{"gene":"GPM6A","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":2016,"finding":"GPM6a-induced neuronal filopodium formation requires a signaling pathway involving coronin-1a (Coro1a), Rac1, and p21-activated kinase 1 (Pak1). Coro1a associates with Gpm6a (shown by co-immunoprecipitation), co-localizes with Gpm6a in F-actin-enriched regions of hippocampal neurons, and co-immunoprecipitates with Rac1 together with Gpm6a. Dominant-negative Coro1a or Coro1a siRNA knockdown interferes with Gpm6a-induced filopodium formation. Pharmacological inhibition of Rac1 or co-expression with GDP-bound (inactive) Rac1 reduces filopodium formation; Gpm6a also facilitates Rac1 membrane recruitment. Kinase activity of Pak1 is required downstream of Rac1 for Gpm6a-induced filopodium formation.","method":"Co-immunoprecipitation, immunofluorescence microscopy, dominant-negative expression, siRNA knockdown, pharmacological inhibition (Rac1 inhibitor), GDP-bound Rac1 co-expression","journal":"Journal of neurochemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, dominant-negative, siRNA, pharmacological inhibition) in a single focused mechanistic study establishing pathway order","pmids":["26809475"],"is_preprint":false},{"year":2018,"finding":"The C-terminal cytosolic tail of Gpm6a is required for filopodium formation; specifically residues K250, K255, and E258 are essential. Deletion of the C-terminus (but not N-terminus) abolishes filopodium induction and diminishes Gpm6a association with clathrin, implicating clathrin-mediated trafficking. Both truncation mutants reduce surface levels of Gpm6a without altering total expression. Alanine substitution of K255 and E258 also reduces total protein, and all three key residues are predicted as part of sorting signals of transmembrane proteins.","method":"Alanine scanning mutagenesis, truncation mutants, immunofluorescence microscopy, flow cytometry (cell surface quantification), colocalization assay with clathrin","journal":"Frontiers in molecular neuroscience","confidence":"High","confidence_rationale":"Tier 1 / Moderate — systematic mutagenesis combined with surface quantification and trafficking assay in a single rigorous study","pmids":["30233315"],"is_preprint":false},{"year":2024,"finding":"Gpm6a is palmitoylated by the DHHC palmitoyltransferases Zdhhc1 and Zdhhc2 at Cys17, Cys18, and Cys246. This palmitoylation is required for Gpm6a to mediate lipid raft formation, which in turn stabilizes the Procr (protein C receptor) protein in adult mammary stem cells. Gpm6a knockout in mice reduces Procr protein stability and impairs mammary stem cell activity and postnatal mammary development.","method":"Gpm6a knockout mouse model, site-directed mutagenesis of palmitoylation sites, lipid raft fractionation, protein stability assays, in vivo mammary development analysis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — knockout mouse combined with mutagenesis of specific palmitoylation sites and lipid raft biochemistry, multiple orthogonal methods in single study","pmids":["39321020"],"is_preprint":false},{"year":2017,"finding":"HDAC5 inhibits neurite elongation at least partially via a MEF2C/GPM6A signaling pathway. GPM6A (M6a) is a direct target gene of the HDAC5-regulated transcription factor MEF2C. miR-124 and miR-9 repress HDAC5, thereby de-repressing MEF2C and increasing GPM6A expression to promote neurite development in differentiated P19 cells and primary neurons.","method":"miRNA overexpression, HDAC5 overexpression/knockdown in P19 cells and primary neurons, reporter assays for MEF2C-GPM6A transcriptional regulation, neurite length measurement","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic pathway established by combined miRNA/HDAC5 manipulation and transcriptional target validation, single lab","pmids":["28332716"],"is_preprint":false},{"year":2014,"finding":"GPM6A/M6 dosage is critical for cognitive function and associates with cholesterol homeostasis. In a Drosophila model, knockdown of M6 (the sole PLP family member in flies) causes wing malformation and lethality; overexpression or loss of M6 in neurons impairs long-term memory. Phenotypes including filopodium-like protrusions in patient-derived lymphoblastoid cells (with GPM6A duplication) and Drosophila M6 knockdown phenotypes are alleviated by cholesterol supplementation, supporting a functional link between GPM6A and cholesterol-rich lipid rafts.","method":"Drosophila M6 knockdown/overexpression (wing and neuron-specific), long-term memory assay (courtship conditioning), cholesterol supplementation rescue, patient-derived lymphoblastoid cell analysis","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic manipulation in intact organism with functional readouts and pharmacological rescue, single lab","pmids":["25224183"],"is_preprint":false},{"year":2024,"finding":"GPM6a interacts with ICAM5 via both cis and trans interactions mediated by GPM6a's extracellular domains. Co-immunoprecipitation and cell aggregation assays in HEK293 cells confirmed physical interaction. In hippocampal neurons, endogenous GPM6a clusters co-localize with ICAM5 clusters in the dendritic shaft. Co-overexpression of GPM6a and ICAM5 additively enhances neurite length, neurite number (in N2a cells), and filopodium formation in neurons.","method":"Co-immunoprecipitation, cell aggregation assay, immunofluorescence co-localization, overexpression in N2a cells and hippocampal neurons","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — reciprocal Co-IP and functional cell aggregation assay plus neuronal phenotype, single lab, multiple methods","pmids":["39352694"],"is_preprint":false},{"year":2025,"finding":"Non-synonymous SNPs (T71P, T76I, M154V, F156Y, R163Q, T210N) within GPM6a's extracellular domains impair GPM6a-induced neuronal plasticity (neurite outgrowth, filopodia formation) without affecting expression level, folding, or general membrane localization, but alter membrane distribution and, in at least one variant, disrupt GPM6a oligomerization. The extracellular domain variants reduce GPM6a's ability to induce cell aggregation, establishing that homophilic cis interactions through extracellular domains are essential for GPM6a function.","method":"Site-directed mutagenesis of nsSNPs, neuronal culture assays (neurite/filopodia quantification), cell aggregation assay, flow cytometry for surface expression","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic mutagenesis of multiple residues with orthogonal functional assays, single lab","pmids":["39938689"],"is_preprint":false},{"year":2009,"finding":"GPM6A expression level directly modulates the differentiation of human ES cell-derived neurons and neuronal migration. Overexpression of GPM6A in human ES cells increases neuroectodermal gene expression, neural stem cell numbers, and production of cholinergic, catecholaminergic, and GABAergic neurons, and enhances neuronal migration. Suppression of GPM6A by shRNA has the opposite effects.","method":"shRNA knockdown, overexpression in human ES cells, real-time PCR, immunocytochemistry, neuronal migration assays","journal":"Stem cells and development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional gain- and loss-of-function in ES-derived neurons with multiple cell-type readouts, single lab","pmids":["19298174"],"is_preprint":false},{"year":2008,"finding":"GPM6A is required for neuronal differentiation of mouse ES cells. shRNA-mediated knockdown of GPM6A in mouse ES cells markedly reduces expression of neuroectodermal genes and decreases the number of neural stem cells and differentiated neurons (cholinergic, catecholaminergic, and GABAergic).","method":"shRNA knockdown in mouse ES cells, real-time PCR, immunocytochemistry","journal":"Stem cells and development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined cellular phenotypes, single lab, consistent with human ES cell study","pmids":["18522499"],"is_preprint":false},{"year":2023,"finding":"GPM6a is required for neurite elongation in rat dorsal root ganglion (DRG) neurons of the peripheral nervous system. Endogenous GPM6a is present on DRG neuron cell surfaces throughout development, and functional experiments (knockdown in vitro) demonstrate that GPM6a is necessary for DRG neurite elongation.","method":"RNA-seq dataset analysis, immunochemistry of DRG cultures, loss-of-function experiments in dissociated DRG neurons","journal":"Biomolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — loss-of-function with defined phenotype in DRG neurons, single lab, single study","pmids":["37189342"],"is_preprint":false},{"year":2023,"finding":"Chronic stress in rats down-regulates hippocampal Gpm6a mRNA, and this is linked to miR-124-3p-mediated modulation of Hdac5 and Mef2c expression. miR-124 overexpression in hippocampal neurons in vitro increases neuronal arborization, Gpm6a, and Mef2c expression while decreasing Hdac5. BDNF treatment elevates miR-124-3p and Gpm6a/Mef2c mRNA while reducing Hdac5.","method":"Chronic restraint stress rat model, qPCR, miR-124 overexpression in hippocampal neurons, BDNF treatment, Sholl analysis of neuronal arborization","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo stress model combined with in vitro miRNA overexpression and BDNF treatment with arborization phenotype, single lab","pmids":["36943192"],"is_preprint":false},{"year":2014,"finding":"GPM6A (isoform 3) overexpression in NIH/3T3 cells alters actin and microtubule networks and induces formation of long filopodia-like protrusions. GPM6A overexpression also confers anchorage-independent growth and enhanced proliferation, suggesting a role in cytoskeletal remodeling.","method":"Overexpression in NIH/3T3 cells, confocal/indirect immunofluorescence microscopy, soft agar colony formation assay, flow cytometry","journal":"Cellular oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — overexpression phenotype in non-neuronal cells, single lab, single study, no mechanistic dissection of cytoskeletal pathway","pmids":["24916915"],"is_preprint":false},{"year":1996,"finding":"The human GPM6A gene encodes a 278-amino-acid transmembrane membrane glycoprotein with specific expression in human brain, and maps to chromosome 4q33→q34.","method":"cDNA cloning, Northern blot, radiation hybrid mapping","journal":"Cytogenetics and cell genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — initial characterization by expression and mapping, no functional mechanism established","pmids":["8893821"],"is_preprint":false}],"current_model":"GPM6a is a four-transmembrane neuronal glycoprotein of the PLP/DM20 family that promotes neurite elongation, filopodium formation, dendritic spine development, and synaptogenesis; filopodium induction requires specific residues (K250, K255, E258) in its C-terminal cytoplasmic tail, involves clathrin-mediated trafficking, and is mechanistically dependent on a coronin-1a/Rac1/Pak1 signaling axis, while its extracellular domains mediate homophilic cis/trans interactions (including with ICAM5) essential for neuronal morphogenesis; GPM6a's activity and membrane targeting are regulated by palmitoylation at Cys17/18/246 by Zdhhc1/Zdhhc2, by transcriptional control through the miR-124/miR-9–HDAC5–MEF2C axis, and by association with cholesterol-rich lipid rafts."},"narrative":{"mechanistic_narrative":"GPM6A is a neuronal four-transmembrane glycoprotein that drives neuronal morphogenesis by promoting neurite elongation, filopodium formation, and the differentiation and migration of stem cell-derived neurons [PMID:19298174, PMID:18522499]. Filopodium induction is governed by its C-terminal cytosolic tail, where residues K250, K255, and E258 function as sorting signals required for clathrin-mediated trafficking and proper surface delivery of the protein [PMID:30233315], and it proceeds through a signaling axis in which GPM6A associates with coronin-1a, facilitates Rac1 membrane recruitment, and requires downstream Pak1 kinase activity [PMID:26809475]. Its extracellular domains mediate homophilic cis/trans interactions and a physical interaction with ICAM5 that additively enhances neurite outgrowth and filopodia, while non-synonymous variants in these domains impair oligomerization, cell aggregation, and plasticity without altering expression or folding [PMID:39352694, PMID:39938689]. GPM6A activity depends on its association with cholesterol-rich lipid rafts, which it organizes through palmitoylation at Cys17/18/246 by the palmitoyltransferases Zdhhc1 and Zdhhc2; in mammary stem cells this raft-forming activity stabilizes the Procr receptor, demonstrating a role beyond neurons [PMID:39321020, PMID:25224183]. GPM6A expression is transcriptionally controlled by a miR-124/miR-9–HDAC5–MEF2C axis, with GPM6A a direct MEF2C target gene that is downregulated by chronic stress and induced by BDNF [PMID:28332716, PMID:36943192].","teleology":[{"year":1996,"claim":"Establishing GPM6A's basic identity was the prerequisite for any functional study, defining it as a brain-specific transmembrane glycoprotein.","evidence":"cDNA cloning, Northern blot, and radiation hybrid mapping of the human gene","pmids":["8893821"],"confidence":"Low","gaps":["No functional mechanism established","Cellular localization beyond brain tissue expression not defined"]},{"year":2008,"claim":"Loss-of-function in ES cells answered whether GPM6A is merely a marker or causally required for neuronal differentiation, establishing it as necessary for neuroectodermal gene expression and neuron production.","evidence":"shRNA knockdown in mouse ES cells with qPCR and immunocytochemistry","pmids":["18522499"],"confidence":"Medium","gaps":["Molecular mechanism of differentiation control not defined","Single direction (loss-of-function) in mouse"]},{"year":2009,"claim":"Bidirectional manipulation in human ES cells confirmed GPM6A as a dosage-dependent regulator of neuronal differentiation and migration across multiple neuron subtypes.","evidence":"shRNA knockdown and overexpression in human ES cells, with neuronal migration assays","pmids":["19298174"],"confidence":"Medium","gaps":["Downstream effectors of migration not identified","Single lab"]},{"year":2014,"claim":"Linking GPM6A to cholesterol homeostasis addressed how the protein operates at the membrane, tying its dosage to cognition and rescuable phenotypes via cholesterol-rich rafts.","evidence":"Drosophila M6 knockdown/overexpression, long-term memory assays, cholesterol rescue, and patient lymphoblastoid cells","pmids":["25224183"],"confidence":"Medium","gaps":["Direct molecular basis of cholesterol dependence not resolved","Reliance on fly ortholog for in vivo phenotypes"]},{"year":2016,"claim":"Identifying the coronin-1a/Rac1/Pak1 axis answered how GPM6A transduces a membrane signal into actin-based filopodium formation, ordering the pathway downstream of the protein.","evidence":"Co-IP, dominant-negative expression, siRNA, and Rac1 pharmacological inhibition in hippocampal neurons","pmids":["26809475"],"confidence":"High","gaps":["How GPM6A physically engages coronin-1a/Rac1 at the membrane unresolved","Link to extracellular interactions not connected"]},{"year":2017,"claim":"Placing GPM6A as a direct MEF2C target answered how its expression is transcriptionally tuned during neurite development via the miR-124/miR-9–HDAC5 cascade.","evidence":"miRNA and HDAC5 manipulation in P19 cells/primary neurons with MEF2C-GPM6A reporter assays","pmids":["28332716"],"confidence":"Medium","gaps":["Direct MEF2C binding site mapping limited","Single lab"]},{"year":2018,"claim":"Mapping the C-terminal sorting residues answered which part of GPM6A controls filopodium induction, tying activity to clathrin-mediated trafficking and surface delivery.","evidence":"Alanine scanning, truncation mutants, flow cytometry surface quantification, and clathrin colocalization","pmids":["30233315"],"confidence":"High","gaps":["Identity of the adaptor recognizing the sorting signal not defined","Connection between trafficking and the Rac1 axis not established"]},{"year":2023,"claim":"Extension to PNS neurons tested whether GPM6A's neurite role is restricted to CNS, showing it is required for DRG neurite elongation.","evidence":"RNA-seq, immunochemistry, and loss-of-function in dissociated rat DRG neurons","pmids":["37189342"],"confidence":"Medium","gaps":["Pathway components in DRG not dissected","Single study"]},{"year":2023,"claim":"Connecting chronic stress to GPM6A regulation answered how environmental input feeds the transcriptional axis, with BDNF and miR-124-3p modulating Hdac5/Mef2c and GPM6A levels.","evidence":"Chronic restraint stress rat model, miR-124 overexpression, BDNF treatment, and Sholl analysis","pmids":["36943192"],"confidence":"Medium","gaps":["Causal contribution of GPM6A to stress phenotypes not isolated","Single lab"]},{"year":2024,"claim":"Defining palmitoylation by Zdhhc1/Zdhhc2 answered how GPM6A organizes lipid rafts and revealed a non-neuronal role stabilizing Procr in mammary stem cells.","evidence":"Gpm6a knockout mouse, palmitoylation-site mutagenesis, lipid raft fractionation, and in vivo mammary analysis","pmids":["39321020"],"confidence":"High","gaps":["Whether raft/palmitoylation mechanism underlies neuronal functions not tested","Generality of Procr-like clients unknown"]},{"year":2024,"claim":"Identifying the GPM6A–ICAM5 cis/trans interaction answered what extracellular partner couples homophilic adhesion to neuronal morphogenesis.","evidence":"Reciprocal Co-IP, cell aggregation assay, and colocalization/overexpression in N2a and hippocampal neurons","pmids":["39352694"],"confidence":"Medium","gaps":["Whether ICAM5 binding feeds the intracellular Rac1 axis not shown","Single lab"]},{"year":2025,"claim":"Functional dissection of extracellular nsSNPs established that homophilic cis interactions via the extracellular domains are required for GPM6A-induced plasticity.","evidence":"Site-directed mutagenesis of multiple variants with neurite/filopodia, aggregation, and surface-expression assays","pmids":["39938689"],"confidence":"Medium","gaps":["Structural basis of oligomerization not resolved","Disease causality of variants not established"]},{"year":null,"claim":"How extracellular homophilic/ICAM5 engagement, C-terminal trafficking, lipid-raft palmitoylation, and the coronin-1a/Rac1/Pak1 axis are integrated into a single mechanistic chain remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model connecting adhesion, trafficking, and actin signaling","No structural model of GPM6A oligomers or its complexes","Direct neuronal requirement for palmitoylation/raft activity untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[5,6]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[2,4]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,11]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,2,5,9]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[7,8]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,9]}],"complexes":[],"partners":["CORO1A","RAC1","PAK1","ICAM5","ZDHHC1","ZDHHC2","CLTC"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P51674","full_name":"Neuronal membrane glycoprotein M6-a","aliases":[],"length_aa":278,"mass_kda":31.2,"function":"Involved in neuronal differentiation, including differentiation and migration of neuronal stem cells. Plays a role in neuronal plasticity and is involved in neurite and filopodia outgrowth, filopodia motility and probably synapse formation. GPM6A-induced filopodia formation involves mitogen-activated protein kinase (MAPK) and Src signaling pathways. May be involved in neuronal NGF-dependent Ca(2+) influx. May be involved in regulation of endocytosis and intracellular trafficking of G-protein-coupled receptors (GPCRs); enhances internalization and recycling of mu-type opioid receptor","subcellular_location":"Cell membrane; Cell projection, axon; Cell projection, growth cone; Cell projection, dendritic spine; Cell projection, filopodium; Cell projection, neuron projection","url":"https://www.uniprot.org/uniprotkb/P51674/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GPM6A","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/GPM6A","total_profiled":1310},"omim":[{"mim_id":"612165","title":"RETINITIS PIGMENTOSA 29; RP29","url":"https://www.omim.org/entry/612165"},{"mim_id":"601275","title":"GLYCOPROTEIN M6A; GPM6A","url":"https://www.omim.org/entry/601275"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":614.0}],"url":"https://www.proteinatlas.org/search/GPM6A"},"hgnc":{"alias_symbol":[],"prev_symbol":["GPM6"]},"alphafold":{"accession":"P51674","domains":[{"cath_id":"-","chopping":"30-147_206-244","consensus_level":"high","plddt":86.837,"start":30,"end":244}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P51674","model_url":"https://alphafold.ebi.ac.uk/files/AF-P51674-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P51674-F1-predicted_aligned_error_v6.png","plddt_mean":82.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GPM6A","jax_strain_url":"https://www.jax.org/strain/search?query=GPM6A"},"sequence":{"accession":"P51674","fasta_url":"https://rest.uniprot.org/uniprotkb/P51674.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P51674/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P51674"}},"corpus_meta":[{"pmid":"28332716","id":"PMC_28332716","title":"miR-124 and miR-9 mediated downregulation of HDAC5 promotes neurite development through activating MEF2C-GPM6A pathway.","date":"2017","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/28332716","citation_count":62,"is_preprint":false},{"pmid":"19298174","id":"PMC_19298174","title":"Human GPM6A is associated with differentiation and neuronal migration of neurons derived from human embryonic stem cells.","date":"2009","source":"Stem cells and development","url":"https://pubmed.ncbi.nlm.nih.gov/19298174","citation_count":46,"is_preprint":false},{"pmid":"18522499","id":"PMC_18522499","title":"Inhibition of mouse GPM6A expression leads to decreased differentiation of neurons derived from mouse embryonic stem cells.","date":"2008","source":"Stem cells and development","url":"https://pubmed.ncbi.nlm.nih.gov/18522499","citation_count":34,"is_preprint":false},{"pmid":"35002514","id":"PMC_35002514","title":"CircCCNB1 silencing acting as a miR-106b-5p sponge inhibited GPM6A expression to promote HCC progression by enhancing DYNC1I1 expression and activating the AKT/ERK signaling pathway.","date":"2022","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35002514","citation_count":29,"is_preprint":false},{"pmid":"25224183","id":"PMC_25224183","title":"Altered GPM6A/M6 dosage impairs cognition and causes phenotypes responsive to cholesterol in human and Drosophila.","date":"2014","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/25224183","citation_count":28,"is_preprint":false},{"pmid":"26809475","id":"PMC_26809475","title":"Neuronal filopodium formation induced by the membrane glycoprotein M6a (Gpm6a) is facilitated by coronin-1a, Rac1, and p21-activated kinase 1 (Pak1).","date":"2016","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26809475","citation_count":21,"is_preprint":false},{"pmid":"24916915","id":"PMC_24916915","title":"Identification of GPM6A and GPM6B as potential new human lymphoid leukemia-associated oncogenes.","date":"2014","source":"Cellular oncology (Dordrecht, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/24916915","citation_count":19,"is_preprint":false},{"pmid":"37189342","id":"PMC_37189342","title":"Endogenous Glycoprotein GPM6a Is Involved in Neurite Outgrowth in Rat Dorsal Root Ganglion Neurons.","date":"2023","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/37189342","citation_count":9,"is_preprint":false},{"pmid":"36943192","id":"PMC_36943192","title":"Role of miR-124-3p in regulatory mechanisms of Gpm6a expression in the hippocampus of chronically stressed rats.","date":"2023","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/36943192","citation_count":9,"is_preprint":false},{"pmid":"39321020","id":"PMC_39321020","title":"Zdhhc1- and Zdhhc2-mediated Gpm6a palmitoylation is essential for maintenance of mammary stem cell activity.","date":"2024","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/39321020","citation_count":8,"is_preprint":false},{"pmid":"35918602","id":"PMC_35918602","title":"GPM6A expression is suppressed in hepatocellular carcinoma through miRNA-96 production.","date":"2022","source":"Laboratory investigation; 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Molecular cell research","url":"https://pubmed.ncbi.nlm.nih.gov/39938689","citation_count":0,"is_preprint":false},{"pmid":"35528814","id":"PMC_35528814","title":"Association of Variants in COMT, RASSF1 and GPM6A with the Risk of Paranoid Schizophrenia Patients in Prof HB Saanin Psychiatric Hospital, West Sumatra, Indonesia.","date":"2022","source":"The Malaysian journal of medical sciences : MJMS","url":"https://pubmed.ncbi.nlm.nih.gov/35528814","citation_count":0,"is_preprint":false},{"pmid":"31333318","id":"PMC_31333318","title":"Retraction Note: Construction of Gpm6a/ReelinGFPCreERT2 by BAC recombination using a specific gene in hepatic mesothelial or stellate cells.","date":"2019","source":"World journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/31333318","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14043,"output_tokens":3753,"usd":0.049212,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11392,"output_tokens":3731,"usd":0.075118,"stage2_stop_reason":"end_turn"},"total_usd":0.12433,"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\": 2016,\n      \"finding\": \"GPM6a-induced neuronal filopodium formation requires a signaling pathway involving coronin-1a (Coro1a), Rac1, and p21-activated kinase 1 (Pak1). Coro1a associates with Gpm6a (shown by co-immunoprecipitation), co-localizes with Gpm6a in F-actin-enriched regions of hippocampal neurons, and co-immunoprecipitates with Rac1 together with Gpm6a. Dominant-negative Coro1a or Coro1a siRNA knockdown interferes with Gpm6a-induced filopodium formation. Pharmacological inhibition of Rac1 or co-expression with GDP-bound (inactive) Rac1 reduces filopodium formation; Gpm6a also facilitates Rac1 membrane recruitment. Kinase activity of Pak1 is required downstream of Rac1 for Gpm6a-induced filopodium formation.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence microscopy, dominant-negative expression, siRNA knockdown, pharmacological inhibition (Rac1 inhibitor), GDP-bound Rac1 co-expression\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, dominant-negative, siRNA, pharmacological inhibition) in a single focused mechanistic study establishing pathway order\",\n      \"pmids\": [\"26809475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The C-terminal cytosolic tail of Gpm6a is required for filopodium formation; specifically residues K250, K255, and E258 are essential. Deletion of the C-terminus (but not N-terminus) abolishes filopodium induction and diminishes Gpm6a association with clathrin, implicating clathrin-mediated trafficking. Both truncation mutants reduce surface levels of Gpm6a without altering total expression. Alanine substitution of K255 and E258 also reduces total protein, and all three key residues are predicted as part of sorting signals of transmembrane proteins.\",\n      \"method\": \"Alanine scanning mutagenesis, truncation mutants, immunofluorescence microscopy, flow cytometry (cell surface quantification), colocalization assay with clathrin\",\n      \"journal\": \"Frontiers in molecular neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic mutagenesis combined with surface quantification and trafficking assay in a single rigorous study\",\n      \"pmids\": [\"30233315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Gpm6a is palmitoylated by the DHHC palmitoyltransferases Zdhhc1 and Zdhhc2 at Cys17, Cys18, and Cys246. This palmitoylation is required for Gpm6a to mediate lipid raft formation, which in turn stabilizes the Procr (protein C receptor) protein in adult mammary stem cells. Gpm6a knockout in mice reduces Procr protein stability and impairs mammary stem cell activity and postnatal mammary development.\",\n      \"method\": \"Gpm6a knockout mouse model, site-directed mutagenesis of palmitoylation sites, lipid raft fractionation, protein stability assays, in vivo mammary development analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — knockout mouse combined with mutagenesis of specific palmitoylation sites and lipid raft biochemistry, multiple orthogonal methods in single study\",\n      \"pmids\": [\"39321020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"HDAC5 inhibits neurite elongation at least partially via a MEF2C/GPM6A signaling pathway. GPM6A (M6a) is a direct target gene of the HDAC5-regulated transcription factor MEF2C. miR-124 and miR-9 repress HDAC5, thereby de-repressing MEF2C and increasing GPM6A expression to promote neurite development in differentiated P19 cells and primary neurons.\",\n      \"method\": \"miRNA overexpression, HDAC5 overexpression/knockdown in P19 cells and primary neurons, reporter assays for MEF2C-GPM6A transcriptional regulation, neurite length measurement\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic pathway established by combined miRNA/HDAC5 manipulation and transcriptional target validation, single lab\",\n      \"pmids\": [\"28332716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"GPM6A/M6 dosage is critical for cognitive function and associates with cholesterol homeostasis. In a Drosophila model, knockdown of M6 (the sole PLP family member in flies) causes wing malformation and lethality; overexpression or loss of M6 in neurons impairs long-term memory. Phenotypes including filopodium-like protrusions in patient-derived lymphoblastoid cells (with GPM6A duplication) and Drosophila M6 knockdown phenotypes are alleviated by cholesterol supplementation, supporting a functional link between GPM6A and cholesterol-rich lipid rafts.\",\n      \"method\": \"Drosophila M6 knockdown/overexpression (wing and neuron-specific), long-term memory assay (courtship conditioning), cholesterol supplementation rescue, patient-derived lymphoblastoid cell analysis\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic manipulation in intact organism with functional readouts and pharmacological rescue, single lab\",\n      \"pmids\": [\"25224183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GPM6a interacts with ICAM5 via both cis and trans interactions mediated by GPM6a's extracellular domains. Co-immunoprecipitation and cell aggregation assays in HEK293 cells confirmed physical interaction. In hippocampal neurons, endogenous GPM6a clusters co-localize with ICAM5 clusters in the dendritic shaft. Co-overexpression of GPM6a and ICAM5 additively enhances neurite length, neurite number (in N2a cells), and filopodium formation in neurons.\",\n      \"method\": \"Co-immunoprecipitation, cell aggregation assay, immunofluorescence co-localization, overexpression in N2a cells and hippocampal neurons\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — reciprocal Co-IP and functional cell aggregation assay plus neuronal phenotype, single lab, multiple methods\",\n      \"pmids\": [\"39352694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Non-synonymous SNPs (T71P, T76I, M154V, F156Y, R163Q, T210N) within GPM6a's extracellular domains impair GPM6a-induced neuronal plasticity (neurite outgrowth, filopodia formation) without affecting expression level, folding, or general membrane localization, but alter membrane distribution and, in at least one variant, disrupt GPM6a oligomerization. The extracellular domain variants reduce GPM6a's ability to induce cell aggregation, establishing that homophilic cis interactions through extracellular domains are essential for GPM6a function.\",\n      \"method\": \"Site-directed mutagenesis of nsSNPs, neuronal culture assays (neurite/filopodia quantification), cell aggregation assay, flow cytometry for surface expression\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic mutagenesis of multiple residues with orthogonal functional assays, single lab\",\n      \"pmids\": [\"39938689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"GPM6A expression level directly modulates the differentiation of human ES cell-derived neurons and neuronal migration. Overexpression of GPM6A in human ES cells increases neuroectodermal gene expression, neural stem cell numbers, and production of cholinergic, catecholaminergic, and GABAergic neurons, and enhances neuronal migration. Suppression of GPM6A by shRNA has the opposite effects.\",\n      \"method\": \"shRNA knockdown, overexpression in human ES cells, real-time PCR, immunocytochemistry, neuronal migration assays\",\n      \"journal\": \"Stem cells and development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional gain- and loss-of-function in ES-derived neurons with multiple cell-type readouts, single lab\",\n      \"pmids\": [\"19298174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"GPM6A is required for neuronal differentiation of mouse ES cells. shRNA-mediated knockdown of GPM6A in mouse ES cells markedly reduces expression of neuroectodermal genes and decreases the number of neural stem cells and differentiated neurons (cholinergic, catecholaminergic, and GABAergic).\",\n      \"method\": \"shRNA knockdown in mouse ES cells, real-time PCR, immunocytochemistry\",\n      \"journal\": \"Stem cells and development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined cellular phenotypes, single lab, consistent with human ES cell study\",\n      \"pmids\": [\"18522499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"GPM6a is required for neurite elongation in rat dorsal root ganglion (DRG) neurons of the peripheral nervous system. Endogenous GPM6a is present on DRG neuron cell surfaces throughout development, and functional experiments (knockdown in vitro) demonstrate that GPM6a is necessary for DRG neurite elongation.\",\n      \"method\": \"RNA-seq dataset analysis, immunochemistry of DRG cultures, loss-of-function experiments in dissociated DRG neurons\",\n      \"journal\": \"Biomolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — loss-of-function with defined phenotype in DRG neurons, single lab, single study\",\n      \"pmids\": [\"37189342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Chronic stress in rats down-regulates hippocampal Gpm6a mRNA, and this is linked to miR-124-3p-mediated modulation of Hdac5 and Mef2c expression. miR-124 overexpression in hippocampal neurons in vitro increases neuronal arborization, Gpm6a, and Mef2c expression while decreasing Hdac5. BDNF treatment elevates miR-124-3p and Gpm6a/Mef2c mRNA while reducing Hdac5.\",\n      \"method\": \"Chronic restraint stress rat model, qPCR, miR-124 overexpression in hippocampal neurons, BDNF treatment, Sholl analysis of neuronal arborization\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo stress model combined with in vitro miRNA overexpression and BDNF treatment with arborization phenotype, single lab\",\n      \"pmids\": [\"36943192\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"GPM6A (isoform 3) overexpression in NIH/3T3 cells alters actin and microtubule networks and induces formation of long filopodia-like protrusions. GPM6A overexpression also confers anchorage-independent growth and enhanced proliferation, suggesting a role in cytoskeletal remodeling.\",\n      \"method\": \"Overexpression in NIH/3T3 cells, confocal/indirect immunofluorescence microscopy, soft agar colony formation assay, flow cytometry\",\n      \"journal\": \"Cellular oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — overexpression phenotype in non-neuronal cells, single lab, single study, no mechanistic dissection of cytoskeletal pathway\",\n      \"pmids\": [\"24916915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The human GPM6A gene encodes a 278-amino-acid transmembrane membrane glycoprotein with specific expression in human brain, and maps to chromosome 4q33→q34.\",\n      \"method\": \"cDNA cloning, Northern blot, radiation hybrid mapping\",\n      \"journal\": \"Cytogenetics and cell genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — initial characterization by expression and mapping, no functional mechanism established\",\n      \"pmids\": [\"8893821\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GPM6a is a four-transmembrane neuronal glycoprotein of the PLP/DM20 family that promotes neurite elongation, filopodium formation, dendritic spine development, and synaptogenesis; filopodium induction requires specific residues (K250, K255, E258) in its C-terminal cytoplasmic tail, involves clathrin-mediated trafficking, and is mechanistically dependent on a coronin-1a/Rac1/Pak1 signaling axis, while its extracellular domains mediate homophilic cis/trans interactions (including with ICAM5) essential for neuronal morphogenesis; GPM6a's activity and membrane targeting are regulated by palmitoylation at Cys17/18/246 by Zdhhc1/Zdhhc2, by transcriptional control through the miR-124/miR-9–HDAC5–MEF2C axis, and by association with cholesterol-rich lipid rafts.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"GPM6A is a neuronal four-transmembrane glycoprotein that drives neuronal morphogenesis by promoting neurite elongation, filopodium formation, and the differentiation and migration of stem cell-derived neurons [#7, #8]. Filopodium induction is governed by its C-terminal cytosolic tail, where residues K250, K255, and E258 function as sorting signals required for clathrin-mediated trafficking and proper surface delivery of the protein [#1], and it proceeds through a signaling axis in which GPM6A associates with coronin-1a, facilitates Rac1 membrane recruitment, and requires downstream Pak1 kinase activity [#0]. Its extracellular domains mediate homophilic cis/trans interactions and a physical interaction with ICAM5 that additively enhances neurite outgrowth and filopodia, while non-synonymous variants in these domains impair oligomerization, cell aggregation, and plasticity without altering expression or folding [#5, #6]. GPM6A activity depends on its association with cholesterol-rich lipid rafts, which it organizes through palmitoylation at Cys17/18/246 by the palmitoyltransferases Zdhhc1 and Zdhhc2; in mammary stem cells this raft-forming activity stabilizes the Procr receptor, demonstrating a role beyond neurons [#2, #4]. GPM6A expression is transcriptionally controlled by a miR-124/miR-9–HDAC5–MEF2C axis, with GPM6A a direct MEF2C target gene that is downregulated by chronic stress and induced by BDNF [#3, #10].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Establishing GPM6A's basic identity was the prerequisite for any functional study, defining it as a brain-specific transmembrane glycoprotein.\",\n      \"evidence\": \"cDNA cloning, Northern blot, and radiation hybrid mapping of the human gene\",\n      \"pmids\": [\"8893821\"],\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No functional mechanism established\", \"Cellular localization beyond brain tissue expression not defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Loss-of-function in ES cells answered whether GPM6A is merely a marker or causally required for neuronal differentiation, establishing it as necessary for neuroectodermal gene expression and neuron production.\",\n      \"evidence\": \"shRNA knockdown in mouse ES cells with qPCR and immunocytochemistry\",\n      \"pmids\": [\"18522499\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Molecular mechanism of differentiation control not defined\", \"Single direction (loss-of-function) in mouse\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Bidirectional manipulation in human ES cells confirmed GPM6A as a dosage-dependent regulator of neuronal differentiation and migration across multiple neuron subtypes.\",\n      \"evidence\": \"shRNA knockdown and overexpression in human ES cells, with neuronal migration assays\",\n      \"pmids\": [\"19298174\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Downstream effectors of migration not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Linking GPM6A to cholesterol homeostasis addressed how the protein operates at the membrane, tying its dosage to cognition and rescuable phenotypes via cholesterol-rich rafts.\",\n      \"evidence\": \"Drosophila M6 knockdown/overexpression, long-term memory assays, cholesterol rescue, and patient lymphoblastoid cells\",\n      \"pmids\": [\"25224183\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct molecular basis of cholesterol dependence not resolved\", \"Reliance on fly ortholog for in vivo phenotypes\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identifying the coronin-1a/Rac1/Pak1 axis answered how GPM6A transduces a membrane signal into actin-based filopodium formation, ordering the pathway downstream of the protein.\",\n      \"evidence\": \"Co-IP, dominant-negative expression, siRNA, and Rac1 pharmacological inhibition in hippocampal neurons\",\n      \"pmids\": [\"26809475\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"How GPM6A physically engages coronin-1a/Rac1 at the membrane unresolved\", \"Link to extracellular interactions not connected\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Placing GPM6A as a direct MEF2C target answered how its expression is transcriptionally tuned during neurite development via the miR-124/miR-9–HDAC5 cascade.\",\n      \"evidence\": \"miRNA and HDAC5 manipulation in P19 cells/primary neurons with MEF2C-GPM6A reporter assays\",\n      \"pmids\": [\"28332716\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct MEF2C binding site mapping limited\", \"Single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Mapping the C-terminal sorting residues answered which part of GPM6A controls filopodium induction, tying activity to clathrin-mediated trafficking and surface delivery.\",\n      \"evidence\": \"Alanine scanning, truncation mutants, flow cytometry surface quantification, and clathrin colocalization\",\n      \"pmids\": [\"30233315\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Identity of the adaptor recognizing the sorting signal not defined\", \"Connection between trafficking and the Rac1 axis not established\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extension to PNS neurons tested whether GPM6A's neurite role is restricted to CNS, showing it is required for DRG neurite elongation.\",\n      \"evidence\": \"RNA-seq, immunochemistry, and loss-of-function in dissociated rat DRG neurons\",\n      \"pmids\": [\"37189342\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Pathway components in DRG not dissected\", \"Single study\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connecting chronic stress to GPM6A regulation answered how environmental input feeds the transcriptional axis, with BDNF and miR-124-3p modulating Hdac5/Mef2c and GPM6A levels.\",\n      \"evidence\": \"Chronic restraint stress rat model, miR-124 overexpression, BDNF treatment, and Sholl analysis\",\n      \"pmids\": [\"36943192\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Causal contribution of GPM6A to stress phenotypes not isolated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defining palmitoylation by Zdhhc1/Zdhhc2 answered how GPM6A organizes lipid rafts and revealed a non-neuronal role stabilizing Procr in mammary stem cells.\",\n      \"evidence\": \"Gpm6a knockout mouse, palmitoylation-site mutagenesis, lipid raft fractionation, and in vivo mammary analysis\",\n      \"pmids\": [\"39321020\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Whether raft/palmitoylation mechanism underlies neuronal functions not tested\", \"Generality of Procr-like clients unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identifying the GPM6A–ICAM5 cis/trans interaction answered what extracellular partner couples homophilic adhesion to neuronal morphogenesis.\",\n      \"evidence\": \"Reciprocal Co-IP, cell aggregation assay, and colocalization/overexpression in N2a and hippocampal neurons\",\n      \"pmids\": [\"39352694\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Whether ICAM5 binding feeds the intracellular Rac1 axis not shown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Functional dissection of extracellular nsSNPs established that homophilic cis interactions via the extracellular domains are required for GPM6A-induced plasticity.\",\n      \"evidence\": \"Site-directed mutagenesis of multiple variants with neurite/filopodia, aggregation, and surface-expression assays\",\n      \"pmids\": [\"39938689\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Structural basis of oligomerization not resolved\", \"Disease causality of variants not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How extracellular homophilic/ICAM5 engagement, C-terminal trafficking, lipid-raft palmitoylation, and the coronin-1a/Rac1/Pak1 axis are integrated into a single mechanistic chain remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No unified model connecting adhesion, trafficking, and actin signaling\", \"No structural model of GPM6A oligomers or its complexes\", \"Direct neuronal requirement for palmitoylation/raft activity untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 2, 5, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [7, 8]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CORO1A\", \"RAC1\", \"PAK1\", \"ICAM5\", \"ZDHHC1\", \"ZDHHC2\", \"CLTC\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}