reporter and mineralization assays in MSCs\",\n      \"pmids\": [\"23840221\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting cytoskeletal GAS7 to Runx2 transcription unknown\", \"Direct molecular intermediates not identified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established GAS7 as a p53-regulated metastasis suppressor acting through CYFIP1/WAVE2 to restrain Rac1-driven actin and integrin signaling.\",\n      \"evidence\": \"Transcriptional analysis of p53 regulation, Co-IP with CYFIP1/WAVE2, Rac1 interaction and actin polymerization assays in breast cancer\",\n      \"pmids\": [\"29706651\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis for blocking CYFIP1–Rac1 not defined\", \"Reconciliation with GAS7's pro-actin activities elsewhere unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined the membrane-shaping mechanism: F-BAR sheet-like assembly on flat membranes via hydrophilic loops drives macrophage phagocytic cup formation.\",\n      \"evidence\": \"Super-resolution and cryo-EM on liposomes, hydrophilic-loop mutagenesis, and phagocytosis assays\",\n      \"pmids\": [\"31628328\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How sheet assembly coordinates with actin machinery at the cup not fully mapped\", \"Regulation of loop-mediated membrane binding unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Structurally characterized the GAS7 SH3 domain, revealing a non-canonical RT-loop ligand-binding mode distinct from typical SH3 pockets.\",\n      \"evidence\": \"Solution NMR structure with proline-rich and phage-display peptide titrations\",\n      \"pmids\": [\"31296381\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological SH3 ligands not identified\", \"Functional role of the SH3 domain in cells untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Uncovered a non-cytoskeletal role: GAS7 controls mitochondrial morphology through the PINK1/Drp-1/Mfn-2 axis in neurons.\",\n      \"evidence\": \"Gas7-knockout mouse with fractionation, phospho-protein Western blots, and ectopic rescue in null neurons\",\n      \"pmids\": [\"32161906\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether GAS7 acts directly on mitochondrial machinery or indirectly unknown\", \"Link between cytoskeletal and mitochondrial functions unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed GAS7 suppresses metastasis in MYCN-driven neuroblastoma by maintaining cell-cell contact, and is repressed by MYCN.\",\n      \"evidence\": \"Zebrafish and mammalian GAS7-deficient neuroblastoma models with expression profiling and in vivo metastasis assays\",\n      \"pmids\": [\"33602789\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct cell-contact genes mediating the effect not pinpointed\", \"Mechanism of MYCN repression of GAS7 not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified GAS7 as an activity-dependent dendritic spine initiation factor requiring PI3K signaling and an intact F-BAR domain.\",\n      \"evidence\": \"Bicuculline activation of hippocampal slices, live imaging, PI3K inhibition, F-BAR mutants, and spine density quantification\",\n      \"pmids\": [\"36963834\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How PI3K triggers GAS7 clustering biochemically not defined\", \"Link between spine initiation and synaptic function not measured\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Reported GAS7 as a tumor suppressor in HCC acting via PI3K/Akt inhibition and repressed by Sp1.\",\n      \"evidence\": \"Functional proliferation/migration/apoptosis/autophagy assays and Sp1 analysis in HCC cells\",\n      \"pmids\": [\"37769891\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"PI3K/Akt mechanism not validated by reconstitution or structure\", \"Direct versus indirect effect of GAS7 on the pathway unresolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined post-translational control of GAS7 by PHF20-mediated ubiquitin degradation, linking GAS7 stability to nuclear F-actin and DNA damage repair.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, PHF20 knockdown, nuclear F-actin imaging, DNA damage assay, and xenografts in cutaneous SCC\",\n      \"pmids\": [\"42215448\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase machinery directing GAS7 ubiquitination not identified\", \"Mechanism by which nuclear GAS7 F-actin impairs repair unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How GAS7's distinct activities—actin assembly, microtubule stabilization, F-BAR membrane shaping, mitochondrial control, and nuclear F-actin—are integrated and switched in a context-dependent manner remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model linking cytoplasmic cytoskeletal and nuclear/mitochondrial roles\", \"Domain-level determinants of context selection not mapped\", \"Regulatory switches controlling pro- versus anti-actin behavior unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [2, 9]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [9, 12]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 13]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [2, 8]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 9, 17]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 12, 16]}\n    ],\n    \"complexes\": [\"WAVE2 complex (CYFIP1/WAVE2)\"],\n    \"partners\": [\"WASL\", \"ACTR2/ACTR3 (Arp2/3)\", \"CYFIP1\", \"WAVE2\", \"PHF20\", \"TUBB\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}