{"gene":"PLEKHA7","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2010,"finding":"PLEKHA7 is a cytoplasmic component of the epithelial adherens junction (AJ) belt, localized at a mean distance of ~28 nm from the plasma membrane, concentrated in the apical junctional belt similarly to E-cadherin and p120-ctn but unlike ZO-1, and not extending along the lateral region of polarized epithelial cells.","method":"Immunoelectron microscopy, immunofluorescence microscopy, immunoblotting, northern blotting in mammalian tissues and cultured epithelial cells","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — immunoelectron microscopy provides direct subcellular localization with nm-precision; multiple orthogonal methods; replicated across several tissue types","pmids":["20808826"],"is_preprint":false},{"year":2011,"finding":"PLEKHA7 directly interacts with paracingulin (through a central region of PLEKHA7 binding the globular head domain of paracingulin) and forms a complex with p120-ctn; depletion of PLEKHA7 from MDCK cells results in loss of junctional localization of paracingulin and decreased paracingulin expression, identifying PLEKHA7 as a recruiter of paracingulin to adherens junctions.","method":"Yeast two-hybrid screen, GST pulldown, co-immunoprecipitation, siRNA knockdown with immunofluorescence","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct interaction confirmed by yeast two-hybrid and in vitro GST pulldown, functional consequence (loss of paracingulin localization) confirmed by KD, multiple orthogonal methods","pmids":["21454477"],"is_preprint":false},{"year":2013,"finding":"PLEKHA7 binds directly to afadin (in addition to p120-ctn) and is recruited to nectin-3α-based cell-cell adhesion sites in an afadin-dependent but p120-ctn-independent manner; this PLEKHA7-afadin binding is required for proper AJ formation but not tight junction formation in epithelial cells.","method":"Co-immunoprecipitation, pulldown, expression of dominant-negative constructs, immunofluorescence in EpH4 cells with KD/rescue experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — direct binding confirmed by pulldown and Co-IP, functional AJ assembly phenotype established by KD, multiple methods in single lab","pmids":["23990464"],"is_preprint":false},{"year":2014,"finding":"PLEKHA7 forms a complex with the cytoplasmic TJ proteins ZO-1 and cingulin (by co-immunoprecipitation), and inducible expression of PLEKHA7 constructs enhances E-cadherin recruitment at the apical zonula adhaerens and modulates TJ barrier dynamics (decreased TER at 18 h post-assembly; attenuated TER fall after calcium removal) through microtubule-dependent mechanisms.","method":"Inducible expression in MDCK cells, transepithelial resistance measurements, calcium-switch assay, nocodazole treatment, co-immunoprecipitation","journal":"Tissue barriers","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — functional TER phenotype and Co-IP data in single lab; nocodazole experiment provides mechanistic link to microtubules","pmids":["24843844"],"is_preprint":false},{"year":2014,"finding":"Zinc-finger nuclease-mediated mutation of Plekha7 in Dahl salt-sensitive rats attenuates salt-sensitive hypertension, reduces total peripheral resistance and perivascular fibrosis, and improves endothelium-dependent vasodilation, correlated with changes in intracellular calcium handling and increased nitric oxide bioavailability in mutant vessels.","method":"Zinc-finger nuclease gene editing in rat model, telemetric blood pressure measurement, myography of isolated mesenteric arteries, histology, calcium imaging","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo loss-of-function genetic model with multiple orthogonal phenotypic readouts (blood pressure, vascular function, calcium handling, nitric oxide)","pmids":["25136115"],"is_preprint":false},{"year":2016,"finding":"PLEKHA7 recruits PDZD11 to adherens junctions via a direct interaction between the N-terminal WW domain of PLEKHA7 and the N-terminal 44 amino acids of PDZD11 (shown by GST pulldown); PLEKHA7 KO abolishes junctional PDZD11 localization; the PLEKHA7-PDZD11 complex stabilizes nectin-1 and nectin-3 (preventing proteasome-mediated degradation) and promotes efficient early junction assembly in the calcium-switch model.","method":"Yeast two-hybrid, mass spectrometry of PLEKHA7 immunoprecipitates, GST pulldown, co-immunoprecipitation, CRISPR/Cas9 KO, immunofluorescence, calcium-switch assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct interaction mapped by in vitro pulldown, multiple orthogonal methods (MS, Co-IP, KO rescue), functional consequence on nectin stability and junction assembly established","pmids":["27044745"],"is_preprint":false},{"year":2016,"finding":"PLEKHA7 loss activates the actin regulator cofilin in a p120-catenin-dependent manner; PLEKHA7 associates with and regulates levels of PP1α phosphatase, which is responsible for cofilin activation, linking PLEKHA7 to cortical actin ring dynamics at the apical zonula adhaerens.","method":"Co-immunoprecipitation, immunoblotting after KD/KO, phospho-cofilin assays, proteomics of PLEKHA7 immunoprecipitates","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP and KD phenotype in single lab; p120-dependence established by double-KD epistasis; mechanistic link to PP1α shown by association","pmids":["26822694"],"is_preprint":false},{"year":2017,"finding":"PLEKHA7 specifically interacts with GTP-bound Rac1 and Cdc42 (but not RhoA) and stimulates their GTP hydrolysis without affecting nucleotide exchange, identifying PLEKHA7 as a novel Rac1/Cdc42 GAP; silencing PLEKHA7 compromises paracellular barrier integrity in non-pigmented ciliary epithelial cells and affects actin cytoskeleton organization.","method":"Co-immunoprecipitation with GTP/GDP-loaded GTPases, GTP hydrolysis assay, siRNA knockdown with transepithelial resistance and actin staining readouts","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — GAP activity confirmed by in vitro GTP hydrolysis assay, GTP-state selectivity shown by pulldown; functional barrier phenotype by KD; single lab","pmids":["29016860"],"is_preprint":false},{"year":2018,"finding":"Insm1 transcription factor represses Plekha7 expression in neural progenitor cells; CRISPR/Cas9-mediated disruption of Plekha7 alone is sufficient to cause NPC delamination from the ventricular surface, converting apical to basal radial glia; Plekha7 overexpression impedes NPC delamination and counteracts Insm1-induced delamination, placing Plekha7 downstream of Insm1 in control of adherens junction belt integrity.","method":"CRISPR/Cas9 KO in mouse neocortex, in utero electroporation overexpression, immunofluorescence, Insm1 forced expression experiments","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis established by KO and rescue in vivo; multiple loss- and gain-of-function experiments across labs/organisms; clear cellular phenotype","pmids":["29503187"],"is_preprint":false},{"year":2018,"finding":"PLEKHA7 overexpression reduces formation of the E-cadherin-EGFR complex, decreases EGFR activation and downstream CDK5 signaling, and reduces cell tumorigenicity in ovarian cancer cells, demonstrating that PLEKHA7 negatively regulates E-cadherin/EGFR crosstalk.","method":"Lentiviral PLEKHA7 overexpression, co-immunoprecipitation of E-cadherin-EGFR complex, EGFR phosphorylation immunoblotting, 3D growth assays, confocal microscopy","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — co-IP and functional growth assays; single lab; mechanistic link to EGFR/CDK5 pathway established by overexpression and co-IP","pmids":["29996940"],"is_preprint":false},{"year":2020,"finding":"The tandem WW domains of PLEKHA7 cooperatively bind PDZD11: Asp-30 of WW1 and His-75 of WW2 form a hydrogen bond and together with Thr-35 of WW1 create a binding pocket for a polyproline stretch in PDZD11; WW2 stabilizes WW1 and promotes PDZD11 binding; PDZD11 binding induces a conformational rearrangement that expands a hydrophobic hot spot on WW1, enabling tetraspanin 33 (via its C-terminal Trp-283/Tyr-282) to bind the WW1 hydrophobic surface.","method":"Site-directed mutagenesis, GST pulldown, immunofluorescence, molecular modeling and docking","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — mutagenesis combined with pulldown and molecular modeling; single lab; mechanistic detail of WW domain interaction defined","pmids":["32371390"],"is_preprint":false},{"year":2021,"finding":"PLEKHA5, PLEKHA6, and PLEKHA7 (WW-PLEKHAs) interact with PDZD11 through their WW domains and are required for efficient anterograde targeting of the Menkes ATPase ATP7A to the cell periphery under elevated copper; CRISPR-KO of WW-PLEKHAs reduces peripheral ATP7A localization; WW-PLEKHAs and PDZD11 are required for maintaining low intracellular copper levels under elevated copper conditions.","method":"CRISPR-KO, pulldown, immunofluorescence microscopy, surface biotinylation, copper measurement, cell viability assays, metallothionein-1 expression","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — CRISPR-KO with rescue, pulldown, multiple functional readouts (copper levels, ATP7A localization, cell viability); multiple labs or comprehensive single-lab study","pmids":["34613798"],"is_preprint":false},{"year":2021,"finding":"The PH domain of PLEKHA7 directly interacts with membrane-embedded phosphatidylinositol lipids (PIPs) in a multivalent manner that induces PIP clustering, distinct from discrete one-to-one binding; residue D175 acts as a 'sentry' preventing PI(3,4)P2 and PI(3,4,5)P3 binding; this PH domain-lipid interaction is critical for PLEKHA7 cellular localization and function.","method":"X-ray crystallography, NMR, molecular dynamics simulations, isothermal titration calorimetry, site-directed mutagenesis","journal":"Structure (London, England : 1993)","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure, NMR, and ITC with mutagenesis in single rigorous study; multiple orthogonal biophysical methods","pmids":["33878292"],"is_preprint":false},{"year":2021,"finding":"The WW domain, PH domain, and C-terminal/coiled-coil regions of PLEKHA7 cooperate to determine its subcellular localization at adherens junctions: the PH domain of PLEKHA7 promotes AJ localization in chimeric proteins, the C-terminal and coiled-coil regions promote AJ localization, and the WW-PDZD11 interaction is required for microtubule association of PLEKHA5.","method":"Expression of mutant and chimeric WW-PLEKHA proteins in cultured epithelial cells, immunofluorescence microscopy","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — domain-swap and deletion analysis in cells; single lab; localization mapped to specific domains","pmids":["34568338"],"is_preprint":false},{"year":2021,"finding":"PLEKHA7 directly interacts with wild-type KRas (but scantily with mutant KRas) as shown by FLIM-FRET; inhibiting the PLEKHA7 PH domain (molecularly or pharmacologically) specifically decreases mutant-KRas cell signaling, proliferation, attachment, migration, and tumor growth, but not wild-type KRas cells.","method":"FLIM-FRET, siRNA/pharmacological inhibition of PH domain, proliferation/migration/attachment assays, in vivo tumor growth","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — FLIM-FRET for direct interaction, functional phenotype by KD/inhibition; single lab; novel interaction with mut-KRas pathway","pmids":["34800542"],"is_preprint":false},{"year":2022,"finding":"PLEKHA7-PDZD11 complex regulates the localization of the plasma membrane calcium ATPase PMCA: KO of PLEKHA7 or PDZD11 increases PMCA accumulation at lateral cell-cell contacts and causes ectopic apical localization of PMCA4x/b; PDZD11 counteracts calcium extrusion activity of PMCA4x/b (but not PMCA4x/a lacking the PDZ-binding motif); KO of PDZD11 increases the rate of calcium extrusion.","method":"CRISPR-KO, immunofluorescence, surface biotinylation, cytosolic calcium transient measurements, PDZD11 co-expression in HeLa cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR-KO with multiple cell lines, surface biotinylation, functional calcium assays, PDZ-binding motif specificity control; multiple orthogonal methods","pmids":["35714771"],"is_preprint":false},{"year":2023,"finding":"The hTERT-p50 homodimer directly binds the PLEKHA7 promoter and represses PLEKHA7 transcription; increased hTERT decreases PLEKHA7 expression and promotes invasion and metastasis in gastric cancer cells in a PLEKHA7-dependent manner.","method":"ChIP assay (hTERT/p50 binding to PLEKHA7 promoter), co-immunoprecipitation, siRNA knockdown, invasion/migration assays, overexpression rescue experiments","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — ChIP establishes direct promoter binding; KD/rescue functional assays; single lab","pmids":["36823376"],"is_preprint":false},{"year":2024,"finding":"PLEKHA7 regulates ECM remodeling by controlling levels and activity of MMP1 and LOX through miR-24 and miR-30c miRNAs; PLEKHA7 depletion causes LOX-dependent ECM remodeling in culture and in the colonic mucosal lamina propria in mice; PLEKHA7-depleted cells show increased migration and invasion that are MMP1- and LOX-dependent.","method":"siRNA/KO depletion, miRNA quantification, MMP1/LOX activity assays, 3D culture, in vivo mouse colonic lamina propria analysis, migration/invasion assays with pharmacological rescue","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — preprint; multiple functional readouts linking PLEKHA7 to miRNA-MMP1/LOX axis; in vivo validation; single lab","pmids":["38853930"],"is_preprint":true}],"current_model":"PLEKHA7 is a cytoplasmic adaptor protein anchored at the apical epithelial adherens junction belt through cooperative interactions between its WW domains (binding p120-ctn, paracingulin, afadin, and PDZD11), PH domain (binding membrane PIPs in a multivalent, clustering manner), and C-terminal/coiled-coil regions; it stabilizes the E-cadherin complex by linking it to microtubules, recruits PDZD11 to stabilize junctional nectins and direct trafficking of transmembrane proteins (ATP7A, PMCA), acts as a Rac1/Cdc42 GAP to regulate actin organization and paracellular barrier function, controls cofilin activation via PP1α in a p120-dependent manner, suppresses E-cadherin/EGFR signaling, and regulates ECM remodeling through miRNA-mediated control of MMP1 and LOX—with loss of PLEKHA7 at the apical junction belt promoting neural progenitor delamination, hypertension, and tumor progression."},"narrative":{"mechanistic_narrative":"PLEKHA7 is a cytoplasmic adaptor protein that defines and stabilizes the apical adherens junction (zonula adhaerens) belt of polarized epithelial cells, where it is concentrated within ~28 nm of the plasma membrane alongside E-cadherin and p120-catenin but excluded from the lateral membrane and tight junction [PMID:20808826]. It assembles a junctional scaffold through cooperative, multidomain interactions: its WW domains and central/C-terminal regions bind p120-catenin, paracingulin, and afadin to recruit these partners to the junction and drive proper AJ assembly [PMID:21454477, PMID:23990464], while its PH domain engages membrane phosphoinositides in a multivalent, clustering mode that is essential for junctional localization [PMID:33878292], and its WW, PH, and coiled-coil regions act in concert to target the protein to adherens junctions [PMID:34568338]. A key effector branch is the recruitment of PDZD11 via cooperative engagement of the tandem WW domains, which stabilizes junctional nectins against proteasomal degradation and promotes junction assembly [PMID:27044745, PMID:32371390]; the same PLEKHA7–PDZD11 module directs trafficking and localization of transmembrane transporters, supporting copper-induced peripheral targeting of the ATPase ATP7A and controlling the distribution and calcium-extrusion activity of the plasma membrane calcium pump PMCA [PMID:34613798, PMID:35714771]. PLEKHA7 also shapes junctional actin dynamics, acting as a Rac1/Cdc42 GAP that stimulates GTP hydrolysis to maintain paracellular barrier integrity [PMID:29016860] and regulating cofilin activation through association with PP1α in a p120-catenin-dependent manner [PMID:26822694]. Through its control of the junctional belt PLEKHA7 restrains tumor-promoting signaling and cell behavior: it suppresses E-cadherin/EGFR complex formation and downstream signaling [PMID:29996940] and limits ECM remodeling via miR-24/miR-30c-mediated control of MMP1 and LOX [PMID:38853930]. Loss of PLEKHA7 at the apical belt drives neural progenitor delamination downstream of the Insm1 transcription factor [PMID:29503187] and contributes to salt-sensitive hypertension with impaired vascular function in vivo [PMID:25136115].","teleology":[{"year":2010,"claim":"Established that PLEKHA7 is a defining cytoplasmic component of the epithelial adherens junction belt rather than a general junctional or tight-junction protein, placing it spatially at the zonula adhaerens.","evidence":"Immunoelectron and immunofluorescence microscopy with immunoblotting/northern blotting across mammalian tissues and epithelial cell lines","pmids":["20808826"],"confidence":"High","gaps":["Molecular partners anchoring it at this position not yet defined","Functional consequence of its junctional localization untested"]},{"year":2011,"claim":"Identified PLEKHA7 as a recruiter of cytoskeletal/junctional partners, showing it binds paracingulin and complexes with p120-catenin to organize junction composition.","evidence":"Yeast two-hybrid, GST pulldown, co-IP, and siRNA knockdown with immunofluorescence in MDCK cells","pmids":["21454477"],"confidence":"High","gaps":["Did not define the full domain requirements for these interactions","Downstream functional output of paracingulin recruitment unresolved"]},{"year":2013,"claim":"Showed PLEKHA7 binds afadin and is recruited to nectin-based adhesion sites in a p120-independent, afadin-dependent manner, establishing multiple recruitment routes specific to AJ (not TJ) assembly.","evidence":"Co-IP, pulldown, dominant-negative expression, and KD/rescue immunofluorescence in EpH4 cells","pmids":["23990464"],"confidence":"High","gaps":["Relative contributions of afadin versus p120 routes in vivo unknown","Structural basis of afadin binding not mapped"]},{"year":2014,"claim":"Linked PLEKHA7 to E-cadherin recruitment and barrier dynamics through microtubule-dependent mechanisms, and to a complex with ZO-1/cingulin.","evidence":"Inducible expression in MDCK cells, transepithelial resistance, calcium-switch and nocodazole treatments, co-IP","pmids":["24843844"],"confidence":"Medium","gaps":["Mechanism connecting PLEKHA7 to microtubules at the molecular level unresolved","ZO-1/cingulin association is correlative without direct binding mapping"]},{"year":2014,"claim":"Demonstrated an in vivo physiological role: PLEKHA7 loss-of-function attenuates salt-sensitive hypertension and improves vascular function, connecting the junctional adaptor to systemic blood pressure regulation.","evidence":"Zinc-finger nuclease editing in Dahl salt-sensitive rats with telemetric BP, myography, histology, and calcium imaging","pmids":["25136115"],"confidence":"High","gaps":["Mechanistic link between junctional function and vascular calcium/NO handling not established","Cell type driving the hypertension phenotype not pinpointed"]},{"year":2016,"claim":"Identified PDZD11 as a WW-domain-bound effector that PLEKHA7 recruits to junctions to stabilize nectins and promote junction assembly, defining a major output branch.","evidence":"Yeast two-hybrid, MS of immunoprecipitates, GST pulldown, CRISPR KO, immunofluorescence, calcium-switch assay","pmids":["27044745"],"confidence":"High","gaps":["Structural detail of the WW-PDZD11 interface not yet resolved","Whether PDZD11 mediates additional PLEKHA7 functions unknown"]},{"year":2016,"claim":"Connected PLEKHA7 to junctional actin regulation, showing it controls cofilin activation via association with PP1α phosphatase in a p120-dependent manner.","evidence":"Co-IP, immunoblotting after KD/KO, phospho-cofilin assays, proteomics of immunoprecipitates","pmids":["26822694"],"confidence":"Medium","gaps":["Direct versus indirect PLEKHA7-PP1α binding not distinguished","Single-lab study without reciprocal validation"]},{"year":2017,"claim":"Assigned an enzymatic activity to PLEKHA7 as a Rac1/Cdc42 GAP, providing a mechanism by which it shapes actin organization and paracellular barrier integrity.","evidence":"Co-IP with GTP/GDP-loaded GTPases, in vitro GTP hydrolysis assay, siRNA KD with TER and actin readouts in ciliary epithelial cells","pmids":["29016860"],"confidence":"Medium","gaps":["GAP domain within PLEKHA7 not mapped","Whether GAP activity operates at the junction in vivo untested"]},{"year":2018,"claim":"Placed PLEKHA7 downstream of Insm1 as a controller of apical junction belt integrity in neural progenitors, where its loss alone drives delamination and apical-to-basal conversion.","evidence":"CRISPR/Cas9 KO and in utero electroporation overexpression in mouse neocortex with Insm1 epistasis","pmids":["29503187"],"confidence":"High","gaps":["Whether junctional partners mediate the delamination phenotype not tested","Link to broader developmental outcomes unresolved"]},{"year":2018,"claim":"Established a tumor-suppressive function: PLEKHA7 limits E-cadherin/EGFR complex formation and downstream CDK5 signaling to reduce tumorigenicity.","evidence":"Lentiviral overexpression, co-IP of E-cadherin-EGFR, EGFR phospho-immunoblotting, 3D growth assays in ovarian cancer cells","pmids":["29996940"],"confidence":"Medium","gaps":["Loss-of-function (rather than overexpression) effects on EGFR not tested here","Single-lab study"]},{"year":2020,"claim":"Resolved how the tandem WW domains cooperatively bind PDZD11 and how PDZD11 binding allosterically licenses tetraspanin 33 engagement, defining the structural logic of WW-mediated partner recruitment.","evidence":"Site-directed mutagenesis, GST pulldown, immunofluorescence, molecular modeling and docking","pmids":["32371390"],"confidence":"Medium","gaps":["No experimental high-resolution structure of the WW-PDZD11 complex","Functional role of tetraspanin 33 recruitment untested"]},{"year":2021,"claim":"Defined the PH domain as a multivalent PIP-clustering module required for PLEKHA7 localization, identifying residue D175 as a lipid-selectivity sentry.","evidence":"X-ray crystallography, NMR, MD simulations, ITC, and site-directed mutagenesis","pmids":["33878292"],"confidence":"High","gaps":["How PIP clustering integrates with protein-protein junctional anchoring not resolved","In vivo relevance of lipid selectivity untested"]},{"year":2021,"claim":"Showed multidomain cooperation (WW, PH, C-terminal/coiled-coil) jointly determines AJ targeting and that the WW-PDZD11 interaction underlies microtubule association in the WW-PLEKHA family.","evidence":"Domain-swap and deletion analysis of chimeric WW-PLEKHA proteins with immunofluorescence in epithelial cells","pmids":["34568338"],"confidence":"Medium","gaps":["Quantitative contribution of each domain to anchoring not dissected","Microtubule link shown for PLEKHA5 rather than PLEKHA7 directly"]},{"year":2021,"claim":"Extended the PLEKHA7-PDZD11 module to transmembrane transporter trafficking, showing it is required for copper-induced peripheral targeting of ATP7A and maintenance of low intracellular copper.","evidence":"CRISPR-KO, pulldown, surface biotinylation, copper measurement, and viability assays","pmids":["34613798"],"confidence":"High","gaps":["Mechanism of how the complex directs ATP7A trafficking not detailed","Whether junctional pool versus other pools mediates this unresolved"]},{"year":2021,"claim":"Identified a PH-domain-dependent interaction with wild-type KRas and showed PH-domain inhibition selectively impairs mutant-KRas cell growth and tumor formation.","evidence":"FLIM-FRET, siRNA/pharmacological PH-domain inhibition, proliferation/migration/attachment assays, in vivo tumor growth","pmids":["34800542"],"confidence":"Medium","gaps":["Mechanism reconciling WT-KRas binding with mutant-KRas dependence unclear","Single-lab study"]},{"year":2022,"claim":"Demonstrated that the PLEKHA7-PDZD11 complex controls PMCA localization and calcium-extrusion activity, with PDZ-binding-motif specificity, linking the junctional scaffold to calcium homeostasis.","evidence":"CRISPR-KO, immunofluorescence, surface biotinylation, cytosolic calcium transient measurements, PDZD11 co-expression in HeLa cells","pmids":["35714771"],"confidence":"High","gaps":["Physiological consequence of altered PMCA calcium extrusion in epithelia untested","Connection to the hypertension calcium phenotype not directly established"]},{"year":2023,"claim":"Showed transcriptional silencing of PLEKHA7 by an hTERT-p50 dimer drives gastric cancer invasion and metastasis in a PLEKHA7-dependent manner, establishing a regulatory input controlling its tumor-suppressive output.","evidence":"ChIP, co-IP, siRNA KD, invasion/migration assays, and overexpression rescue","pmids":["36823376"],"confidence":"Medium","gaps":["Whether this regulation occurs in non-gastric tissues unknown","Mechanistic link from PLEKHA7 loss to invasion not fully resolved here"]},{"year":2024,"claim":"Connected PLEKHA7 to ECM remodeling through miR-24/miR-30c control of MMP1 and LOX, providing a mechanism for invasion downstream of PLEKHA7 loss.","evidence":"siRNA/KO depletion, miRNA quantification, MMP1/LOX activity assays, 3D culture, in vivo mouse colonic lamina propria analysis (preprint)","pmids":["38853930"],"confidence":"Medium","gaps":["Preprint not yet peer-reviewed","How junctional PLEKHA7 controls miRNA levels mechanistically unresolved"]},{"year":null,"claim":"How PLEKHA7's distinct activities — junctional scaffolding, Rho-family GAP activity, PIP clustering, transporter trafficking, and miRNA/transcriptional regulation — are coordinated into a single integrated function, and whether they operate from the same junctional pool, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking GAP activity, lipid binding, and transporter trafficking","No high-resolution structure of full-length PLEKHA7 or its junctional complex","Tissue-specific functions not systematically compared"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,2,5,11,15]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[7,15]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[12]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[3,6]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,12]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[3,13]}],"pathway":[{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[0,2,5]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[17]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[11,15]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,9,14]}],"complexes":["PLEKHA7-PDZD11 complex","adherens junction belt (zonula adhaerens)"],"partners":["PDZD11","P120-CATENIN (CTNND1)","PARACINGULIN (CGNL1)","AFADIN (AFDN)","PP1Α","ATP7A","PMCA4","KRAS"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6IQ23","full_name":"Pleckstrin homology domain-containing family A member 7","aliases":[],"length_aa":1121,"mass_kda":127.1,"function":"Required for zonula adherens biogenesis and maintenance (PubMed:19041755). Acts via its interaction with CAMSAP3, which anchors microtubules at their minus-ends to zonula adherens, leading to the recruitment of KIFC3 kinesin to the junctional site (PubMed:19041755). Mediates docking of ADAM10 to zonula adherens through a PDZD11-dependent interaction with the ADAM10-binding protein TSPAN33 (PubMed:30463011)","subcellular_location":"Cell junction, adherens junction; Cytoplasm; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome","url":"https://www.uniprot.org/uniprotkb/Q6IQ23/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PLEKHA7","classification":"Not Classified","n_dependent_lines":6,"n_total_lines":1208,"dependency_fraction":0.004966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PLEKHA7","total_profiled":1310},"omim":[{"mim_id":"612686","title":"PLECKSTRIN HOMOLOGY DOMAIN-CONTAINING PROTEIN, FAMILY A, MEMBER 7; PLEKHA7","url":"https://www.omim.org/entry/612686"},{"mim_id":"612685","title":"CALMODULIN-REGULATED SPECTRIN-ASSOCIATED PROTEIN 3; CAMSAP3","url":"https://www.omim.org/entry/612685"},{"mim_id":"604535","title":"KINESIN FAMILY MEMBER C3; KIFC3","url":"https://www.omim.org/entry/604535"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"},{"location":"Cell Junctions","reliability":"Enhanced"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PLEKHA7"},"hgnc":{"alias_symbol":["DKFZp686M22243"],"prev_symbol":[]},"alphafold":{"accession":"Q6IQ23","domains":[{"cath_id":"2.20.70.10","chopping":"9-93","consensus_level":"medium","plddt":84.2642,"start":9,"end":93},{"cath_id":"2.30.29.30","chopping":"166-240_258-284","consensus_level":"high","plddt":88.7366,"start":166,"end":284},{"cath_id":"-","chopping":"691-838","consensus_level":"high","plddt":93.2504,"start":691,"end":838}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6IQ23","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6IQ23-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6IQ23-F1-predicted_aligned_error_v6.png","plddt_mean":56.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PLEKHA7","jax_strain_url":"https://www.jax.org/strain/search?query=PLEKHA7"},"sequence":{"accession":"Q6IQ23","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6IQ23.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6IQ23/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6IQ23"}},"corpus_meta":[{"pmid":"20808826","id":"PMC_20808826","title":"PLEKHA7 is an adherens junction protein with a tissue distribution and subcellular localization distinct from ZO-1 and E-cadherin.","date":"2010","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/20808826","citation_count":75,"is_preprint":false},{"pmid":"29503187","id":"PMC_29503187","title":"Insm1 Induces Neural Progenitor Delamination in Developing Neocortex via Downregulation of the Adherens Junction Belt-Specific Protein Plekha7.","date":"2018","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/29503187","citation_count":66,"is_preprint":false},{"pmid":"21454477","id":"PMC_21454477","title":"A role for ZO-1 and PLEKHA7 in recruiting paracingulin to tight and adherens junctions of epithelial cells.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21454477","citation_count":57,"is_preprint":false},{"pmid":"21963141","id":"PMC_21963141","title":"Genetic variations in CYP17A1, CACNB2 and PLEKHA7 are associated with blood pressure and/or hypertension in She ethnic minority of China.","date":"2011","source":"Atherosclerosis","url":"https://pubmed.ncbi.nlm.nih.gov/21963141","citation_count":56,"is_preprint":false},{"pmid":"22671598","id":"PMC_22671598","title":"Cingulin, paracingulin, and PLEKHA7: signaling and cytoskeletal adaptors at the apical junctional complex.","date":"2012","source":"Annals of the New York Academy of Sciences","url":"https://pubmed.ncbi.nlm.nih.gov/22671598","citation_count":51,"is_preprint":false},{"pmid":"25136115","id":"PMC_25136115","title":"Mutation of Plekha7 attenuates salt-sensitive hypertension in the rat.","date":"2014","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/25136115","citation_count":51,"is_preprint":false},{"pmid":"23990464","id":"PMC_23990464","title":"Binding between the junctional proteins afadin and PLEKHA7 and implication in the formation of adherens junction in epithelial cells.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23990464","citation_count":49,"is_preprint":false},{"pmid":"24843844","id":"PMC_24843844","title":"PLEKHA7 modulates epithelial tight junction barrier function.","date":"2014","source":"Tissue barriers","url":"https://pubmed.ncbi.nlm.nih.gov/24843844","citation_count":39,"is_preprint":false},{"pmid":"34613798","id":"PMC_34613798","title":"PLEKHA5, PLEKHA6, and PLEKHA7 bind to PDZD11 to target the Menkes ATPase ATP7A to the cell periphery and regulate copper homeostasis.","date":"2021","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/34613798","citation_count":36,"is_preprint":false},{"pmid":"27044745","id":"PMC_27044745","title":"PLEKHA7 Recruits PDZD11 to Adherens Junctions to Stabilize Nectins.","date":"2016","source":"The Journal of biological 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CR","url":"https://pubmed.ncbi.nlm.nih.gov/29996940","citation_count":24,"is_preprint":false},{"pmid":"31993771","id":"PMC_31993771","title":"ALK-rearranged renal cell carcinoma with a novel PLEKHA7-ALK translocation and metanephric adenoma-like morphology.","date":"2020","source":"Virchows Archiv : an international journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/31993771","citation_count":23,"is_preprint":false},{"pmid":"24801512","id":"PMC_24801512","title":"Expression of the primary angle closure glaucoma (PACG) susceptibility gene PLEKHA7 in endothelial and epithelial cell junctions in the eye.","date":"2014","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/24801512","citation_count":22,"is_preprint":false},{"pmid":"26822694","id":"PMC_26822694","title":"PLEKHA7 defines an apical junctional complex with cytoskeletal associations and miRNA-mediated growth implications.","date":"2016","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/26822694","citation_count":21,"is_preprint":false},{"pmid":"29016860","id":"PMC_29016860","title":"Primary angle closure glaucoma (PACG) susceptibility gene PLEKHA7 encodes a novel Rac1/Cdc42 GAP that modulates cell migration and blood-aqueous barrier function.","date":"2017","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29016860","citation_count":20,"is_preprint":false},{"pmid":"33878292","id":"PMC_33878292","title":"Structural basis for the association of PLEKHA7 with membrane-embedded phosphatidylinositol lipids.","date":"2021","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/33878292","citation_count":18,"is_preprint":false},{"pmid":"34568338","id":"PMC_34568338","title":"WW, PH and C-Terminal Domains Cooperate to Direct the Subcellular Localizations of PLEKHA5, PLEKHA6 and PLEKHA7.","date":"2021","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/34568338","citation_count":18,"is_preprint":false},{"pmid":"26270346","id":"PMC_26270346","title":"The Expression of the Zonula Adhaerens Protein PLEKHA7 Is Strongly Decreased in High Grade Ductal and Lobular Breast Carcinomas.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26270346","citation_count":17,"is_preprint":false},{"pmid":"22542108","id":"PMC_22542108","title":"Genetic up-regulation and overexpression of PLEKHA7 differentiates invasive lobular carcinomas from invasive ductal carcinomas.","date":"2012","source":"Human pathology","url":"https://pubmed.ncbi.nlm.nih.gov/22542108","citation_count":12,"is_preprint":false},{"pmid":"33525380","id":"PMC_33525380","title":"PLEKHA7, an Apical Adherens Junction Protein, Suppresses Inflammatory Breast Cancer in the Context of High E-Cadherin and p120-Catenin Expression.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33525380","citation_count":10,"is_preprint":false},{"pmid":"32371390","id":"PMC_32371390","title":"Cooperative binding of the tandem WW domains of PLEKHA7 to PDZD11 promotes conformation-dependent interaction with tetraspanin 33.","date":"2020","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32371390","citation_count":9,"is_preprint":false},{"pmid":"34800542","id":"PMC_34800542","title":"PLEKHA7 signaling is necessary for the growth of mutant KRAS driven colorectal cancer.","date":"2021","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/34800542","citation_count":7,"is_preprint":false},{"pmid":"35399503","id":"PMC_35399503","title":"Origin and Evolution of the Multifaceted Adherens Junction Component Plekha7.","date":"2022","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/35399503","citation_count":6,"is_preprint":false},{"pmid":"35714771","id":"PMC_35714771","title":"The PLEKHA7-PDZD11 complex regulates the localization of the calcium pump PMCA and calcium handling in cultured cells.","date":"2022","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/35714771","citation_count":6,"is_preprint":false},{"pmid":"34804680","id":"PMC_34804680","title":"Genetic Markers PLEKHA7, ABCC5, and KALRN Are Not Associated With the Progression of Primary Angle Closure Glaucoma (PACG) in Malays.","date":"2021","source":"Cureus","url":"https://pubmed.ncbi.nlm.nih.gov/34804680","citation_count":6,"is_preprint":false},{"pmid":"38853930","id":"PMC_38853930","title":"The epithelial adherens junction component PLEKHA7 regulates ECM remodeling and cell behavior through miRNA-mediated regulation of MMP1 and LOX.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/38853930","citation_count":5,"is_preprint":false},{"pmid":"38379102","id":"PMC_38379102","title":"Concomitant double-fusion of PLEKHA7-ALK and INPP5D-ALK reveals favorable alectinib sensitivity in lung adenocarcinoma: a case report and literature review.","date":"2024","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/38379102","citation_count":5,"is_preprint":false},{"pmid":"36823376","id":"PMC_36823376","title":"The hTERT-p50 homodimer inhibits PLEKHA7 expression to promote gastric cancer invasion and metastasis.","date":"2023","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/36823376","citation_count":2,"is_preprint":false},{"pmid":"39522087","id":"PMC_39522087","title":"A novel double fusion of EML4-ALK and PLEKHA7-ALK contribute to rapid progression of lung adenocarcinoma: a case report and literature review.","date":"2024","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/39522087","citation_count":2,"is_preprint":false},{"pmid":"36036827","id":"PMC_36036827","title":"Impact of rs11024102 PLEKHA7, rs3753841 COL11A1 single nucleotide polymorphisms, and serum levels of oxidative stress markers on the risk of primary angle-closure glaucoma in Egyptians.","date":"2022","source":"Journal, genetic engineering & biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/36036827","citation_count":2,"is_preprint":false},{"pmid":"27455018","id":"PMC_27455018","title":"[Association of PLEKHA7, COL11A1 and PCMTD1-ST18 gene polymorphisms with primary angle closure glaucoma in ethnic Han Chinese from Sichuan].","date":"2016","source":"Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27455018","citation_count":2,"is_preprint":false},{"pmid":"36824159","id":"PMC_36824159","title":"Bioengineered PLEKHA7 nanodelivery regularly induces behavior alteration and growth retardation of acute myeloid leukemia.","date":"2022","source":"Biomaterials and biosystems","url":"https://pubmed.ncbi.nlm.nih.gov/36824159","citation_count":1,"is_preprint":false},{"pmid":"40688283","id":"PMC_40688283","title":"Role of PLEKHA7 in promoting radioresistance in esophageal cancer cells via the inhibition of cuproptosis.","date":"2025","source":"Journal of thoracic disease","url":"https://pubmed.ncbi.nlm.nih.gov/40688283","citation_count":1,"is_preprint":false},{"pmid":"39903387","id":"PMC_39903387","title":"Genetic association of single nucleotide polymorphisms in PLEKHA7 gene with primary angle closure glaucoma (PACG) in a Central-Eastern Punjab cohort of Pakistan.","date":"2025","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/39903387","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":21736,"output_tokens":5102,"usd":0.070869,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13336,"output_tokens":5796,"usd":0.10579,"stage2_stop_reason":"end_turn"},"total_usd":0.176659,"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\": 2010,\n      \"finding\": \"PLEKHA7 is a cytoplasmic component of the epithelial adherens junction (AJ) belt, localized at a mean distance of ~28 nm from the plasma membrane, concentrated in the apical junctional belt similarly to E-cadherin and p120-ctn but unlike ZO-1, and not extending along the lateral region of polarized epithelial cells.\",\n      \"method\": \"Immunoelectron microscopy, immunofluorescence microscopy, immunoblotting, northern blotting in mammalian tissues and cultured epithelial cells\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — immunoelectron microscopy provides direct subcellular localization with nm-precision; multiple orthogonal methods; replicated across several tissue types\",\n      \"pmids\": [\"20808826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PLEKHA7 directly interacts with paracingulin (through a central region of PLEKHA7 binding the globular head domain of paracingulin) and forms a complex with p120-ctn; depletion of PLEKHA7 from MDCK cells results in loss of junctional localization of paracingulin and decreased paracingulin expression, identifying PLEKHA7 as a recruiter of paracingulin to adherens junctions.\",\n      \"method\": \"Yeast two-hybrid screen, GST pulldown, co-immunoprecipitation, siRNA knockdown with immunofluorescence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct interaction confirmed by yeast two-hybrid and in vitro GST pulldown, functional consequence (loss of paracingulin localization) confirmed by KD, multiple orthogonal methods\",\n      \"pmids\": [\"21454477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PLEKHA7 binds directly to afadin (in addition to p120-ctn) and is recruited to nectin-3α-based cell-cell adhesion sites in an afadin-dependent but p120-ctn-independent manner; this PLEKHA7-afadin binding is required for proper AJ formation but not tight junction formation in epithelial cells.\",\n      \"method\": \"Co-immunoprecipitation, pulldown, expression of dominant-negative constructs, immunofluorescence in EpH4 cells with KD/rescue experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct binding confirmed by pulldown and Co-IP, functional AJ assembly phenotype established by KD, multiple methods in single lab\",\n      \"pmids\": [\"23990464\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PLEKHA7 forms a complex with the cytoplasmic TJ proteins ZO-1 and cingulin (by co-immunoprecipitation), and inducible expression of PLEKHA7 constructs enhances E-cadherin recruitment at the apical zonula adhaerens and modulates TJ barrier dynamics (decreased TER at 18 h post-assembly; attenuated TER fall after calcium removal) through microtubule-dependent mechanisms.\",\n      \"method\": \"Inducible expression in MDCK cells, transepithelial resistance measurements, calcium-switch assay, nocodazole treatment, co-immunoprecipitation\",\n      \"journal\": \"Tissue barriers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — functional TER phenotype and Co-IP data in single lab; nocodazole experiment provides mechanistic link to microtubules\",\n      \"pmids\": [\"24843844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Zinc-finger nuclease-mediated mutation of Plekha7 in Dahl salt-sensitive rats attenuates salt-sensitive hypertension, reduces total peripheral resistance and perivascular fibrosis, and improves endothelium-dependent vasodilation, correlated with changes in intracellular calcium handling and increased nitric oxide bioavailability in mutant vessels.\",\n      \"method\": \"Zinc-finger nuclease gene editing in rat model, telemetric blood pressure measurement, myography of isolated mesenteric arteries, histology, calcium imaging\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo loss-of-function genetic model with multiple orthogonal phenotypic readouts (blood pressure, vascular function, calcium handling, nitric oxide)\",\n      \"pmids\": [\"25136115\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PLEKHA7 recruits PDZD11 to adherens junctions via a direct interaction between the N-terminal WW domain of PLEKHA7 and the N-terminal 44 amino acids of PDZD11 (shown by GST pulldown); PLEKHA7 KO abolishes junctional PDZD11 localization; the PLEKHA7-PDZD11 complex stabilizes nectin-1 and nectin-3 (preventing proteasome-mediated degradation) and promotes efficient early junction assembly in the calcium-switch model.\",\n      \"method\": \"Yeast two-hybrid, mass spectrometry of PLEKHA7 immunoprecipitates, GST pulldown, co-immunoprecipitation, CRISPR/Cas9 KO, immunofluorescence, calcium-switch assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct interaction mapped by in vitro pulldown, multiple orthogonal methods (MS, Co-IP, KO rescue), functional consequence on nectin stability and junction assembly established\",\n      \"pmids\": [\"27044745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PLEKHA7 loss activates the actin regulator cofilin in a p120-catenin-dependent manner; PLEKHA7 associates with and regulates levels of PP1α phosphatase, which is responsible for cofilin activation, linking PLEKHA7 to cortical actin ring dynamics at the apical zonula adhaerens.\",\n      \"method\": \"Co-immunoprecipitation, immunoblotting after KD/KO, phospho-cofilin assays, proteomics of PLEKHA7 immunoprecipitates\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP and KD phenotype in single lab; p120-dependence established by double-KD epistasis; mechanistic link to PP1α shown by association\",\n      \"pmids\": [\"26822694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PLEKHA7 specifically interacts with GTP-bound Rac1 and Cdc42 (but not RhoA) and stimulates their GTP hydrolysis without affecting nucleotide exchange, identifying PLEKHA7 as a novel Rac1/Cdc42 GAP; silencing PLEKHA7 compromises paracellular barrier integrity in non-pigmented ciliary epithelial cells and affects actin cytoskeleton organization.\",\n      \"method\": \"Co-immunoprecipitation with GTP/GDP-loaded GTPases, GTP hydrolysis assay, siRNA knockdown with transepithelial resistance and actin staining readouts\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — GAP activity confirmed by in vitro GTP hydrolysis assay, GTP-state selectivity shown by pulldown; functional barrier phenotype by KD; single lab\",\n      \"pmids\": [\"29016860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Insm1 transcription factor represses Plekha7 expression in neural progenitor cells; CRISPR/Cas9-mediated disruption of Plekha7 alone is sufficient to cause NPC delamination from the ventricular surface, converting apical to basal radial glia; Plekha7 overexpression impedes NPC delamination and counteracts Insm1-induced delamination, placing Plekha7 downstream of Insm1 in control of adherens junction belt integrity.\",\n      \"method\": \"CRISPR/Cas9 KO in mouse neocortex, in utero electroporation overexpression, immunofluorescence, Insm1 forced expression experiments\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis established by KO and rescue in vivo; multiple loss- and gain-of-function experiments across labs/organisms; clear cellular phenotype\",\n      \"pmids\": [\"29503187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PLEKHA7 overexpression reduces formation of the E-cadherin-EGFR complex, decreases EGFR activation and downstream CDK5 signaling, and reduces cell tumorigenicity in ovarian cancer cells, demonstrating that PLEKHA7 negatively regulates E-cadherin/EGFR crosstalk.\",\n      \"method\": \"Lentiviral PLEKHA7 overexpression, co-immunoprecipitation of E-cadherin-EGFR complex, EGFR phosphorylation immunoblotting, 3D growth assays, confocal microscopy\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — co-IP and functional growth assays; single lab; mechanistic link to EGFR/CDK5 pathway established by overexpression and co-IP\",\n      \"pmids\": [\"29996940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The tandem WW domains of PLEKHA7 cooperatively bind PDZD11: Asp-30 of WW1 and His-75 of WW2 form a hydrogen bond and together with Thr-35 of WW1 create a binding pocket for a polyproline stretch in PDZD11; WW2 stabilizes WW1 and promotes PDZD11 binding; PDZD11 binding induces a conformational rearrangement that expands a hydrophobic hot spot on WW1, enabling tetraspanin 33 (via its C-terminal Trp-283/Tyr-282) to bind the WW1 hydrophobic surface.\",\n      \"method\": \"Site-directed mutagenesis, GST pulldown, immunofluorescence, molecular modeling and docking\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — mutagenesis combined with pulldown and molecular modeling; single lab; mechanistic detail of WW domain interaction defined\",\n      \"pmids\": [\"32371390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PLEKHA5, PLEKHA6, and PLEKHA7 (WW-PLEKHAs) interact with PDZD11 through their WW domains and are required for efficient anterograde targeting of the Menkes ATPase ATP7A to the cell periphery under elevated copper; CRISPR-KO of WW-PLEKHAs reduces peripheral ATP7A localization; WW-PLEKHAs and PDZD11 are required for maintaining low intracellular copper levels under elevated copper conditions.\",\n      \"method\": \"CRISPR-KO, pulldown, immunofluorescence microscopy, surface biotinylation, copper measurement, cell viability assays, metallothionein-1 expression\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — CRISPR-KO with rescue, pulldown, multiple functional readouts (copper levels, ATP7A localization, cell viability); multiple labs or comprehensive single-lab study\",\n      \"pmids\": [\"34613798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The PH domain of PLEKHA7 directly interacts with membrane-embedded phosphatidylinositol lipids (PIPs) in a multivalent manner that induces PIP clustering, distinct from discrete one-to-one binding; residue D175 acts as a 'sentry' preventing PI(3,4)P2 and PI(3,4,5)P3 binding; this PH domain-lipid interaction is critical for PLEKHA7 cellular localization and function.\",\n      \"method\": \"X-ray crystallography, NMR, molecular dynamics simulations, isothermal titration calorimetry, site-directed mutagenesis\",\n      \"journal\": \"Structure (London, England : 1993)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure, NMR, and ITC with mutagenesis in single rigorous study; multiple orthogonal biophysical methods\",\n      \"pmids\": [\"33878292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The WW domain, PH domain, and C-terminal/coiled-coil regions of PLEKHA7 cooperate to determine its subcellular localization at adherens junctions: the PH domain of PLEKHA7 promotes AJ localization in chimeric proteins, the C-terminal and coiled-coil regions promote AJ localization, and the WW-PDZD11 interaction is required for microtubule association of PLEKHA5.\",\n      \"method\": \"Expression of mutant and chimeric WW-PLEKHA proteins in cultured epithelial cells, immunofluorescence microscopy\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — domain-swap and deletion analysis in cells; single lab; localization mapped to specific domains\",\n      \"pmids\": [\"34568338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PLEKHA7 directly interacts with wild-type KRas (but scantily with mutant KRas) as shown by FLIM-FRET; inhibiting the PLEKHA7 PH domain (molecularly or pharmacologically) specifically decreases mutant-KRas cell signaling, proliferation, attachment, migration, and tumor growth, but not wild-type KRas cells.\",\n      \"method\": \"FLIM-FRET, siRNA/pharmacological inhibition of PH domain, proliferation/migration/attachment assays, in vivo tumor growth\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — FLIM-FRET for direct interaction, functional phenotype by KD/inhibition; single lab; novel interaction with mut-KRas pathway\",\n      \"pmids\": [\"34800542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PLEKHA7-PDZD11 complex regulates the localization of the plasma membrane calcium ATPase PMCA: KO of PLEKHA7 or PDZD11 increases PMCA accumulation at lateral cell-cell contacts and causes ectopic apical localization of PMCA4x/b; PDZD11 counteracts calcium extrusion activity of PMCA4x/b (but not PMCA4x/a lacking the PDZ-binding motif); KO of PDZD11 increases the rate of calcium extrusion.\",\n      \"method\": \"CRISPR-KO, immunofluorescence, surface biotinylation, cytosolic calcium transient measurements, PDZD11 co-expression in HeLa cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR-KO with multiple cell lines, surface biotinylation, functional calcium assays, PDZ-binding motif specificity control; multiple orthogonal methods\",\n      \"pmids\": [\"35714771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The hTERT-p50 homodimer directly binds the PLEKHA7 promoter and represses PLEKHA7 transcription; increased hTERT decreases PLEKHA7 expression and promotes invasion and metastasis in gastric cancer cells in a PLEKHA7-dependent manner.\",\n      \"method\": \"ChIP assay (hTERT/p50 binding to PLEKHA7 promoter), co-immunoprecipitation, siRNA knockdown, invasion/migration assays, overexpression rescue experiments\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — ChIP establishes direct promoter binding; KD/rescue functional assays; single lab\",\n      \"pmids\": [\"36823376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PLEKHA7 regulates ECM remodeling by controlling levels and activity of MMP1 and LOX through miR-24 and miR-30c miRNAs; PLEKHA7 depletion causes LOX-dependent ECM remodeling in culture and in the colonic mucosal lamina propria in mice; PLEKHA7-depleted cells show increased migration and invasion that are MMP1- and LOX-dependent.\",\n      \"method\": \"siRNA/KO depletion, miRNA quantification, MMP1/LOX activity assays, 3D culture, in vivo mouse colonic lamina propria analysis, migration/invasion assays with pharmacological rescue\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — preprint; multiple functional readouts linking PLEKHA7 to miRNA-MMP1/LOX axis; in vivo validation; single lab\",\n      \"pmids\": [\"38853930\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"PLEKHA7 is a cytoplasmic adaptor protein anchored at the apical epithelial adherens junction belt through cooperative interactions between its WW domains (binding p120-ctn, paracingulin, afadin, and PDZD11), PH domain (binding membrane PIPs in a multivalent, clustering manner), and C-terminal/coiled-coil regions; it stabilizes the E-cadherin complex by linking it to microtubules, recruits PDZD11 to stabilize junctional nectins and direct trafficking of transmembrane proteins (ATP7A, PMCA), acts as a Rac1/Cdc42 GAP to regulate actin organization and paracellular barrier function, controls cofilin activation via PP1α in a p120-dependent manner, suppresses E-cadherin/EGFR signaling, and regulates ECM remodeling through miRNA-mediated control of MMP1 and LOX—with loss of PLEKHA7 at the apical junction belt promoting neural progenitor delamination, hypertension, and tumor progression.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PLEKHA7 is a cytoplasmic adaptor protein that defines and stabilizes the apical adherens junction (zonula adhaerens) belt of polarized epithelial cells, where it is concentrated within ~28 nm of the plasma membrane alongside E-cadherin and p120-catenin but excluded from the lateral membrane and tight junction [#0]. It assembles a junctional scaffold through cooperative, multidomain interactions: its WW domains and central/C-terminal regions bind p120-catenin, paracingulin, and afadin to recruit these partners to the junction and drive proper AJ assembly [#1, #2], while its PH domain engages membrane phosphoinositides in a multivalent, clustering mode that is essential for junctional localization [#12], and its WW, PH, and coiled-coil regions act in concert to target the protein to adherens junctions [#13]. A key effector branch is the recruitment of PDZD11 via cooperative engagement of the tandem WW domains, which stabilizes junctional nectins against proteasomal degradation and promotes junction assembly [#5, #10]; the same PLEKHA7–PDZD11 module directs trafficking and localization of transmembrane transporters, supporting copper-induced peripheral targeting of the ATPase ATP7A and controlling the distribution and calcium-extrusion activity of the plasma membrane calcium pump PMCA [#11, #15]. PLEKHA7 also shapes junctional actin dynamics, acting as a Rac1/Cdc42 GAP that stimulates GTP hydrolysis to maintain paracellular barrier integrity [#7] and regulating cofilin activation through association with PP1\\u03b1 in a p120-catenin-dependent manner [#6]. Through its control of the junctional belt PLEKHA7 restrains tumor-promoting signaling and cell behavior: it suppresses E-cadherin/EGFR complex formation and downstream signaling [#9] and limits ECM remodeling via miR-24/miR-30c-mediated control of MMP1 and LOX [#17]. Loss of PLEKHA7 at the apical belt drives neural progenitor delamination downstream of the Insm1 transcription factor [#8] and contributes to salt-sensitive hypertension with impaired vascular function in vivo [#4].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established that PLEKHA7 is a defining cytoplasmic component of the epithelial adherens junction belt rather than a general junctional or tight-junction protein, placing it spatially at the zonula adhaerens.\",\n      \"evidence\": \"Immunoelectron and immunofluorescence microscopy with immunoblotting/northern blotting across mammalian tissues and epithelial cell lines\",\n      \"pmids\": [\"20808826\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular partners anchoring it at this position not yet defined\", \"Functional consequence of its junctional localization untested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified PLEKHA7 as a recruiter of cytoskeletal/junctional partners, showing it binds paracingulin and complexes with p120-catenin to organize junction composition.\",\n      \"evidence\": \"Yeast two-hybrid, GST pulldown, co-IP, and siRNA knockdown with immunofluorescence in MDCK cells\",\n      \"pmids\": [\"21454477\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the full domain requirements for these interactions\", \"Downstream functional output of paracingulin recruitment unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed PLEKHA7 binds afadin and is recruited to nectin-based adhesion sites in a p120-independent, afadin-dependent manner, establishing multiple recruitment routes specific to AJ (not TJ) assembly.\",\n      \"evidence\": \"Co-IP, pulldown, dominant-negative expression, and KD/rescue immunofluorescence in EpH4 cells\",\n      \"pmids\": [\"23990464\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contributions of afadin versus p120 routes in vivo unknown\", \"Structural basis of afadin binding not mapped\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Linked PLEKHA7 to E-cadherin recruitment and barrier dynamics through microtubule-dependent mechanisms, and to a complex with ZO-1/cingulin.\",\n      \"evidence\": \"Inducible expression in MDCK cells, transepithelial resistance, calcium-switch and nocodazole treatments, co-IP\",\n      \"pmids\": [\"24843844\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting PLEKHA7 to microtubules at the molecular level unresolved\", \"ZO-1/cingulin association is correlative without direct binding mapping\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated an in vivo physiological role: PLEKHA7 loss-of-function attenuates salt-sensitive hypertension and improves vascular function, connecting the junctional adaptor to systemic blood pressure regulation.\",\n      \"evidence\": \"Zinc-finger nuclease editing in Dahl salt-sensitive rats with telemetric BP, myography, histology, and calcium imaging\",\n      \"pmids\": [\"25136115\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic link between junctional function and vascular calcium/NO handling not established\", \"Cell type driving the hypertension phenotype not pinpointed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified PDZD11 as a WW-domain-bound effector that PLEKHA7 recruits to junctions to stabilize nectins and promote junction assembly, defining a major output branch.\",\n      \"evidence\": \"Yeast two-hybrid, MS of immunoprecipitates, GST pulldown, CRISPR KO, immunofluorescence, calcium-switch assay\",\n      \"pmids\": [\"27044745\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural detail of the WW-PDZD11 interface not yet resolved\", \"Whether PDZD11 mediates additional PLEKHA7 functions unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected PLEKHA7 to junctional actin regulation, showing it controls cofilin activation via association with PP1\\u03b1 phosphatase in a p120-dependent manner.\",\n      \"evidence\": \"Co-IP, immunoblotting after KD/KO, phospho-cofilin assays, proteomics of immunoprecipitates\",\n      \"pmids\": [\"26822694\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect PLEKHA7-PP1\\u03b1 binding not distinguished\", \"Single-lab study without reciprocal validation\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Assigned an enzymatic activity to PLEKHA7 as a Rac1/Cdc42 GAP, providing a mechanism by which it shapes actin organization and paracellular barrier integrity.\",\n      \"evidence\": \"Co-IP with GTP/GDP-loaded GTPases, in vitro GTP hydrolysis assay, siRNA KD with TER and actin readouts in ciliary epithelial cells\",\n      \"pmids\": [\"29016860\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"GAP domain within PLEKHA7 not mapped\", \"Whether GAP activity operates at the junction in vivo untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placed PLEKHA7 downstream of Insm1 as a controller of apical junction belt integrity in neural progenitors, where its loss alone drives delamination and apical-to-basal conversion.\",\n      \"evidence\": \"CRISPR/Cas9 KO and in utero electroporation overexpression in mouse neocortex with Insm1 epistasis\",\n      \"pmids\": [\"29503187\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether junctional partners mediate the delamination phenotype not tested\", \"Link to broader developmental outcomes unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established a tumor-suppressive function: PLEKHA7 limits E-cadherin/EGFR complex formation and downstream CDK5 signaling to reduce tumorigenicity.\",\n      \"evidence\": \"Lentiviral overexpression, co-IP of E-cadherin-EGFR, EGFR phospho-immunoblotting, 3D growth assays in ovarian cancer cells\",\n      \"pmids\": [\"29996940\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Loss-of-function (rather than overexpression) effects on EGFR not tested here\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Resolved how the tandem WW domains cooperatively bind PDZD11 and how PDZD11 binding allosterically licenses tetraspanin 33 engagement, defining the structural logic of WW-mediated partner recruitment.\",\n      \"evidence\": \"Site-directed mutagenesis, GST pulldown, immunofluorescence, molecular modeling and docking\",\n      \"pmids\": [\"32371390\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No experimental high-resolution structure of the WW-PDZD11 complex\", \"Functional role of tetraspanin 33 recruitment untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined the PH domain as a multivalent PIP-clustering module required for PLEKHA7 localization, identifying residue D175 as a lipid-selectivity sentry.\",\n      \"evidence\": \"X-ray crystallography, NMR, MD simulations, ITC, and site-directed mutagenesis\",\n      \"pmids\": [\"33878292\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How PIP clustering integrates with protein-protein junctional anchoring not resolved\", \"In vivo relevance of lipid selectivity untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed multidomain cooperation (WW, PH, C-terminal/coiled-coil) jointly determines AJ targeting and that the WW-PDZD11 interaction underlies microtubule association in the WW-PLEKHA family.\",\n      \"evidence\": \"Domain-swap and deletion analysis of chimeric WW-PLEKHA proteins with immunofluorescence in epithelial cells\",\n      \"pmids\": [\"34568338\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Quantitative contribution of each domain to anchoring not dissected\", \"Microtubule link shown for PLEKHA5 rather than PLEKHA7 directly\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended the PLEKHA7-PDZD11 module to transmembrane transporter trafficking, showing it is required for copper-induced peripheral targeting of ATP7A and maintenance of low intracellular copper.\",\n      \"evidence\": \"CRISPR-KO, pulldown, surface biotinylation, copper measurement, and viability assays\",\n      \"pmids\": [\"34613798\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of how the complex directs ATP7A trafficking not detailed\", \"Whether junctional pool versus other pools mediates this unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified a PH-domain-dependent interaction with wild-type KRas and showed PH-domain inhibition selectively impairs mutant-KRas cell growth and tumor formation.\",\n      \"evidence\": \"FLIM-FRET, siRNA/pharmacological PH-domain inhibition, proliferation/migration/attachment assays, in vivo tumor growth\",\n      \"pmids\": [\"34800542\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism reconciling WT-KRas binding with mutant-KRas dependence unclear\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated that the PLEKHA7-PDZD11 complex controls PMCA localization and calcium-extrusion activity, with PDZ-binding-motif specificity, linking the junctional scaffold to calcium homeostasis.\",\n      \"evidence\": \"CRISPR-KO, immunofluorescence, surface biotinylation, cytosolic calcium transient measurements, PDZD11 co-expression in HeLa cells\",\n      \"pmids\": [\"35714771\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological consequence of altered PMCA calcium extrusion in epithelia untested\", \"Connection to the hypertension calcium phenotype not directly established\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed transcriptional silencing of PLEKHA7 by an hTERT-p50 dimer drives gastric cancer invasion and metastasis in a PLEKHA7-dependent manner, establishing a regulatory input controlling its tumor-suppressive output.\",\n      \"evidence\": \"ChIP, co-IP, siRNA KD, invasion/migration assays, and overexpression rescue\",\n      \"pmids\": [\"36823376\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether this regulation occurs in non-gastric tissues unknown\", \"Mechanistic link from PLEKHA7 loss to invasion not fully resolved here\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected PLEKHA7 to ECM remodeling through miR-24/miR-30c control of MMP1 and LOX, providing a mechanism for invasion downstream of PLEKHA7 loss.\",\n      \"evidence\": \"siRNA/KO depletion, miRNA quantification, MMP1/LOX activity assays, 3D culture, in vivo mouse colonic lamina propria analysis (preprint)\",\n      \"pmids\": [\"38853930\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint not yet peer-reviewed\", \"How junctional PLEKHA7 controls miRNA levels mechanistically unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PLEKHA7's distinct activities — junctional scaffolding, Rho-family GAP activity, PIP clustering, transporter trafficking, and miRNA/transcriptional regulation — are coordinated into a single integrated function, and whether they operate from the same junctional pool, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking GAP activity, lipid binding, and transporter trafficking\", \"No high-resolution structure of full-length PLEKHA7 or its junctional complex\", \"Tissue-specific functions not systematically compared\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 2, 5, 11, 15]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [7, 15]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [3, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 12]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [3, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [0, 2, 5]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [17]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [11, 15]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 9, 14]}\n    ],\n    \"complexes\": [\n      \"PLEKHA7-PDZD11 complex\",\n      \"adherens junction belt (zonula adhaerens)\"\n    ],\n    \"partners\": [\n      \"PDZD11\",\n      \"p120-catenin (CTNND1)\",\n      \"paracingulin (CGNL1)\",\n      \"afadin (AFDN)\",\n      \"PP1\\u03b1\",\n      \"ATP7A\",\n      \"PMCA4\",\n      \"KRAS\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}