{"gene":"PLCXD2","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2025,"finding":"PLCXD2 is a constitutively active phospholipase C (PLC) family member that forms a postsynaptic signaling complex with the GPCR GPR158; unrestrained PLCXD2 activity (in the absence of GPR158) impedes spine apparatus (SA) incorporation into dendritic spines and hampers structural and functional dendritic spine maturation in mouse cortical neurons in vivo.","method":"Sparse genetic manipulations (loss-of-function) of mouse cortical neurons in vivo; identification of GPR158-PLCXD2 complex; functional readouts of spine apparatus abundance and dendritic spine maturation","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo genetic manipulation with defined cellular phenotype (SA abundance, spine maturation), complex identification, and functional epistasis between GPR158 and PLCXD2 in a single rigorous study","pmids":["40393451"],"is_preprint":false},{"year":2025,"finding":"GPR158 restrains PLCXD2 activity by direct interaction, and extracellular heparan sulfate proteoglycan (HSPG) binding modulates the GPR158-PLCXD2 interaction, providing spatiotemporal control over GPR158 signaling; this represents a direct GPCR-like receptor-to-PLC signaling pathway that bypasses canonical PLC regulation via G proteins.","method":"Complex identification and functional epistasis in cortical neurons in vivo; HSPG binding modulation of the GPR158-PLCXD2 interaction","journal":"Developmental cell","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, mechanistic model supported by in vivo epistasis but HSPG modulation mechanism not yet reconstituted biochemically in the abstract","pmids":["40393451"],"is_preprint":false},{"year":2022,"finding":"PLCXD2 mRNA is a direct target of miR-378a-3p, which suppresses its expression; the lncRNA ACTA2-AS1 acts as a competing endogenous RNA (ceRNA) to sequester miR-378a-3p and thereby de-repress PLCXD2 expression in gastric cancer cells.","method":"RNA pulldown assays, luciferase reporter assays, RNA immunoprecipitation assays, PLCXD2 knockdown rescue experiments","journal":"Open medicine (Warsaw, Poland)","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple orthogonal RNA-based methods (luciferase reporter, RIP, pulldown) in a single lab establishing miR-378a-3p as a repressor of PLCXD2 expression","pmids":["35274046"],"is_preprint":false}],"current_model":"PLCXD2 is a constitutively active phospholipase C that is held in check by direct interaction with the postsynaptic GPCR GPR158 (modulated by extracellular heparan sulfate proteoglycans), such that unrestrained PLCXD2 activity blocks spine apparatus incorporation and dendritic spine maturation; at the post-transcriptional level, PLCXD2 expression is repressed by miR-378a-3p, which can be sequestered by the lncRNA ACTA2-AS1."},"narrative":{"mechanistic_narrative":"PLCXD2 is a constitutively active phospholipase C family member that functions in postsynaptic signaling to control dendritic spine maturation [PMID:40393451]. In mouse cortical neurons, PLCXD2 forms a complex with the postsynaptic GPCR GPR158, which directly restrains its activity; when this restraint is lost, unrestrained PLCXD2 activity impedes incorporation of the spine apparatus into dendritic spines and blocks structural and functional spine maturation [PMID:40393451]. Binding of extracellular heparan sulfate proteoglycans modulates the GPR158-PLCXD2 interaction, defining a direct receptor-to-PLC signaling route that operates independently of canonical G-protein-mediated PLC activation [PMID:40393451]. At the post-transcriptional level, PLCXD2 mRNA is directly repressed by miR-378a-3p, and the lncRNA ACTA2-AS1 sequesters this microRNA as a competing endogenous RNA to de-repress PLCXD2 in gastric cancer cells [PMID:35274046]. Beyond these findings, the catalytic substrate specificity and structural basis of PLCXD2 regulation have not been characterized in the available corpus.","teleology":[{"year":2022,"claim":"Established a post-transcriptional control axis for PLCXD2, answering how its expression level is set in a disease context.","evidence":"RNA pulldown, luciferase reporter, RIP, and knockdown rescue assays in gastric cancer cells","pmids":["35274046"],"confidence":"Medium","gaps":["Single lab; mechanism connecting PLCXD2 level to the cancer phenotype not resolved","No link drawn between this regulatory axis and PLCXD2 catalytic or neuronal function"]},{"year":2025,"claim":"Defined PLCXD2 as a constitutively active PLC whose unrestrained activity blocks spine apparatus incorporation and dendritic spine maturation, identifying its functional role in postsynaptic biology.","evidence":"Sparse in vivo loss-of-function genetic manipulation of mouse cortical neurons with spine apparatus and spine maturation readouts","pmids":["40393451"],"confidence":"High","gaps":["Substrate and lipid second-messenger output of PLCXD2 not defined","Downstream effectors linking PLCXD2 activity to spine apparatus incorporation unknown"]},{"year":2025,"claim":"Showed that GPR158 directly restrains PLCXD2 and that heparan sulfate proteoglycan binding tunes this interaction, establishing a non-canonical GPCR-to-PLC pathway bypassing G proteins.","evidence":"Complex identification and functional epistasis in cortical neurons in vivo with HSPG modulation","pmids":["40393451"],"confidence":"Medium","gaps":["HSPG modulation mechanism not reconstituted biochemically","Structural basis of the GPR158-PLCXD2 interaction not determined","Single lab"]},{"year":null,"claim":"The catalytic substrate, lipid products, and structural mechanism by which GPR158 inhibits PLCXD2 remain undefined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No in vitro reconstitution of PLCXD2 enzymatic activity","No structural model of the inhibitory complex"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0]}],"localization":[],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1]}],"complexes":["GPR158-PLCXD2 postsynaptic signaling complex"],"partners":["GPR158"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q0VAA5","full_name":"PI-PLC X domain-containing protein 2","aliases":["Phospholipase C X-domain containing protein 2","PLCXD-2"],"length_aa":305,"mass_kda":34.8,"function":"Catalyzes the hydrolysis of inositol from phosphatidylinositol (1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol), PI) (PubMed:22732399). Could also hydrolyze various multi-phosphorylated derivatives of PI, such as phosphatidylinositol-4,5 bisphosphate (PIP2), releasing inositol-1,4,5-trisphosphate (IP3) and the protein kinase C activator diacylglycerol (DAG), therefore mediating cell signaling (Probable)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q0VAA5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PLCXD2","classification":"Not Classified","n_dependent_lines":9,"n_total_lines":1208,"dependency_fraction":0.0074503311258278145},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PLCXD2","total_profiled":1310},"omim":[{"mim_id":"617016","title":"PHOSPHOLIPASE C, PHOSPHATIDYLINOSITOL-SPECIFIC, X DOMAIN-CONTAINING PROTEIN 3; PLCXD3","url":"https://www.omim.org/entry/617016"},{"mim_id":"617015","title":"PHOSPHOLIPASE C, PHOSPHATIDYLINOSITOL-SPECIFIC, X DOMAIN-CONTAINING PROTEIN 2; PLCXD2","url":"https://www.omim.org/entry/617015"},{"mim_id":"300974","title":"PHOSPHOLIPASE C, PHOSPHATIDYLINOSITOL-SPECIFIC, X DOMAIN-CONTAINING PROTEIN 1; PLCXD1","url":"https://www.omim.org/entry/300974"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"retina","ntpm":13.7}],"url":"https://www.proteinatlas.org/search/PLCXD2"},"hgnc":{"alias_symbol":["FLJ31579"],"prev_symbol":[]},"alphafold":{"accession":"Q0VAA5","domains":[{"cath_id":"3.20.20.190","chopping":"3-7_31-287","consensus_level":"high","plddt":86.8533,"start":3,"end":287}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q0VAA5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q0VAA5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q0VAA5-F1-predicted_aligned_error_v6.png","plddt_mean":79.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PLCXD2","jax_strain_url":"https://www.jax.org/strain/search?query=PLCXD2"},"sequence":{"accession":"Q0VAA5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q0VAA5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q0VAA5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q0VAA5"}},"corpus_meta":[{"pmid":"35274046","id":"PMC_35274046","title":"lncRNA ACTA2-AS1 inhibits malignant phenotypes of gastric cancer cells.","date":"2022","source":"Open medicine (Warsaw, Poland)","url":"https://pubmed.ncbi.nlm.nih.gov/35274046","citation_count":8,"is_preprint":false},{"pmid":"40393451","id":"PMC_40393451","title":"A postsynaptic GPR158-PLCXD2 complex controls spine apparatus abundance and dendritic spine maturation.","date":"2025","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/40393451","citation_count":4,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":3246,"output_tokens":941,"usd":0.011926,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7408,"output_tokens":1470,"usd":0.036895,"stage2_stop_reason":"end_turn"},"total_usd":0.048821,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2025,\n      \"finding\": \"PLCXD2 is a constitutively active phospholipase C (PLC) family member that forms a postsynaptic signaling complex with the GPCR GPR158; unrestrained PLCXD2 activity (in the absence of GPR158) impedes spine apparatus (SA) incorporation into dendritic spines and hampers structural and functional dendritic spine maturation in mouse cortical neurons in vivo.\",\n      \"method\": \"Sparse genetic manipulations (loss-of-function) of mouse cortical neurons in vivo; identification of GPR158-PLCXD2 complex; functional readouts of spine apparatus abundance and dendritic spine maturation\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic manipulation with defined cellular phenotype (SA abundance, spine maturation), complex identification, and functional epistasis between GPR158 and PLCXD2 in a single rigorous study\",\n      \"pmids\": [\"40393451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GPR158 restrains PLCXD2 activity by direct interaction, and extracellular heparan sulfate proteoglycan (HSPG) binding modulates the GPR158-PLCXD2 interaction, providing spatiotemporal control over GPR158 signaling; this represents a direct GPCR-like receptor-to-PLC signaling pathway that bypasses canonical PLC regulation via G proteins.\",\n      \"method\": \"Complex identification and functional epistasis in cortical neurons in vivo; HSPG binding modulation of the GPR158-PLCXD2 interaction\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, mechanistic model supported by in vivo epistasis but HSPG modulation mechanism not yet reconstituted biochemically in the abstract\",\n      \"pmids\": [\"40393451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PLCXD2 mRNA is a direct target of miR-378a-3p, which suppresses its expression; the lncRNA ACTA2-AS1 acts as a competing endogenous RNA (ceRNA) to sequester miR-378a-3p and thereby de-repress PLCXD2 expression in gastric cancer cells.\",\n      \"method\": \"RNA pulldown assays, luciferase reporter assays, RNA immunoprecipitation assays, PLCXD2 knockdown rescue experiments\",\n      \"journal\": \"Open medicine (Warsaw, Poland)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple orthogonal RNA-based methods (luciferase reporter, RIP, pulldown) in a single lab establishing miR-378a-3p as a repressor of PLCXD2 expression\",\n      \"pmids\": [\"35274046\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PLCXD2 is a constitutively active phospholipase C that is held in check by direct interaction with the postsynaptic GPCR GPR158 (modulated by extracellular heparan sulfate proteoglycans), such that unrestrained PLCXD2 activity blocks spine apparatus incorporation and dendritic spine maturation; at the post-transcriptional level, PLCXD2 expression is repressed by miR-378a-3p, which can be sequestered by the lncRNA ACTA2-AS1.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PLCXD2 is a constitutively active phospholipase C family member that functions in postsynaptic signaling to control dendritic spine maturation [#0]. In mouse cortical neurons, PLCXD2 forms a complex with the postsynaptic GPCR GPR158, which directly restrains its activity; when this restraint is lost, unrestrained PLCXD2 activity impedes incorporation of the spine apparatus into dendritic spines and blocks structural and functional spine maturation [#0]. Binding of extracellular heparan sulfate proteoglycans modulates the GPR158-PLCXD2 interaction, defining a direct receptor-to-PLC signaling route that operates independently of canonical G-protein-mediated PLC activation [#1]. At the post-transcriptional level, PLCXD2 mRNA is directly repressed by miR-378a-3p, and the lncRNA ACTA2-AS1 sequesters this microRNA as a competing endogenous RNA to de-repress PLCXD2 in gastric cancer cells [#2]. Beyond these findings, the catalytic substrate specificity and structural basis of PLCXD2 regulation have not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2022,\n      \"claim\": \"Established a post-transcriptional control axis for PLCXD2, answering how its expression level is set in a disease context.\",\n      \"evidence\": \"RNA pulldown, luciferase reporter, RIP, and knockdown rescue assays in gastric cancer cells\",\n      \"pmids\": [\"35274046\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single lab; mechanism connecting PLCXD2 level to the cancer phenotype not resolved\",\n        \"No link drawn between this regulatory axis and PLCXD2 catalytic or neuronal function\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined PLCXD2 as a constitutively active PLC whose unrestrained activity blocks spine apparatus incorporation and dendritic spine maturation, identifying its functional role in postsynaptic biology.\",\n      \"evidence\": \"Sparse in vivo loss-of-function genetic manipulation of mouse cortical neurons with spine apparatus and spine maturation readouts\",\n      \"pmids\": [\"40393451\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Substrate and lipid second-messenger output of PLCXD2 not defined\",\n        \"Downstream effectors linking PLCXD2 activity to spine apparatus incorporation unknown\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed that GPR158 directly restrains PLCXD2 and that heparan sulfate proteoglycan binding tunes this interaction, establishing a non-canonical GPCR-to-PLC pathway bypassing G proteins.\",\n      \"evidence\": \"Complex identification and functional epistasis in cortical neurons in vivo with HSPG modulation\",\n      \"pmids\": [\"40393451\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"HSPG modulation mechanism not reconstituted biochemically\",\n        \"Structural basis of the GPR158-PLCXD2 interaction not determined\",\n        \"Single lab\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The catalytic substrate, lipid products, and structural mechanism by which GPR158 inhibits PLCXD2 remain undefined.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No in vitro reconstitution of PLCXD2 enzymatic activity\",\n        \"No structural model of the inhibitory complex\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [\"GPR158-PLCXD2 postsynaptic signaling complex\"],\n    \"partners\": [\"GPR158\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}