{"gene":"PHLDB1","run_date":"2026-04-28T19:45:44","timeline":{"discoveries":[{"year":2010,"finding":"PHLDB1 (LL5α) contains a pleckstrin homology domain that binds phosphoinositides PI(3,4)P2, PI(3,5)P2, and PI(3,4,5)P3, and translocates from cytoplasm to plasma membrane in response to insulin stimulation in adipocytes.","method":"PH domain lipid-binding assay; live-cell imaging of GFP/HA-tagged PHLDB1 in cultured adipocytes","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — direct lipid-binding assay plus subcellular localization with functional consequence, single paper with multiple orthogonal methods","pmids":["20587420"],"is_preprint":false},{"year":2010,"finding":"PHLDB1 is required for insulin-stimulated Akt phosphorylation downstream of IRS-1 tyrosine phosphorylation in adipocytes; siRNA-mediated depletion of PHLDB1 inhibits Akt phosphorylation and p70 S6 kinase phosphorylation without affecting IRS-1 tyrosine phosphorylation.","method":"siRNA knockdown followed by western blot for phospho-Akt, phospho-p70 S6K, and phospho-IRS-1 in cultured adipocytes; adenoviral overexpression rescue","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — clean KD with defined molecular phenotype plus OE rescue, multiple orthogonal readouts, single rigorous paper","pmids":["20587420"],"is_preprint":false},{"year":2010,"finding":"PHLDB1 is specifically required for insulin-stimulated GLUT4 translocation to the plasma membrane and deoxyglucose transport in adipocytes; knockdown of the isoform PHLDB2 does not replicate this effect, establishing isoform specificity.","method":"siRNA knockdown of PHLDB1 or PHLDB2 followed by Myc-GLUT4-EGFP translocation assay and deoxyglucose transport measurement in cultured adipocytes","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — clean isoform-specific KD with defined functional readout, confirmed by multiple assays in single rigorous paper","pmids":["20587420"],"is_preprint":false},{"year":2003,"finding":"PHLDB1 (LL5α) encodes a protein with a Forkhead-associated (FHA) domain, a bipartite nuclear localization signal, a chromosome segregation ATPase (SMC) domain, and a pleckstrin homology (PH) domain; its PH domain is homologous to the PI(3,4,5)P3-sensor protein LL5β, predicting a role as a PtdIns(3,4,5)P3 transducer.","method":"In silico sequence and domain analysis; cDNA assembly and isoform characterization","journal":"International journal of oncology","confidence":"Low","confidence_rationale":"Tier 4 — computational prediction only, no experimental validation in this paper","pmids":["14532993"],"is_preprint":false},{"year":2014,"finding":"PHLDB1 (LL5α) forms a functional complex with liprin-α1 and ERC1a at the leading edge of migrating cells; depletion of PHLDB1 reduces lamellipodial persistence, cell migration, tumor cell invasion, and internalization of active integrin β1 at the cell front.","method":"siRNA depletion, live-cell migration and invasion assays (Matrigel), integrin β1 internalization assay, confocal imaging of polarized cytoplasmic structures at the cell edge","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — clean KD with multiple orthogonal functional readouts (migration, invasion, integrin trafficking, lamellipodia), and complex membership validated by co-localization and functional epistasis","pmids":["24982445"],"is_preprint":false},{"year":2022,"finding":"Biallelic loss-of-function frameshift variants in PHLDB1 cause autosomal recessive osteogenesis imperfecta; patient fibroblasts show loss of PHLDB1 protein by western blot, linking PHLDB1 to bone fragility through its role in insulin-dependent Akt phosphorylation.","method":"Whole-exome sequencing; RT-PCR and western blot on patient blood and skin fibroblasts confirming loss of PHLDB1 mRNA and protein","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 — human genetic + molecular confirmation in patient-derived cells, but mechanism is inferred from prior functional work rather than directly demonstrated in bone cells","pmids":["36543534"],"is_preprint":false},{"year":2015,"finding":"PHLDB1 and DDX6 both contribute to a glioma-relevant cellular phenotype at 11q23.3; knockdown experiments in 3D cell culture assays demonstrate that both genes affect tumor cell behavior, and chromatin conformation capture (3C) identifies a physical interaction between an enhancer element containing a functional SNP (rs73001406) and the DDX6 promoter within this locus.","method":"siRNA knockdown; 3D invasion/growth assays; luciferase-based enhancer scanning; chromatin conformation capture (3C)","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2–3 — multiple orthogonal methods in single study but phenotypic readout for PHLDB1 KD is not fully characterized mechanistically","pmids":["26610392"],"is_preprint":false}],"current_model":"PHLDB1 encodes a PH-domain-containing scaffold protein that senses PI(3,4,5)P3 at the plasma membrane to potentiate insulin-stimulated Akt phosphorylation and GLUT4 translocation in adipocytes, and also assembles with liprin-α1 and ERC1a at the leading edge of migrating cells to sustain lamellipodial persistence and active integrin β1 internalization required for cell motility; loss-of-function mutations cause autosomal recessive osteogenesis imperfecta in humans."},"narrative":{"teleology":[{"year":2003,"claim":"Computational domain analysis established that PHLDB1 encodes a multi-domain protein with an FHA domain, SMC domain, and a PH domain homologous to the PIP3 sensor LL5β, predicting a signaling role that awaited experimental validation.","evidence":"In silico sequence and domain analysis with cDNA assembly","pmids":["14532993"],"confidence":"Low","gaps":["Purely computational prediction with no experimental validation in this study","Lipid-binding specificity of the PH domain was not tested","No cellular function assigned"]},{"year":2010,"claim":"Direct biochemical and functional experiments answered the central question of what PHLDB1 does at the plasma membrane: its PH domain binds PI(3,4,5)P3 and related phosphoinositides, and PHLDB1 is required downstream of IRS-1 for insulin-stimulated Akt phosphorylation, GLUT4 translocation, and glucose uptake — with isoform specificity over PHLDB2.","evidence":"PH domain lipid-binding assays, live-cell imaging in adipocytes, siRNA knockdown of PHLDB1 vs PHLDB2, phospho-Akt/p70S6K western blots, GLUT4 translocation and deoxyglucose transport assays, adenoviral rescue","pmids":["20587420"],"confidence":"High","gaps":["Direct binding partners linking PH-domain engagement to Akt activation were not identified","In vivo metabolic phenotype of PHLDB1 loss was not assessed","Mechanism by which PHLDB1 specifically promotes GLUT4 vesicle fusion was not resolved"]},{"year":2014,"claim":"Beyond metabolic signaling, PHLDB1 was shown to organize a leading-edge complex with liprin-α1 and ERC1a that sustains lamellipodial dynamics, active integrin β1 endocytosis, and cell migration/invasion — establishing a second major functional axis for this scaffold.","evidence":"siRNA depletion in migrating cells, live-cell migration and Matrigel invasion assays, integrin β1 internalization assay, confocal imaging of polarized leading-edge structures","pmids":["24982445"],"confidence":"High","gaps":["Whether PI(3,4,5)P3 binding by the PH domain is required for leading-edge complex assembly was not directly tested","The structural basis of PHLDB1–liprin-α1–ERC1a complex formation is unknown","Contribution of PHLDB1 to in vivo tumor metastasis was not demonstrated"]},{"year":2015,"claim":"PHLDB1 knockdown was linked to altered tumor cell behavior in a glioma-associated 11q23.3 locus alongside DDX6, though the specific mechanistic contribution of PHLDB1 to gliomagenesis remained unclear.","evidence":"siRNA knockdown in 3D growth/invasion assays, luciferase enhancer scanning, chromatin conformation capture (3C)","pmids":["26610392"],"confidence":"Medium","gaps":["PHLDB1 knockdown phenotype was not mechanistically dissected in glioma cells","The functional SNP-enhancer interaction mapped to DDX6 rather than PHLDB1","No separation of PHLDB1 vs DDX6 contribution at the molecular level"]},{"year":2022,"claim":"Human genetic evidence established that biallelic loss-of-function of PHLDB1 causes autosomal recessive osteogenesis imperfecta, connecting the scaffold's signaling functions to bone homeostasis.","evidence":"Whole-exome sequencing of affected individuals, RT-PCR and western blot confirmation of PHLDB1 loss in patient fibroblasts","pmids":["36543534"],"confidence":"Medium","gaps":["Mechanism linking PHLDB1 loss to impaired bone formation was inferred from prior Akt-signaling data rather than demonstrated in osteoblasts or bone tissue","No animal model of PHLDB1 loss-of-function bone phenotype reported","Whether the migration/integrin-trafficking axis also contributes to the bone phenotype is unknown"]},{"year":null,"claim":"Key open questions include the structural basis of PHLDB1 scaffold assembly, whether its PI(3,4,5)P3-sensing and leading-edge organizing functions are mechanistically coupled, and how PHLDB1 loss specifically impairs osteoblast or bone matrix biology to cause osteogenesis imperfecta.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of full-length PHLDB1 or its domain-mediated interactions","Direct demonstration of PHLDB1 function in bone-forming cells is lacking","In vivo metabolic and skeletal phenotypes of PHLDB1 knockout animals have not been reported"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,4]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,4]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,2]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[2]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[4]}],"complexes":["PHLDB1–liprin-α1–ERC1a leading-edge complex"],"partners":["PPFIA1","ERC1"],"other_free_text":[]},"mechanistic_narrative":"PHLDB1 (also known as LL5α) is a PH-domain-containing scaffold protein that senses phosphoinositides at the plasma membrane and organizes signaling and cytoskeletal complexes to control insulin-dependent glucose uptake and cell migration. Its PH domain binds PI(3,4)P2, PI(3,5)P2, and PI(3,4,5)P3, mediating insulin-stimulated translocation to the plasma membrane in adipocytes where it is required for Akt phosphorylation, p70 S6K activation, and isoform-specific GLUT4 translocation [PMID:20587420]. At the leading edge of migrating cells, PHLDB1 assembles with liprin-α1 and ERC1a into a complex that sustains lamellipodial persistence, promotes active integrin β1 internalization, and supports tumor cell invasion [PMID:24982445]. Biallelic loss-of-function frameshift variants in PHLDB1 cause autosomal recessive osteogenesis imperfecta [PMID:36543534]."},"prefetch_data":{"uniprot":{"accession":"Q86UU1","full_name":"Pleckstrin homology-like domain family B member 1","aliases":["Protein LL5-alpha"],"length_aa":1377,"mass_kda":151.2,"function":"","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q86UU1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PHLDB1","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000019144","cell_line_id":"CID001613","localizations":[{"compartment":"membrane","grade":3}],"interactors":[],"url":"https://opencell.sf.czbiohub.org/target/CID001613","total_profiled":1310},"omim":[{"mim_id":"620639","title":"OSTEOGENESIS IMPERFECTA, TYPE XXIII; OI23","url":"https://www.omim.org/entry/620639"},{"mim_id":"612834","title":"PLECKSTRIN HOMOLOGY-LIKE DOMAIN, FAMILY B, MEMBER 1; PHLDB1","url":"https://www.omim.org/entry/612834"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Plasma membrane","reliability":"Additional"},{"location":"Cytokinetic bridge","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PHLDB1"},"hgnc":{"alias_symbol":["FLJ00141","LL5a","KIAA0638"],"prev_symbol":[]},"alphafold":{"accession":"Q86UU1","domains":[{"cath_id":"2.60.200.20","chopping":"26-134","consensus_level":"high","plddt":84.7342,"start":26,"end":134},{"cath_id":"2.30.29.30","chopping":"1229-1368","consensus_level":"high","plddt":83.4503,"start":1229,"end":1368},{"cath_id":"1.20.5","chopping":"723-865","consensus_level":"medium","plddt":91.3659,"start":723,"end":865},{"cath_id":"1.20.5","chopping":"1154-1220","consensus_level":"medium","plddt":78.9775,"start":1154,"end":1220}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86UU1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q86UU1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q86UU1-F1-predicted_aligned_error_v6.png","plddt_mean":59.03},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PHLDB1","jax_strain_url":"https://www.jax.org/strain/search?query=PHLDB1"},"sequence":{"accession":"Q86UU1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q86UU1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q86UU1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86UU1"}},"corpus_meta":[{"pmid":"24982445","id":"PMC_24982445","title":"Liprin-α1, 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\"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct lipid-binding assay plus subcellular localization with functional consequence, single paper with multiple orthogonal methods\",\n      \"pmids\": [\"20587420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PHLDB1 is required for insulin-stimulated Akt phosphorylation downstream of IRS-1 tyrosine phosphorylation in adipocytes; siRNA-mediated depletion of PHLDB1 inhibits Akt phosphorylation and p70 S6 kinase phosphorylation without affecting IRS-1 tyrosine phosphorylation.\",\n      \"method\": \"siRNA knockdown followed by western blot for phospho-Akt, phospho-p70 S6K, and phospho-IRS-1 in cultured adipocytes; adenoviral overexpression rescue\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with defined molecular phenotype plus OE rescue, multiple orthogonal readouts, single rigorous paper\",\n      \"pmids\": [\"20587420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PHLDB1 is specifically required for insulin-stimulated GLUT4 translocation to the plasma membrane and deoxyglucose transport in adipocytes; knockdown of the isoform PHLDB2 does not replicate this effect, establishing isoform specificity.\",\n      \"method\": \"siRNA knockdown of PHLDB1 or PHLDB2 followed by Myc-GLUT4-EGFP translocation assay and deoxyglucose transport measurement in cultured adipocytes\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean isoform-specific KD with defined functional readout, confirmed by multiple assays in single rigorous paper\",\n      \"pmids\": [\"20587420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"PHLDB1 (LL5α) encodes a protein with a Forkhead-associated (FHA) domain, a bipartite nuclear localization signal, a chromosome segregation ATPase (SMC) domain, and a pleckstrin homology (PH) domain; its PH domain is homologous to the PI(3,4,5)P3-sensor protein LL5β, predicting a role as a PtdIns(3,4,5)P3 transducer.\",\n      \"method\": \"In silico sequence and domain analysis; cDNA assembly and isoform characterization\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — computational prediction only, no experimental validation in this paper\",\n      \"pmids\": [\"14532993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PHLDB1 (LL5α) forms a functional complex with liprin-α1 and ERC1a at the leading edge of migrating cells; depletion of PHLDB1 reduces lamellipodial persistence, cell migration, tumor cell invasion, and internalization of active integrin β1 at the cell front.\",\n      \"method\": \"siRNA depletion, live-cell migration and invasion assays (Matrigel), integrin β1 internalization assay, confocal imaging of polarized cytoplasmic structures at the cell edge\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with multiple orthogonal functional readouts (migration, invasion, integrin trafficking, lamellipodia), and complex membership validated by co-localization and functional epistasis\",\n      \"pmids\": [\"24982445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Biallelic loss-of-function frameshift variants in PHLDB1 cause autosomal recessive osteogenesis imperfecta; patient fibroblasts show loss of PHLDB1 protein by western blot, linking PHLDB1 to bone fragility through its role in insulin-dependent Akt phosphorylation.\",\n      \"method\": \"Whole-exome sequencing; RT-PCR and western blot on patient blood and skin fibroblasts confirming loss of PHLDB1 mRNA and protein\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — human genetic + molecular confirmation in patient-derived cells, but mechanism is inferred from prior functional work rather than directly demonstrated in bone cells\",\n      \"pmids\": [\"36543534\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PHLDB1 and DDX6 both contribute to a glioma-relevant cellular phenotype at 11q23.3; knockdown experiments in 3D cell culture assays demonstrate that both genes affect tumor cell behavior, and chromatin conformation capture (3C) identifies a physical interaction between an enhancer element containing a functional SNP (rs73001406) and the DDX6 promoter within this locus.\",\n      \"method\": \"siRNA knockdown; 3D invasion/growth assays; luciferase-based enhancer scanning; chromatin conformation capture (3C)\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — multiple orthogonal methods in single study but phenotypic readout for PHLDB1 KD is not fully characterized mechanistically\",\n      \"pmids\": [\"26610392\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PHLDB1 encodes a PH-domain-containing scaffold protein that senses PI(3,4,5)P3 at the plasma membrane to potentiate insulin-stimulated Akt phosphorylation and GLUT4 translocation in adipocytes, and also assembles with liprin-α1 and ERC1a at the leading edge of migrating cells to sustain lamellipodial persistence and active integrin β1 internalization required for cell motility; loss-of-function mutations cause autosomal recessive osteogenesis imperfecta in humans.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PHLDB1 (also known as LL5α) is a PH-domain-containing scaffold protein that senses phosphoinositides at the plasma membrane and organizes signaling and cytoskeletal complexes to control insulin-dependent glucose uptake and cell migration. Its PH domain binds PI(3,4)P2, PI(3,5)P2, and PI(3,4,5)P3, mediating insulin-stimulated translocation to the plasma membrane in adipocytes where it is required for Akt phosphorylation, p70 S6K activation, and isoform-specific GLUT4 translocation [PMID:20587420]. At the leading edge of migrating cells, PHLDB1 assembles with liprin-α1 and ERC1a into a complex that sustains lamellipodial persistence, promotes active integrin β1 internalization, and supports tumor cell invasion [PMID:24982445]. Biallelic loss-of-function frameshift variants in PHLDB1 cause autosomal recessive osteogenesis imperfecta [PMID:36543534].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Computational domain analysis established that PHLDB1 encodes a multi-domain protein with an FHA domain, SMC domain, and a PH domain homologous to the PIP3 sensor LL5β, predicting a signaling role that awaited experimental validation.\",\n      \"evidence\": \"In silico sequence and domain analysis with cDNA assembly\",\n      \"pmids\": [\"14532993\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Purely computational prediction with no experimental validation in this study\",\n        \"Lipid-binding specificity of the PH domain was not tested\",\n        \"No cellular function assigned\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Direct biochemical and functional experiments answered the central question of what PHLDB1 does at the plasma membrane: its PH domain binds PI(3,4,5)P3 and related phosphoinositides, and PHLDB1 is required downstream of IRS-1 for insulin-stimulated Akt phosphorylation, GLUT4 translocation, and glucose uptake — with isoform specificity over PHLDB2.\",\n      \"evidence\": \"PH domain lipid-binding assays, live-cell imaging in adipocytes, siRNA knockdown of PHLDB1 vs PHLDB2, phospho-Akt/p70S6K western blots, GLUT4 translocation and deoxyglucose transport assays, adenoviral rescue\",\n      \"pmids\": [\"20587420\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct binding partners linking PH-domain engagement to Akt activation were not identified\",\n        \"In vivo metabolic phenotype of PHLDB1 loss was not assessed\",\n        \"Mechanism by which PHLDB1 specifically promotes GLUT4 vesicle fusion was not resolved\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Beyond metabolic signaling, PHLDB1 was shown to organize a leading-edge complex with liprin-α1 and ERC1a that sustains lamellipodial dynamics, active integrin β1 endocytosis, and cell migration/invasion — establishing a second major functional axis for this scaffold.\",\n      \"evidence\": \"siRNA depletion in migrating cells, live-cell migration and Matrigel invasion assays, integrin β1 internalization assay, confocal imaging of polarized leading-edge structures\",\n      \"pmids\": [\"24982445\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether PI(3,4,5)P3 binding by the PH domain is required for leading-edge complex assembly was not directly tested\",\n        \"The structural basis of PHLDB1–liprin-α1–ERC1a complex formation is unknown\",\n        \"Contribution of PHLDB1 to in vivo tumor metastasis was not demonstrated\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"PHLDB1 knockdown was linked to altered tumor cell behavior in a glioma-associated 11q23.3 locus alongside DDX6, though the specific mechanistic contribution of PHLDB1 to gliomagenesis remained unclear.\",\n      \"evidence\": \"siRNA knockdown in 3D growth/invasion assays, luciferase enhancer scanning, chromatin conformation capture (3C)\",\n      \"pmids\": [\"26610392\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"PHLDB1 knockdown phenotype was not mechanistically dissected in glioma cells\",\n        \"The functional SNP-enhancer interaction mapped to DDX6 rather than PHLDB1\",\n        \"No separation of PHLDB1 vs DDX6 contribution at the molecular level\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Human genetic evidence established that biallelic loss-of-function of PHLDB1 causes autosomal recessive osteogenesis imperfecta, connecting the scaffold's signaling functions to bone homeostasis.\",\n      \"evidence\": \"Whole-exome sequencing of affected individuals, RT-PCR and western blot confirmation of PHLDB1 loss in patient fibroblasts\",\n      \"pmids\": [\"36543534\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism linking PHLDB1 loss to impaired bone formation was inferred from prior Akt-signaling data rather than demonstrated in osteoblasts or bone tissue\",\n        \"No animal model of PHLDB1 loss-of-function bone phenotype reported\",\n        \"Whether the migration/integrin-trafficking axis also contributes to the bone phenotype is unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include the structural basis of PHLDB1 scaffold assembly, whether its PI(3,4,5)P3-sensing and leading-edge organizing functions are mechanistically coupled, and how PHLDB1 loss specifically impairs osteoblast or bone matrix biology to cause osteogenesis imperfecta.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural model of full-length PHLDB1 or its domain-mediated interactions\",\n        \"Direct demonstration of PHLDB1 function in bone-forming cells is lacking\",\n        \"In vivo metabolic and skeletal phenotypes of PHLDB1 knockout animals have not been reported\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [\n      \"PHLDB1–liprin-α1–ERC1a leading-edge complex\"\n    ],\n    \"partners\": [\n      \"PPFIA1\",\n      \"ERC1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}