{"gene":"PLEKHA1","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2001,"finding":"Crystal structure of the C-terminal PH domain of TAPP1 (PLEKHA1) at 1.4 Å resolution revealed the molecular basis for its specific binding to PtdIns(3,4)P2 but not PtdIns(3,4,5)P3. A key alanine residue adjacent to the D-5 inositol-phosphate-binding site (versus glycine in the related DAPP1) both sterically excludes PtdIns(3,4,5)P3 and induces a conformational change in neighboring residues. Mutagenesis confirmed this: the DAPP1 G→A mutation converted it to a TAPP1-like domain that only binds PtdIns(3,4)P2, while the TAPP1 A→G mutation permitted binding to PtdIns(3,4,5)P3.","method":"X-ray crystallography (1.4 Å) combined with site-directed mutagenesis and lipid-binding assays","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional mutagenesis validation, multiple orthogonal methods in one study","pmids":["11513726"],"is_preprint":false},{"year":2002,"finding":"TAPP1 (PLEKHA1) translocates from cytoplasm to plasma membrane upon agonist-stimulated PtdIns(3,4)P2 production in Swiss 3T3 and 293 cells. Translocation requires a functional PtdIns(3,4)P2-binding C-terminal PH domain and is blocked by the PI3K inhibitor wortmannin. Endogenously expressed TAPP1 co-immunoprecipitates with endogenous MUPP1 (a multi-PDZ-domain protein), and TAPP1/TAPP2 interact with the 10th and 13th PDZ domains of MUPP1 via their C-terminal amino acids, suggesting TAPP1 recruits MUPP1 to the plasma membrane in response to PtdIns(3,4)P2 elevation.","method":"Live-cell imaging, co-immunoprecipitation of endogenous proteins, PH-domain mutant analysis, wortmannin inhibition","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP of endogenous proteins combined with live-cell translocation assay and domain mutagenesis, two orthogonal methods","pmids":["11802782"],"is_preprint":false},{"year":2002,"finding":"TAPP1 and TAPP2 are recruited to the plasma membrane of human B-lymphoma cells (BJAB) upon B-cell antigen receptor (BCR) activation, with kinetics that are slow and sustained. The C-terminal PH domain alone is necessary and sufficient for BCR-induced membrane recruitment. Recruitment is abolished by PI3K blockade and constitutively driven by active PI3K. Membrane accumulation correlates with PtdIns(3,4)P2 (not PtdIns(3,4,5)P3) production. TAPP1 and TAPP2 preferentially accumulate in F-actin-rich membrane ruffles, implicating them in PI3K-driven cytoskeletal reorganization.","method":"Live-cell imaging, PI3K inhibitor/activator treatment, C-terminal PH domain truncation mutants, lipid production kinetics analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (live imaging, pharmacological inhibition, constitutive activation, domain mapping) in a single rigorous study","pmids":["12101241"],"is_preprint":false},{"year":2003,"finding":"Endogenously expressed TAPP1 is constitutively associated with the protein-tyrosine phosphatase PTPL1 (FAP-1). PTPL1 binds TAPP1 and TAPP2 principally through its first PDZ domain, enabling PTPL1 to associate with PtdIns(3,4)P2 in vitro. The TAPP1–PTPL1 interaction maintains PTPL1 in the cytoplasm; upon hydrogen-peroxide-stimulated PtdIns(3,4)P2 production, the TAPP1–PTPL1 complex translocates to the plasma membrane. TAPP1 binding does not alter PTPL1 phosphatase activity itself. RNAi-mediated knockdown of TAPP1 in HEK-293 cells enhanced IGF1-stimulated Akt activation and phosphorylation, consistent with a negative-regulatory role.","method":"Co-immunoprecipitation of endogenous proteins, in vitro lipid-binding assay, cellular localization imaging, siRNA knockdown with Akt phosphorylation readout","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — endogenous co-IP plus in vitro lipid binding plus siRNA functional rescue, multiple orthogonal methods","pmids":["14516276"],"is_preprint":false},{"year":2004,"finding":"Using GST-TAPP1-PH domain as a specific probe in on-section immunoelectron microscopy, PtdIns(3,4)P2 was detected not only at the plasma membrane but also on intracellular organelles including the endoplasmic reticulum and multivesicular endosomes after PDGF or hydrogen peroxide stimulation. Intracellular and plasma-membrane pools of PtdIns(3,4)P2 showed differential sensitivity to PTEN phosphatase, revealing compartmentally distinct signaling pools.","method":"Immunoelectron microscopy using GST-TAPP1-PH domain as a lipid probe, PTEN re-expression in PTEN-null cells","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct subcellular localization by electron microscopy with functional PTEN validation, single lab","pmids":["14604433"],"is_preprint":false},{"year":2004,"finding":"TAPP1 interacts with the PDZ domains of gamma1-, alpha1-, and beta2-syntrophin via its C-terminal amino acids; this interaction is required for correct subcellular localization of TAPP1. Both TAPP1 and syntrophins co-localize to PDGF-induced dorsal circular membrane ruffles in NIH-3T3 cells. Ectopic overexpression of TAPP1 blocks PDGF-induced dorsal circular ruffle formation, but co-expression of alpha1- or gamma1-syntrophin rescues this blockade, indicating that syntrophins regulate TAPP1-mediated actin cytoskeletal remodeling downstream of PI3K/PtdIns(3,4)P2 signaling.","method":"Yeast two-hybrid screen, biochemical PDZ domain binding assays, co-localization imaging, overexpression and rescue experiments in NIH-3T3 cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — yeast two-hybrid confirmed biochemically, functional overexpression rescue with syntrophin, multiple orthogonal methods in one study","pmids":["15485858"],"is_preprint":false},{"year":2011,"finding":"Knock-in mice homozygous for PtdIns(3,4)P2-binding-deficient mutations in both TAPP1 (R211L) and TAPP2 (R218L) are viable but display significantly enhanced Akt activation and improved whole-body insulin sensitivity with increased glucose disposal into muscle. Embryonic fibroblasts from double knock-in mice show enhanced IGF1-stimulated PtdIns(3,4,5)P3 production and Akt activity. This establishes that TAPP1/TAPP2 binding to PtdIns(3,4)P2 acts as a negative regulator of the PI3K–Akt–insulin signaling axis.","method":"Knock-in mouse genetics (R211L mutation), insulin clamp/glucose disposal assays, primary embryonic fibroblasts with PtdIns(3,4,5)P3 measurement and Akt phosphorylation","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vivo knock-in genetic epistasis with multiple physiological readouts, replicated in primary cells","pmids":["21204784"],"is_preprint":false},{"year":2015,"finding":"TAPP1 (PLEKHA1) is selectively expressed in differentiating oligodendrocyte precursor cells (OPCs). Knockdown of TAPP1 promotes OPC differentiation and myelin gene expression, while overexpression suppresses differentiation. TAPP1 inhibition alters Erk1/2 (but not Akt) phosphorylation, placing TAPP1 as a negative regulator of OPC differentiation specifically through the Mek/Erk pathway rather than the canonical PI3K/Akt axis.","method":"siRNA knockdown and overexpression in primary OPC cultures, myelin gene expression assays, western blot for Erk1/2 and Akt phosphorylation","journal":"Neuroscience bulletin","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function and loss-of-function with defined molecular readout (Erk vs Akt), single lab with two complementary perturbations","pmids":["26242484"],"is_preprint":false},{"year":2024,"finding":"EIF4G2 (a translation initiation factor) regulates PLEKHA1 protein expression via IRES-dependent translation in hepatocellular carcinoma (HCC). RNA immunoprecipitation showed EIF4G2 associates with PLEKHA1 mRNA, and dual-luciferase reporter assays confirmed IRES-dependent translational control. Polysome analysis and nascent protein synthesis assays validated EIF4G2 as the writer of this translational regulation. Combined depletion of EIF4G2 and PLEKHA1 synergistically inhibits HCC cell migration and invasion.","method":"RNA immunoprecipitation (RIP), dual-luciferase reporter assay, polysome profiling, nascent protein synthesis assay, siRNA knockdown","journal":"Journal of proteome research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal biochemical methods (RIP, reporter assay, polysome profiling) in a single lab study","pmids":["39213495"],"is_preprint":false},{"year":2025,"finding":"A PLEKHA1-TACC2 chromosomal fusion gene produces a fusion protein that upregulates the EphA2/AKT/MMP2 signaling pathway and promotes vascular mimicry formation in esophageal squamous-cell carcinoma (ESCC) by reducing ubiquitylation of EphA2. In vivo, PLEKHA1-TACC2 fusion combined with Trp53 deletion significantly increases tumor incidence in a transgenic mouse model, suppressible by EphA2 inhibitors.","method":"RNA sequencing identification of fusion transcript, in vitro and in vivo functional assays, ubiquitylation assay for EphA2, transgenic mouse model, pharmacological inhibition with EphA2 inhibitors","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (ubiquitylation assay, transgenic mouse model, pharmacological rescue) in a single study for a fusion-protein context","pmids":["40615663"],"is_preprint":false},{"year":2025,"finding":"Live imaging with a TAPP1 (PLEKHA1) 3xcPH domain probe in Xenopus laevis retinal ganglion cell filopodia showed that PtdIns(3,4)P2 accumulates specifically at filopodial tips. Quantitative cross-correlation and Granger causality analysis demonstrated that PI(3,4)P2 at filopodial tips both generates tip extension and responds to forward filopodial movement. Disruption of actin polymerization rapidly depleted tip PI(3,4)P2 prior to filopodial stalling, establishing a bidirectional relationship between PI(3,4)P2 and actin dynamics at filopodial tips.","method":"Live-cell TAPP1-3xcPH domain imaging, pharmacological PI3K perturbation, quantitative cross-correlation and Granger causality analysis, actin polymerization disruption","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct live imaging with validated lipid biosensor combined with quantitative causality analysis, preprint single study","pmids":["bio_10.1101_2025.10.13.681625"],"is_preprint":true}],"current_model":"PLEKHA1 (TAPP1) is a cytoplasmic adaptor protein whose C-terminal PH domain selectively binds PtdIns(3,4)P2 (but not PtdIns(3,4,5)P3) — a specificity structurally explained by an alanine residue that sterically excludes the D-5 phosphate of PtdIns(3,4,5)P3 — causing its PI3K-dependent translocation to the plasma membrane, where it recruits PDZ-domain-containing partners (MUPP1, PTPL1, syntrophins) to act as a negative regulator of PI3K–Akt–insulin signaling; it also modulates actin cytoskeletal remodeling (dorsal ruffles, filopodial dynamics) and OPC differentiation via the Mek/Erk pathway, while a chromosomal PLEKHA1-TACC2 fusion drives oncogenic EphA2/AKT/MMP2 signaling in esophageal carcinoma."},"narrative":{"mechanistic_narrative":"PLEKHA1 (TAPP1) is a cytoplasmic adaptor protein that reads the lipid second messenger PtdIns(3,4)P2 through its C-terminal PH domain and acts as a negative regulator of PI3K-driven signaling [PMID:14516276, PMID:21204784]. A 1.4 Å crystal structure defined the basis for its lipid selectivity: an alanine adjacent to the D-5 phosphate-binding site sterically excludes PtdIns(3,4,5)P3, restricting binding to PtdIns(3,4)P2, a specificity reversible by reciprocal Ala/Gly swaps with the related DAPP1 [PMID:11513726]. Agonist- or receptor-stimulated, PI3K-dependent production of PtdIns(3,4)P2 drives translocation of PLEKHA1 from cytosol to the plasma membrane via this PH domain [PMID:11802782, PMID:12101241]. At the membrane it functions as a scaffold, recruiting PDZ-domain partners including MUPP1, the tyrosine phosphatase PTPL1, and syntrophins through its C-terminal residues [PMID:11802782, PMID:14516276, PMID:15485858]. Genetic disruption of PtdIns(3,4)P2 binding in TAPP1/TAPP2 double knock-in mice enhances Akt activation and whole-body insulin sensitivity, establishing the PtdIns(3,4)P2–PLEKHA1 interaction as a brake on the PI3K–Akt–insulin axis [PMID:21204784]. Through its syntrophin interaction PLEKHA1 also modulates actin-based remodeling, controlling PDGF-induced dorsal circular ruffles [PMID:15485858], and a TAPP1 PH-domain biosensor reveals PtdIns(3,4)P2 enrichment at the plasma membrane and on intracellular organelles [PMID:14604433]. In disease contexts, a PLEKHA1-TACC2 fusion drives oncogenic EphA2/AKT/MMP2 signaling and vascular mimicry in esophageal squamous-cell carcinoma [PMID:40615663].","teleology":[{"year":2001,"claim":"Resolved why PLEKHA1 distinguishes PtdIns(3,4)P2 from PtdIns(3,4,5)P3, defining the structural code for its phosphoinositide selectivity.","evidence":"1.4 Å crystal structure of the C-terminal PH domain with reciprocal Ala/Gly mutagenesis and lipid-binding assays","pmids":["11513726"],"confidence":"High","gaps":["Does not address full-length protein conformation or in vivo membrane engagement","No structure of partner-bound complexes"]},{"year":2002,"claim":"Established that PtdIns(3,4)P2 binding by the PH domain drives PI3K-dependent membrane translocation and links PLEKHA1 to a PDZ-scaffold partner.","evidence":"Live-cell imaging, endogenous co-IP with MUPP1, PH-domain mutants, and wortmannin inhibition in Swiss 3T3/293 cells; BCR-stimulated recruitment in B-lymphoma cells","pmids":["11802782","12101241"],"confidence":"High","gaps":["Functional consequence of MUPP1 recruitment at the membrane not defined","Accumulation in F-actin ruffles is correlative, not mechanistic"]},{"year":2003,"claim":"Identified PLEKHA1 as a negative regulator of Akt signaling that also tethers the phosphatase PTPL1, partially defining its adaptor output.","evidence":"Endogenous co-IP, in vitro lipid binding, localization imaging, and siRNA knockdown with IGF1-stimulated Akt readout in HEK-293 cells","pmids":["14516276"],"confidence":"High","gaps":["Mechanism by which PLEKHA1 dampens Akt not resolved","PTPL1 substrate at the membrane not identified"]},{"year":2004,"claim":"Extended PtdIns(3,4)P2 signaling beyond the plasma membrane and mapped PLEKHA1 to a syntrophin-dependent actin-remodeling role.","evidence":"Immunoelectron microscopy with GST-TAPP1-PH probe and PTEN re-expression; yeast two-hybrid, PDZ-binding assays, and overexpression/rescue with syntrophins in NIH-3T3 cells","pmids":["14604433","15485858"],"confidence":"Medium","gaps":["Role of intracellular PtdIns(3,4)P2 pools for PLEKHA1 unclear","How syntrophin binding mechanistically controls dorsal ruffle formation not defined"]},{"year":2011,"claim":"Provided in vivo genetic proof that PtdIns(3,4)P2 binding by TAPP1/TAPP2 restrains the PI3K–Akt–insulin axis.","evidence":"TAPP1 R211L / TAPP2 R218L knock-in mice with insulin clamp/glucose disposal assays and PtdIns(3,4,5)P3/Akt measurement in primary fibroblasts","pmids":["21204784"],"confidence":"High","gaps":["Effector mechanism downstream of membrane-bound TAPP1 not pinned down","Tissue-specific contributions of each paralog not separated"]},{"year":2015,"claim":"Showed a PI3K-independent role: PLEKHA1 negatively regulates oligodendrocyte precursor differentiation via the Mek/Erk pathway.","evidence":"siRNA knockdown and overexpression in primary OPC cultures with myelin gene expression and Erk1/2 vs Akt phosphorylation readouts","pmids":["26242484"],"confidence":"Medium","gaps":["Molecular link between PLEKHA1 and Erk activation not established","Single-lab finding without in vivo validation"]},{"year":2024,"claim":"Identified upstream translational control of PLEKHA1 by EIF4G2 and a pro-invasive role in hepatocellular carcinoma.","evidence":"RNA immunoprecipitation, IRES dual-luciferase reporter, polysome profiling, nascent synthesis assays, and combined siRNA depletion in HCC cells","pmids":["39213495"],"confidence":"Medium","gaps":["How PLEKHA1 levels mechanistically drive migration/invasion not defined","IRES element within PLEKHA1 mRNA not mapped"]},{"year":2025,"claim":"Demonstrated that a PLEKHA1-TACC2 fusion is oncogenic, driving EphA2/AKT/MMP2 signaling and vascular mimicry.","evidence":"RNA-seq fusion identification, EphA2 ubiquitylation assay, transgenic mouse model with Trp53 deletion, and EphA2 inhibitor rescue in ESCC","pmids":["40615663"],"confidence":"Medium","gaps":["Contribution of the PLEKHA1 portion versus TACC2 to fusion activity not dissected","Mechanism of reduced EphA2 ubiquitylation unresolved"]},{"year":null,"claim":"How PLEKHA1's PtdIns(3,4)P2-dependent scaffolding mechanistically connects to its diverse downstream outputs (Akt suppression, Erk regulation, actin/filopodial dynamics) across cell types remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying effector mechanism linking membrane recruitment to specific signaling outputs","Filopodial PtdIns(3,4)P2–actin coupling shown only with biosensor in a preprint","PLEKHA1's direct catalytic or enzymatic partners at the membrane not fully enumerated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0,1,2,3,4]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,3,5]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,6]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,2,3,4]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1,3]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[4]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[4]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[2,5]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,6]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[6]}],"complexes":[],"partners":["MUPP1","PTPL1","SNTA1","SNTB2","SNTG1","TACC2","EIF4G2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9HB21","full_name":"Pleckstrin homology domain-containing family A member 1","aliases":["Tandem PH domain-containing protein 1","TAPP-1"],"length_aa":404,"mass_kda":45.6,"function":"Binds specifically to phosphatidylinositol 3,4-diphosphate (PtdIns3,4P2), but not to other phosphoinositides. May recruit other proteins to the plasma membrane","subcellular_location":"Cytoplasm; Cell membrane; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9HB21/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PLEKHA1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"DOCK7","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PLEKHA1","total_profiled":1310},"omim":[{"mim_id":"613778","title":"MACULAR DEGENERATION, AGE-RELATED, 8; ARMD8","url":"https://www.omim.org/entry/613778"},{"mim_id":"611313","title":"ARMS2 GENE; ARMS2","url":"https://www.omim.org/entry/611313"},{"mim_id":"610698","title":"MACULAR DEGENERATION, AGE-RELATED, 4; ARMD4","url":"https://www.omim.org/entry/610698"},{"mim_id":"607772","title":"PLECKSTRIN HOMOLOGY DOMAIN-CONTAINING PROTEIN, FAMILY A, MEMBER 1; PLEKHA1","url":"https://www.omim.org/entry/607772"},{"mim_id":"605512","title":"ELONGATION OF VERY LONG CHAIN FATTY ACIDS-LIKE 4; ELOVL4","url":"https://www.omim.org/entry/605512"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PLEKHA1"},"hgnc":{"alias_symbol":["TAPP1"],"prev_symbol":[]},"alphafold":{"accession":"Q9HB21","domains":[{"cath_id":"2.30.29.30","chopping":"4-112","consensus_level":"high","plddt":91.5417,"start":4,"end":112},{"cath_id":"2.30.29.30","chopping":"195-293","consensus_level":"high","plddt":91.9659,"start":195,"end":293}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HB21","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9HB21-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9HB21-F1-predicted_aligned_error_v6.png","plddt_mean":70.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PLEKHA1","jax_strain_url":"https://www.jax.org/strain/search?query=PLEKHA1"},"sequence":{"accession":"Q9HB21","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9HB21.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9HB21/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HB21"}},"corpus_meta":[{"pmid":"11802782","id":"PMC_11802782","title":"Evidence 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dynamics","date":"2025-10-14","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.13.681625","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13611,"output_tokens":3827,"usd":0.049119,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11482,"output_tokens":3393,"usd":0.071118,"stage2_stop_reason":"end_turn"},"total_usd":0.120237,"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\": 2001,\n      \"finding\": \"Crystal structure of the C-terminal PH domain of TAPP1 (PLEKHA1) at 1.4 Å resolution revealed the molecular basis for its specific binding to PtdIns(3,4)P2 but not PtdIns(3,4,5)P3. A key alanine residue adjacent to the D-5 inositol-phosphate-binding site (versus glycine in the related DAPP1) both sterically excludes PtdIns(3,4,5)P3 and induces a conformational change in neighboring residues. Mutagenesis confirmed this: the DAPP1 G→A mutation converted it to a TAPP1-like domain that only binds PtdIns(3,4)P2, while the TAPP1 A→G mutation permitted binding to PtdIns(3,4,5)P3.\",\n      \"method\": \"X-ray crystallography (1.4 Å) combined with site-directed mutagenesis and lipid-binding assays\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional mutagenesis validation, multiple orthogonal methods in one study\",\n      \"pmids\": [\"11513726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"TAPP1 (PLEKHA1) translocates from cytoplasm to plasma membrane upon agonist-stimulated PtdIns(3,4)P2 production in Swiss 3T3 and 293 cells. Translocation requires a functional PtdIns(3,4)P2-binding C-terminal PH domain and is blocked by the PI3K inhibitor wortmannin. Endogenously expressed TAPP1 co-immunoprecipitates with endogenous MUPP1 (a multi-PDZ-domain protein), and TAPP1/TAPP2 interact with the 10th and 13th PDZ domains of MUPP1 via their C-terminal amino acids, suggesting TAPP1 recruits MUPP1 to the plasma membrane in response to PtdIns(3,4)P2 elevation.\",\n      \"method\": \"Live-cell imaging, co-immunoprecipitation of endogenous proteins, PH-domain mutant analysis, wortmannin inhibition\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP of endogenous proteins combined with live-cell translocation assay and domain mutagenesis, two orthogonal methods\",\n      \"pmids\": [\"11802782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"TAPP1 and TAPP2 are recruited to the plasma membrane of human B-lymphoma cells (BJAB) upon B-cell antigen receptor (BCR) activation, with kinetics that are slow and sustained. The C-terminal PH domain alone is necessary and sufficient for BCR-induced membrane recruitment. Recruitment is abolished by PI3K blockade and constitutively driven by active PI3K. Membrane accumulation correlates with PtdIns(3,4)P2 (not PtdIns(3,4,5)P3) production. TAPP1 and TAPP2 preferentially accumulate in F-actin-rich membrane ruffles, implicating them in PI3K-driven cytoskeletal reorganization.\",\n      \"method\": \"Live-cell imaging, PI3K inhibitor/activator treatment, C-terminal PH domain truncation mutants, lipid production kinetics analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (live imaging, pharmacological inhibition, constitutive activation, domain mapping) in a single rigorous study\",\n      \"pmids\": [\"12101241\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Endogenously expressed TAPP1 is constitutively associated with the protein-tyrosine phosphatase PTPL1 (FAP-1). PTPL1 binds TAPP1 and TAPP2 principally through its first PDZ domain, enabling PTPL1 to associate with PtdIns(3,4)P2 in vitro. The TAPP1–PTPL1 interaction maintains PTPL1 in the cytoplasm; upon hydrogen-peroxide-stimulated PtdIns(3,4)P2 production, the TAPP1–PTPL1 complex translocates to the plasma membrane. TAPP1 binding does not alter PTPL1 phosphatase activity itself. RNAi-mediated knockdown of TAPP1 in HEK-293 cells enhanced IGF1-stimulated Akt activation and phosphorylation, consistent with a negative-regulatory role.\",\n      \"method\": \"Co-immunoprecipitation of endogenous proteins, in vitro lipid-binding assay, cellular localization imaging, siRNA knockdown with Akt phosphorylation readout\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — endogenous co-IP plus in vitro lipid binding plus siRNA functional rescue, multiple orthogonal methods\",\n      \"pmids\": [\"14516276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Using GST-TAPP1-PH domain as a specific probe in on-section immunoelectron microscopy, PtdIns(3,4)P2 was detected not only at the plasma membrane but also on intracellular organelles including the endoplasmic reticulum and multivesicular endosomes after PDGF or hydrogen peroxide stimulation. Intracellular and plasma-membrane pools of PtdIns(3,4)P2 showed differential sensitivity to PTEN phosphatase, revealing compartmentally distinct signaling pools.\",\n      \"method\": \"Immunoelectron microscopy using GST-TAPP1-PH domain as a lipid probe, PTEN re-expression in PTEN-null cells\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct subcellular localization by electron microscopy with functional PTEN validation, single lab\",\n      \"pmids\": [\"14604433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"TAPP1 interacts with the PDZ domains of gamma1-, alpha1-, and beta2-syntrophin via its C-terminal amino acids; this interaction is required for correct subcellular localization of TAPP1. Both TAPP1 and syntrophins co-localize to PDGF-induced dorsal circular membrane ruffles in NIH-3T3 cells. Ectopic overexpression of TAPP1 blocks PDGF-induced dorsal circular ruffle formation, but co-expression of alpha1- or gamma1-syntrophin rescues this blockade, indicating that syntrophins regulate TAPP1-mediated actin cytoskeletal remodeling downstream of PI3K/PtdIns(3,4)P2 signaling.\",\n      \"method\": \"Yeast two-hybrid screen, biochemical PDZ domain binding assays, co-localization imaging, overexpression and rescue experiments in NIH-3T3 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — yeast two-hybrid confirmed biochemically, functional overexpression rescue with syntrophin, multiple orthogonal methods in one study\",\n      \"pmids\": [\"15485858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Knock-in mice homozygous for PtdIns(3,4)P2-binding-deficient mutations in both TAPP1 (R211L) and TAPP2 (R218L) are viable but display significantly enhanced Akt activation and improved whole-body insulin sensitivity with increased glucose disposal into muscle. Embryonic fibroblasts from double knock-in mice show enhanced IGF1-stimulated PtdIns(3,4,5)P3 production and Akt activity. This establishes that TAPP1/TAPP2 binding to PtdIns(3,4)P2 acts as a negative regulator of the PI3K–Akt–insulin signaling axis.\",\n      \"method\": \"Knock-in mouse genetics (R211L mutation), insulin clamp/glucose disposal assays, primary embryonic fibroblasts with PtdIns(3,4,5)P3 measurement and Akt phosphorylation\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vivo knock-in genetic epistasis with multiple physiological readouts, replicated in primary cells\",\n      \"pmids\": [\"21204784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TAPP1 (PLEKHA1) is selectively expressed in differentiating oligodendrocyte precursor cells (OPCs). Knockdown of TAPP1 promotes OPC differentiation and myelin gene expression, while overexpression suppresses differentiation. TAPP1 inhibition alters Erk1/2 (but not Akt) phosphorylation, placing TAPP1 as a negative regulator of OPC differentiation specifically through the Mek/Erk pathway rather than the canonical PI3K/Akt axis.\",\n      \"method\": \"siRNA knockdown and overexpression in primary OPC cultures, myelin gene expression assays, western blot for Erk1/2 and Akt phosphorylation\",\n      \"journal\": \"Neuroscience bulletin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function and loss-of-function with defined molecular readout (Erk vs Akt), single lab with two complementary perturbations\",\n      \"pmids\": [\"26242484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"EIF4G2 (a translation initiation factor) regulates PLEKHA1 protein expression via IRES-dependent translation in hepatocellular carcinoma (HCC). RNA immunoprecipitation showed EIF4G2 associates with PLEKHA1 mRNA, and dual-luciferase reporter assays confirmed IRES-dependent translational control. Polysome analysis and nascent protein synthesis assays validated EIF4G2 as the writer of this translational regulation. Combined depletion of EIF4G2 and PLEKHA1 synergistically inhibits HCC cell migration and invasion.\",\n      \"method\": \"RNA immunoprecipitation (RIP), dual-luciferase reporter assay, polysome profiling, nascent protein synthesis assay, siRNA knockdown\",\n      \"journal\": \"Journal of proteome research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal biochemical methods (RIP, reporter assay, polysome profiling) in a single lab study\",\n      \"pmids\": [\"39213495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A PLEKHA1-TACC2 chromosomal fusion gene produces a fusion protein that upregulates the EphA2/AKT/MMP2 signaling pathway and promotes vascular mimicry formation in esophageal squamous-cell carcinoma (ESCC) by reducing ubiquitylation of EphA2. In vivo, PLEKHA1-TACC2 fusion combined with Trp53 deletion significantly increases tumor incidence in a transgenic mouse model, suppressible by EphA2 inhibitors.\",\n      \"method\": \"RNA sequencing identification of fusion transcript, in vitro and in vivo functional assays, ubiquitylation assay for EphA2, transgenic mouse model, pharmacological inhibition with EphA2 inhibitors\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (ubiquitylation assay, transgenic mouse model, pharmacological rescue) in a single study for a fusion-protein context\",\n      \"pmids\": [\"40615663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Live imaging with a TAPP1 (PLEKHA1) 3xcPH domain probe in Xenopus laevis retinal ganglion cell filopodia showed that PtdIns(3,4)P2 accumulates specifically at filopodial tips. Quantitative cross-correlation and Granger causality analysis demonstrated that PI(3,4)P2 at filopodial tips both generates tip extension and responds to forward filopodial movement. Disruption of actin polymerization rapidly depleted tip PI(3,4)P2 prior to filopodial stalling, establishing a bidirectional relationship between PI(3,4)P2 and actin dynamics at filopodial tips.\",\n      \"method\": \"Live-cell TAPP1-3xcPH domain imaging, pharmacological PI3K perturbation, quantitative cross-correlation and Granger causality analysis, actin polymerization disruption\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct live imaging with validated lipid biosensor combined with quantitative causality analysis, preprint single study\",\n      \"pmids\": [\"bio_10.1101_2025.10.13.681625\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"PLEKHA1 (TAPP1) is a cytoplasmic adaptor protein whose C-terminal PH domain selectively binds PtdIns(3,4)P2 (but not PtdIns(3,4,5)P3) — a specificity structurally explained by an alanine residue that sterically excludes the D-5 phosphate of PtdIns(3,4,5)P3 — causing its PI3K-dependent translocation to the plasma membrane, where it recruits PDZ-domain-containing partners (MUPP1, PTPL1, syntrophins) to act as a negative regulator of PI3K–Akt–insulin signaling; it also modulates actin cytoskeletal remodeling (dorsal ruffles, filopodial dynamics) and OPC differentiation via the Mek/Erk pathway, while a chromosomal PLEKHA1-TACC2 fusion drives oncogenic EphA2/AKT/MMP2 signaling in esophageal carcinoma.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PLEKHA1 (TAPP1) is a cytoplasmic adaptor protein that reads the lipid second messenger PtdIns(3,4)P2 through its C-terminal PH domain and acts as a negative regulator of PI3K-driven signaling [#3, #6]. A 1.4 Å crystal structure defined the basis for its lipid selectivity: an alanine adjacent to the D-5 phosphate-binding site sterically excludes PtdIns(3,4,5)P3, restricting binding to PtdIns(3,4)P2, a specificity reversible by reciprocal Ala/Gly swaps with the related DAPP1 [#0]. Agonist- or receptor-stimulated, PI3K-dependent production of PtdIns(3,4)P2 drives translocation of PLEKHA1 from cytosol to the plasma membrane via this PH domain [#1, #2]. At the membrane it functions as a scaffold, recruiting PDZ-domain partners including MUPP1, the tyrosine phosphatase PTPL1, and syntrophins through its C-terminal residues [#1, #3, #5]. Genetic disruption of PtdIns(3,4)P2 binding in TAPP1/TAPP2 double knock-in mice enhances Akt activation and whole-body insulin sensitivity, establishing the PtdIns(3,4)P2–PLEKHA1 interaction as a brake on the PI3K–Akt–insulin axis [#6]. Through its syntrophin interaction PLEKHA1 also modulates actin-based remodeling, controlling PDGF-induced dorsal circular ruffles [#5], and a TAPP1 PH-domain biosensor reveals PtdIns(3,4)P2 enrichment at the plasma membrane and on intracellular organelles [#4]. In disease contexts, a PLEKHA1-TACC2 fusion drives oncogenic EphA2/AKT/MMP2 signaling and vascular mimicry in esophageal squamous-cell carcinoma [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Resolved why PLEKHA1 distinguishes PtdIns(3,4)P2 from PtdIns(3,4,5)P3, defining the structural code for its phosphoinositide selectivity.\",\n      \"evidence\": \"1.4 Å crystal structure of the C-terminal PH domain with reciprocal Ala/Gly mutagenesis and lipid-binding assays\",\n      \"pmids\": [\"11513726\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address full-length protein conformation or in vivo membrane engagement\", \"No structure of partner-bound complexes\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Established that PtdIns(3,4)P2 binding by the PH domain drives PI3K-dependent membrane translocation and links PLEKHA1 to a PDZ-scaffold partner.\",\n      \"evidence\": \"Live-cell imaging, endogenous co-IP with MUPP1, PH-domain mutants, and wortmannin inhibition in Swiss 3T3/293 cells; BCR-stimulated recruitment in B-lymphoma cells\",\n      \"pmids\": [\"11802782\", \"12101241\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of MUPP1 recruitment at the membrane not defined\", \"Accumulation in F-actin ruffles is correlative, not mechanistic\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identified PLEKHA1 as a negative regulator of Akt signaling that also tethers the phosphatase PTPL1, partially defining its adaptor output.\",\n      \"evidence\": \"Endogenous co-IP, in vitro lipid binding, localization imaging, and siRNA knockdown with IGF1-stimulated Akt readout in HEK-293 cells\",\n      \"pmids\": [\"14516276\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which PLEKHA1 dampens Akt not resolved\", \"PTPL1 substrate at the membrane not identified\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Extended PtdIns(3,4)P2 signaling beyond the plasma membrane and mapped PLEKHA1 to a syntrophin-dependent actin-remodeling role.\",\n      \"evidence\": \"Immunoelectron microscopy with GST-TAPP1-PH probe and PTEN re-expression; yeast two-hybrid, PDZ-binding assays, and overexpression/rescue with syntrophins in NIH-3T3 cells\",\n      \"pmids\": [\"14604433\", \"15485858\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Role of intracellular PtdIns(3,4)P2 pools for PLEKHA1 unclear\", \"How syntrophin binding mechanistically controls dorsal ruffle formation not defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Provided in vivo genetic proof that PtdIns(3,4)P2 binding by TAPP1/TAPP2 restrains the PI3K–Akt–insulin axis.\",\n      \"evidence\": \"TAPP1 R211L / TAPP2 R218L knock-in mice with insulin clamp/glucose disposal assays and PtdIns(3,4,5)P3/Akt measurement in primary fibroblasts\",\n      \"pmids\": [\"21204784\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Effector mechanism downstream of membrane-bound TAPP1 not pinned down\", \"Tissue-specific contributions of each paralog not separated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed a PI3K-independent role: PLEKHA1 negatively regulates oligodendrocyte precursor differentiation via the Mek/Erk pathway.\",\n      \"evidence\": \"siRNA knockdown and overexpression in primary OPC cultures with myelin gene expression and Erk1/2 vs Akt phosphorylation readouts\",\n      \"pmids\": [\"26242484\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between PLEKHA1 and Erk activation not established\", \"Single-lab finding without in vivo validation\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified upstream translational control of PLEKHA1 by EIF4G2 and a pro-invasive role in hepatocellular carcinoma.\",\n      \"evidence\": \"RNA immunoprecipitation, IRES dual-luciferase reporter, polysome profiling, nascent synthesis assays, and combined siRNA depletion in HCC cells\",\n      \"pmids\": [\"39213495\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How PLEKHA1 levels mechanistically drive migration/invasion not defined\", \"IRES element within PLEKHA1 mRNA not mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated that a PLEKHA1-TACC2 fusion is oncogenic, driving EphA2/AKT/MMP2 signaling and vascular mimicry.\",\n      \"evidence\": \"RNA-seq fusion identification, EphA2 ubiquitylation assay, transgenic mouse model with Trp53 deletion, and EphA2 inhibitor rescue in ESCC\",\n      \"pmids\": [\"40615663\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Contribution of the PLEKHA1 portion versus TACC2 to fusion activity not dissected\", \"Mechanism of reduced EphA2 ubiquitylation unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PLEKHA1's PtdIns(3,4)P2-dependent scaffolding mechanistically connects to its diverse downstream outputs (Akt suppression, Erk regulation, actin/filopodial dynamics) across cell types remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying effector mechanism linking membrane recruitment to specific signaling outputs\", \"Filopodial PtdIns(3,4)P2–actin coupling shown only with biosensor in a preprint\", \"PLEKHA1's direct catalytic or enzymatic partners at the membrane not fully enumerated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 1, 2, 3, 4]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 3, 5]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 2, 3, 4]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [2, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 6]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MUPP1\", \"PTPL1\", \"SNTA1\", \"SNTB2\", \"SNTG1\", \"TACC2\", \"EIF4G2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}