{"gene":"PDLIM7","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":1998,"finding":"PDLIM7 (Enigma) binds to Ret/ptc2 via the tyrosine 586-containing sequence and mediates localization of Ret/ptc2 to the cell periphery, which is required for mitogenic signaling. Dimerization of Ret/ptc2 allows simultaneous recruitment of Shc (for Ras/Raf signaling) and Enigma (for subcellular localization) because both bind the same site on a monomer.","method":"Co-immunoprecipitation, dominant-negative coexpression, chimeric protein coexpression, subcellular localization studies","journal":"Molecular and Cellular Biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding demonstrated, chimeric protein rescue experiments, subcellular localization tied to functional mitogenic output, multiple orthogonal methods in one study","pmids":["9528800"],"is_preprint":false},{"year":2005,"finding":"PDLIM7 (Enigma) interacts with the adaptor protein APS through its LIM domains (binding to the NPTY motif of APS), and this complex localizes to F-actin-containing ruffles in response to insulin. Expression of Enigma alone induces F-actin cluster formation, whereas the APS/Enigma complex (requiring intact NPTY motif) modulates actin cytoskeleton organization.","method":"Yeast two-hybrid screening, co-immunoprecipitation in HEK293 cells, co-localization by immunofluorescence, mutagenesis of NPTY motif","journal":"Experimental Cell Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP and localization data in single lab, multiple methods, but no in vitro reconstitution","pmids":["15946664"],"is_preprint":false},{"year":2009,"finding":"In zebrafish, Pdlim7 regulates nuclear/cytoplasmic shuttling of the transcription factor Tbx5. Knockdown of Pdlim7 causes a non-looped heart phenotype similar to the tbx5 mutant but with opposite valve defects (no valve tissue vs. excess valve tissue), demonstrating that Pdlim7 controls Tbx5 activity at the atrio-ventricular boundary by modulating expression of Tbx5 target genes nppa and tbx2b.","method":"Zebrafish morpholino knockdown, molecular and histological analysis, in vivo genetic epistasis, gene expression analysis","journal":"Developmental Biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo loss-of-function with defined molecular phenotype, epistasis with Tbx5, target gene expression readouts, multiple orthogonal methods","pmids":["19895804"],"is_preprint":false},{"year":2009,"finding":"PDLIM7 (Enigma) and related ALP/Enigma family members bind α-actinin through their PDZ domains and bind signaling molecules through their LIM domains, functioning as scaffold proteins in cardiac and skeletal muscle. These proteins have been implicated in cardiac structure, function, and disease.","method":"Review synthesizing binding domain mapping and functional studies (PDZ-domain interaction with α-actinin, LIM-domain interactions)","journal":"Journal of Molecular Cell Biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — review summarizing multiple prior binding studies; domain-function assignments are based on replicated findings across the subfamily","pmids":["20042479"],"is_preprint":false},{"year":2010,"finding":"PDLIM7 (Enigma) directly interacts with MDM2 to form a ternary complex with p53, inhibits MDM2 self-ubiquitination, and thereby increases MDM2's ubiquitin ligase activity toward p53, leading to p53 degradation. Mitogenic stimuli (serum, FGF, HGF) increase Enigma transcription via serum response factor (SRF), stabilizing MDM2 and suppressing p53-mediated apoptosis.","method":"Co-immunoprecipitation, in vitro ubiquitination assays, cell-based apoptosis assays, mouse xenograft model, HGF treatment of mice, SRF transcription factor binding assays","journal":"The Journal of Clinical Investigation","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro ubiquitination assay plus co-IP plus in vivo mouse data plus multiple cell lines; multiple orthogonal methods establishing mechanism","pmids":["21060154"],"is_preprint":false},{"year":2015,"finding":"PDLIM7 is a substrate of the E3 ubiquitin ligase Nedd4-1 in skeletal muscle. PDLIM7 co-immunoprecipitates with Nedd4-1 via binding between the PY motif of PDLIM7 and the second and third WW domains of Nedd4-1; this interaction leads to PDLIM7 ubiquitination. In denervated muscle, increased Nedd4-1 expression coincides with decreased PDLIM7, and PDLIM7 is stabilized in Nedd4-1 muscle-specific knockout mice.","method":"Co-immunoprecipitation, ubiquitination assay in HEK293 cells, Nedd4-1 muscle-specific knockout mouse model, domain-mapping mutagenesis (PY motif)","journal":"The Biochemical Journal","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro ubiquitination, reciprocal co-IP, PY-motif domain mapping, and in vivo genetic validation in knockout mice; multiple orthogonal methods","pmids":["26556890"],"is_preprint":false},{"year":2016,"finding":"PDLIM7 silencing in cultured smooth muscle cells leads to downregulation of SMC markers, disruption of the actin cytoskeleton, decreased cell spreading, and increased proliferation, establishing a role for PDLIM7 in maintaining the contractile SMC phenotype via cytoskeletal organization.","method":"siRNA knockdown in cultured SMCs, actin cytoskeleton imaging, proliferation assays, chromatin immunoprecipitation-sequencing (H3K27ac)","journal":"Arteriosclerosis, Thrombosis, and Vascular Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined loss-of-function phenotype in cultured cells with multiple readouts (cytoskeleton, spreading, proliferation), single lab","pmids":["27470516"],"is_preprint":false},{"year":2018,"finding":"PDLIM7 (and PDLIM5) are required for integrin-mediated mechanotransduction leading to YAP/TAZ nuclear localization and TEAD-dependent transcription. YAP binds to PDLIM7 via its C-terminal PDZ-binding motif (PBM). In response to mechanical force, PDLIM7 is recruited from the cytoplasm to integrin adhesions and F-actin stress fibers by direct binding to α-actinin. Silencing PDLIM5/7 reduces YAP nuclear localization, tyrosine phosphorylation, and transcriptional activity.","method":"siRNA knockdown, co-immunoprecipitation, immunofluorescence/live cell imaging, transcriptional reporter assays, force application experiments","journal":"Journal of Cell Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, direct binding to α-actinin, functional rescue with PBM mutants, multiple orthogonal methods showing both binding and downstream transcriptional output","pmids":["30404826"],"is_preprint":false},{"year":2018,"finding":"PDLIM7 regulates MDM2 protein turnover during CDK4/6 inhibitor-induced senescence. In CDK4/6 inhibitor-treated cells, PDLIM7 plays a defined role in downregulating MDM2 protein levels, contributing to the transition from quiescence to senescence.","method":"Cell line experiments with CDK4/6 inhibitors, Western blotting, knockdown experiments in human cell lines","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined cellular mechanism in cultured human cell lines with pharmacological and genetic perturbation, single lab","pmids":["29789718"],"is_preprint":false},{"year":2020,"finding":"PDLIM7 is a ubiquitin E3 ligase that directly polyubiquitinates the p65 subunit of NF-κB, promoting its proteasomal degradation and suppressing NF-κB-mediated inflammatory responses. PDLIM7 heterodimerizes with PDLIM2, and promotes K63-linked ubiquitination of PDLIM2; p62/Sqstm1 then bridges polyubiquitinated PDLIM2 and the proteasome to facilitate delivery and degradation of the NF-κB–PDLIM2 complex. Double knockdown of PDLIM7 and either PDLIM2 or p62/Sqstm1 results in augmented proinflammatory cytokine production.","method":"In vitro ubiquitination assay, co-immunoprecipitation, siRNA double knockdown, cytokine measurement, proteasome inhibitor experiments","journal":"Frontiers in Immunology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct in vitro ubiquitination assay, reciprocal co-IP, genetic double-knockdown with functional readout (cytokine production), mechanistic epistasis established","pmids":["32849529"],"is_preprint":false},{"year":2023,"finding":"PDLIM7 mediates nuclear translocation of YAP1 in prostate cancer cells. TPM2 competes with YAP1 for binding to PDLIM7 through its PDZ-binding motif, thereby blocking PDLIM7-dependent nuclear transport of YAP1 and resulting in cytoplasmic sequestration, S127 phosphorylation, and inactivation/degradation of YAP1 and suppression of its downstream target genes.","method":"Co-immunoprecipitation, immunofluorescence, Western blotting, in vitro and in vivo tumor growth assays, PDZ-binding motif mutagenesis","journal":"Cell & Bioscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP, competition assay, mutagenesis of PDZ-binding motif, in vivo xenograft validation; single lab","pmids":["36823643"],"is_preprint":false}],"current_model":"PDLIM7 (Enigma) is a scaffold/E3 ubiquitin ligase that, through its PDZ domain (binding α-actinin and transcription factors such as Tbx5 and YAP1) and LIM domains (binding signaling proteins including MDM2 and APS), coordinates actin cytoskeletal organization, mechanotransduction (recruiting to stress fibers/integrin adhesions to drive YAP nuclear localization), p53 regulation (stabilizing MDM2 to promote p53 ubiquitination and degradation via an SRF-induced pathway), NF-κB suppression (directly ubiquitinating p65 and facilitating PDLIM2/p62-mediated proteasomal degradation), and is itself a substrate of the E3 ligase Nedd4-1 in skeletal muscle (ubiquitinated via PY motif–WW domain interaction, contributing to denervation atrophy)."},"narrative":{"mechanistic_narrative":"PDLIM7 (Enigma) is a multidomain cytoskeletal scaffold and E3 ubiquitin ligase that couples actin-based architecture and integrin adhesions to transcriptional and signaling outputs [PMID:20042479, PMID:30404826]. Through its PDZ domain it binds α-actinin to localize at F-actin stress fibers and integrin adhesions, while its LIM domains and PY motif engage signaling and effector proteins, allowing it to organize the actin cytoskeleton and maintain contractile cell phenotypes [PMID:20042479, PMID:27470516, PMID:30404826]. In mechanotransduction, force recruits PDLIM7 from the cytoplasm to adhesions where it binds YAP via the YAP C-terminal PDZ-binding motif to drive YAP/TAZ nuclear localization and TEAD-dependent transcription [PMID:30404826]; this interface is competitively antagonized by TPM2, which displaces YAP and promotes its cytoplasmic sequestration and inactivation [PMID:36823643]. PDLIM7 also controls developmental transcription factor activity, regulating nuclear/cytoplasmic shuttling of Tbx5 at the cardiac atrio-ventricular boundary [PMID:19895804]. As an E3 ligase, PDLIM7 stabilizes MDM2 by inhibiting its self-ubiquitination, thereby enhancing MDM2-directed p53 ubiquitination and degradation in a serum/SRF-induced pathway, and modulates MDM2 turnover during CDK4/6-inhibitor-induced senescence [PMID:21060154, PMID:29789718]. It additionally polyubiquitinates the NF-κB p65 subunit and heterodimerizes with PDLIM2, using p62/SQSTM1 to bridge ubiquitinated PDLIM2 to the proteasome and suppress proinflammatory cytokine production [PMID:32849529]. PDLIM7 is itself a substrate of the E3 ligase Nedd4-1, ubiquitinated through a PY-motif–WW-domain interaction, linking its turnover to denervation-associated skeletal muscle atrophy [PMID:26556890].","teleology":[{"year":1998,"claim":"Established PDLIM7 as a localization scaffold linking a receptor tyrosine kinase to subcellular positioning required for mitogenic signaling.","evidence":"Co-IP, dominant-negative and chimeric coexpression, and subcellular localization studies of Ret/ptc2","pmids":["9528800"],"confidence":"High","gaps":["Did not define the structural basis of LIM-domain binding to the tyrosine 586 site","Relevance beyond Ret/ptc2 signaling not addressed"]},{"year":2005,"claim":"Connected PDLIM7 to insulin-responsive actin remodeling by identifying LIM-domain binding to the APS NPTY motif.","evidence":"Yeast two-hybrid, co-IP in HEK293, immunofluorescence colocalization, and NPTY-motif mutagenesis","pmids":["15946664"],"confidence":"Medium","gaps":["No in vitro reconstitution of the APS/Enigma complex","Functional consequence for insulin signaling outputs not quantified"]},{"year":2009,"claim":"Demonstrated in vivo that PDLIM7 controls a transcription factor's nucleocytoplasmic shuttling, governing Tbx5 activity during heart development.","evidence":"Zebrafish morpholino knockdown with epistasis and target-gene expression analysis (nppa, tbx2b)","pmids":["19895804"],"confidence":"High","gaps":["Direct PDLIM7–Tbx5 binding interface not mapped","Mechanism of shuttling control not biochemically defined"]},{"year":2009,"claim":"Consolidated the domain logic of the ALP/Enigma family, assigning α-actinin binding to the PDZ domain and signaling-protein binding to LIM domains in muscle scaffolding.","evidence":"Review synthesizing prior binding and functional studies","pmids":["20042479"],"confidence":"Medium","gaps":["Review-level synthesis, not new primary data","PDLIM7-specific contributions not separated from paralogs"]},{"year":2010,"claim":"Defined PDLIM7 as a positive regulator of MDM2 that suppresses p53, revealing an SRF-driven mitogenic survival pathway.","evidence":"In vitro ubiquitination assays, co-IP, apoptosis assays, mouse xenografts, and SRF binding assays","pmids":["21060154"],"confidence":"High","gaps":["Whether PDLIM7 directly ubiquitinates any substrate here versus modulating MDM2 not fully resolved","Structural basis of MDM2–p53 ternary complex formation undefined"]},{"year":2015,"claim":"Identified PDLIM7 as a Nedd4-1 substrate, placing its own turnover under E3-ligase control relevant to muscle atrophy.","evidence":"Co-IP, ubiquitination assay, PY-motif domain mapping, and Nedd4-1 muscle-specific knockout mice","pmids":["26556890"],"confidence":"High","gaps":["Functional consequence of PDLIM7 loss for atrophy not directly demonstrated by PDLIM7 manipulation","Ubiquitin chain topology on PDLIM7 not characterized"]},{"year":2016,"claim":"Showed PDLIM7 maintains the contractile smooth muscle phenotype through cytoskeletal organization, restraining proliferation.","evidence":"siRNA knockdown in cultured SMCs with cytoskeleton imaging, spreading and proliferation assays, and H3K27ac ChIP-seq","pmids":["27470516"],"confidence":"Medium","gaps":["Single lab, cultured cells only","Direct molecular link between cytoskeletal disruption and marker downregulation not established"]},{"year":2018,"claim":"Established PDLIM7 as a force-recruited adaptor driving YAP/TAZ nuclear localization and TEAD transcription via α-actinin and the YAP PDZ-binding motif.","evidence":"siRNA knockdown, co-IP, live-cell imaging, force application, and reporter assays","pmids":["30404826"],"confidence":"High","gaps":["How PDLIM7 promotes YAP nuclear import mechanistically not resolved","Redundancy with PDLIM5 not fully dissected"]},{"year":2018,"claim":"Extended PDLIM7's MDM2 regulation to a senescence context, implicating it in CDK4/6-inhibitor-induced MDM2 downregulation.","evidence":"CDK4/6 inhibitor treatment, Western blotting, and knockdown in human cell lines","pmids":["29789718"],"confidence":"Medium","gaps":["Direction of MDM2 regulation here differs in context from stabilization model; reconciliation not provided","Single lab"]},{"year":2020,"claim":"Demonstrated PDLIM7 acts as a direct E3 ligase against NF-κB p65 and partners with PDLIM2/p62 to suppress inflammatory signaling.","evidence":"In vitro ubiquitination, co-IP, siRNA double knockdown, cytokine measurement, and proteasome inhibition","pmids":["32849529"],"confidence":"High","gaps":["Catalytic domain of PDLIM7 responsible for ligase activity not mapped","In vivo physiological role in inflammation not tested"]},{"year":2023,"claim":"Revealed competitive regulation of the PDLIM7–YAP1 axis by TPM2 in prostate cancer, controlling YAP1 nuclear transport and stability.","evidence":"Co-IP, competition and PDZ-binding motif mutagenesis, immunofluorescence, and in vivo tumor assays","pmids":["36823643"],"confidence":"Medium","gaps":["Single lab","Generality beyond prostate cancer cells not established"]},{"year":null,"claim":"How PDLIM7's scaffolding and intrinsic E3-ligase activities are mechanistically coordinated, and which catalytic determinants drive its ubiquitination of substrates, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the catalytic/substrate-binding interface","Context-dependent opposing effects on MDM2 not reconciled","In vivo physiological roles of the ligase functions largely untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[4,9]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[4,9]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,7,10]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[3,7]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[6,7]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[7]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,10]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[4,5,9]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[9]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2]}],"complexes":[],"partners":["MDM2","YAP1","ACTN","PDLIM2","NEDD4","RELA","TBX5","SH2B2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NR12","full_name":"PDZ and LIM domain protein 7","aliases":["LIM mineralization protein","LMP","Protein enigma"],"length_aa":457,"mass_kda":49.8,"function":"May function as a scaffold on which the coordinated assembly of proteins can occur. May play a role as an adapter that, via its PDZ domain, localizes LIM-binding proteins to actin filaments of both skeletal muscle and nonmuscle tissues. Involved in both of the two fundamental mechanisms of bone formation, direct bone formation (e.g. embryonic flat bones mandible and cranium), and endochondral bone formation (e.g. embryonic long bone development). Plays a role during fracture repair. Involved in BMP6 signaling pathway (By similarity)","subcellular_location":"Cytoplasm; Cytoplasm, cytoskeleton","url":"https://www.uniprot.org/uniprotkb/Q9NR12/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PDLIM7","classification":"Not Classified","n_dependent_lines":19,"n_total_lines":1208,"dependency_fraction":0.015728476821192054},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"BRD2","stoichiometry":10.0},{"gene":"CTNNB1","stoichiometry":10.0},{"gene":"PTDSS1","stoichiometry":10.0},{"gene":"MAP2K7","stoichiometry":4.0},{"gene":"EEA1","stoichiometry":0.2},{"gene":"IPO13","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PDLIM7","total_profiled":1310},"omim":[{"mim_id":"605903","title":"PDZ AND LIM DOMAIN PROTEIN 7; PDLIM7","url":"https://www.omim.org/entry/605903"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Actin filaments","reliability":"Enhanced"},{"location":"Focal adhesion sites","reliability":"Enhanced"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"blood vessel","ntpm":549.7},{"tissue":"intestine","ntpm":568.3},{"tissue":"skeletal muscle","ntpm":620.5}],"url":"https://www.proteinatlas.org/search/PDLIM7"},"hgnc":{"alias_symbol":["ENIGMA"],"prev_symbol":[]},"alphafold":{"accession":"Q9NR12","domains":[{"cath_id":"2.30.42.10","chopping":"4-84","consensus_level":"high","plddt":91.0802,"start":4,"end":84},{"cath_id":"2.10.110.10","chopping":"243-247_340-396","consensus_level":"high","plddt":90.1703,"start":243,"end":396},{"cath_id":"2.10.110.10","chopping":"249-265_280-338","consensus_level":"medium","plddt":81.2828,"start":249,"end":338},{"cath_id":"2.10.110.10","chopping":"399-457","consensus_level":"medium","plddt":87.448,"start":399,"end":457}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NR12","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NR12-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NR12-F1-predicted_aligned_error_v6.png","plddt_mean":70.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PDLIM7","jax_strain_url":"https://www.jax.org/strain/search?query=PDLIM7"},"sequence":{"accession":"Q9NR12","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NR12.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NR12/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NR12"}},"corpus_meta":[{"pmid":"11325054","id":"PMC_11325054","title":"Coincidence, coevolution, or causation? 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mediates localization of Ret/ptc2 to the cell periphery, which is required for mitogenic signaling. Dimerization of Ret/ptc2 allows simultaneous recruitment of Shc (for Ras/Raf signaling) and Enigma (for subcellular localization) because both bind the same site on a monomer.\",\n      \"method\": \"Co-immunoprecipitation, dominant-negative coexpression, chimeric protein coexpression, subcellular localization studies\",\n      \"journal\": \"Molecular and Cellular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding demonstrated, chimeric protein rescue experiments, subcellular localization tied to functional mitogenic output, multiple orthogonal methods in one study\",\n      \"pmids\": [\"9528800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"PDLIM7 (Enigma) interacts with the adaptor protein APS through its LIM domains (binding to the NPTY motif of APS), and this complex localizes to F-actin-containing ruffles in response to insulin. Expression of Enigma alone induces F-actin cluster formation, whereas the APS/Enigma complex (requiring intact NPTY motif) modulates actin cytoskeleton organization.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation in HEK293 cells, co-localization by immunofluorescence, mutagenesis of NPTY motif\",\n      \"journal\": \"Experimental Cell Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP and localization data in single lab, multiple methods, but no in vitro reconstitution\",\n      \"pmids\": [\"15946664\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"In zebrafish, Pdlim7 regulates nuclear/cytoplasmic shuttling of the transcription factor Tbx5. Knockdown of Pdlim7 causes a non-looped heart phenotype similar to the tbx5 mutant but with opposite valve defects (no valve tissue vs. excess valve tissue), demonstrating that Pdlim7 controls Tbx5 activity at the atrio-ventricular boundary by modulating expression of Tbx5 target genes nppa and tbx2b.\",\n      \"method\": \"Zebrafish morpholino knockdown, molecular and histological analysis, in vivo genetic epistasis, gene expression analysis\",\n      \"journal\": \"Developmental Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo loss-of-function with defined molecular phenotype, epistasis with Tbx5, target gene expression readouts, multiple orthogonal methods\",\n      \"pmids\": [\"19895804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PDLIM7 (Enigma) and related ALP/Enigma family members bind α-actinin through their PDZ domains and bind signaling molecules through their LIM domains, functioning as scaffold proteins in cardiac and skeletal muscle. These proteins have been implicated in cardiac structure, function, and disease.\",\n      \"method\": \"Review synthesizing binding domain mapping and functional studies (PDZ-domain interaction with α-actinin, LIM-domain interactions)\",\n      \"journal\": \"Journal of Molecular Cell Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — review summarizing multiple prior binding studies; domain-function assignments are based on replicated findings across the subfamily\",\n      \"pmids\": [\"20042479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PDLIM7 (Enigma) directly interacts with MDM2 to form a ternary complex with p53, inhibits MDM2 self-ubiquitination, and thereby increases MDM2's ubiquitin ligase activity toward p53, leading to p53 degradation. Mitogenic stimuli (serum, FGF, HGF) increase Enigma transcription via serum response factor (SRF), stabilizing MDM2 and suppressing p53-mediated apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, in vitro ubiquitination assays, cell-based apoptosis assays, mouse xenograft model, HGF treatment of mice, SRF transcription factor binding assays\",\n      \"journal\": \"The Journal of Clinical Investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro ubiquitination assay plus co-IP plus in vivo mouse data plus multiple cell lines; multiple orthogonal methods establishing mechanism\",\n      \"pmids\": [\"21060154\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PDLIM7 is a substrate of the E3 ubiquitin ligase Nedd4-1 in skeletal muscle. PDLIM7 co-immunoprecipitates with Nedd4-1 via binding between the PY motif of PDLIM7 and the second and third WW domains of Nedd4-1; this interaction leads to PDLIM7 ubiquitination. In denervated muscle, increased Nedd4-1 expression coincides with decreased PDLIM7, and PDLIM7 is stabilized in Nedd4-1 muscle-specific knockout mice.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay in HEK293 cells, Nedd4-1 muscle-specific knockout mouse model, domain-mapping mutagenesis (PY motif)\",\n      \"journal\": \"The Biochemical Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro ubiquitination, reciprocal co-IP, PY-motif domain mapping, and in vivo genetic validation in knockout mice; multiple orthogonal methods\",\n      \"pmids\": [\"26556890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PDLIM7 silencing in cultured smooth muscle cells leads to downregulation of SMC markers, disruption of the actin cytoskeleton, decreased cell spreading, and increased proliferation, establishing a role for PDLIM7 in maintaining the contractile SMC phenotype via cytoskeletal organization.\",\n      \"method\": \"siRNA knockdown in cultured SMCs, actin cytoskeleton imaging, proliferation assays, chromatin immunoprecipitation-sequencing (H3K27ac)\",\n      \"journal\": \"Arteriosclerosis, Thrombosis, and Vascular Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined loss-of-function phenotype in cultured cells with multiple readouts (cytoskeleton, spreading, proliferation), single lab\",\n      \"pmids\": [\"27470516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PDLIM7 (and PDLIM5) are required for integrin-mediated mechanotransduction leading to YAP/TAZ nuclear localization and TEAD-dependent transcription. YAP binds to PDLIM7 via its C-terminal PDZ-binding motif (PBM). In response to mechanical force, PDLIM7 is recruited from the cytoplasm to integrin adhesions and F-actin stress fibers by direct binding to α-actinin. Silencing PDLIM5/7 reduces YAP nuclear localization, tyrosine phosphorylation, and transcriptional activity.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation, immunofluorescence/live cell imaging, transcriptional reporter assays, force application experiments\",\n      \"journal\": \"Journal of Cell Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, direct binding to α-actinin, functional rescue with PBM mutants, multiple orthogonal methods showing both binding and downstream transcriptional output\",\n      \"pmids\": [\"30404826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PDLIM7 regulates MDM2 protein turnover during CDK4/6 inhibitor-induced senescence. In CDK4/6 inhibitor-treated cells, PDLIM7 plays a defined role in downregulating MDM2 protein levels, contributing to the transition from quiescence to senescence.\",\n      \"method\": \"Cell line experiments with CDK4/6 inhibitors, Western blotting, knockdown experiments in human cell lines\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined cellular mechanism in cultured human cell lines with pharmacological and genetic perturbation, single lab\",\n      \"pmids\": [\"29789718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PDLIM7 is a ubiquitin E3 ligase that directly polyubiquitinates the p65 subunit of NF-κB, promoting its proteasomal degradation and suppressing NF-κB-mediated inflammatory responses. PDLIM7 heterodimerizes with PDLIM2, and promotes K63-linked ubiquitination of PDLIM2; p62/Sqstm1 then bridges polyubiquitinated PDLIM2 and the proteasome to facilitate delivery and degradation of the NF-κB–PDLIM2 complex. Double knockdown of PDLIM7 and either PDLIM2 or p62/Sqstm1 results in augmented proinflammatory cytokine production.\",\n      \"method\": \"In vitro ubiquitination assay, co-immunoprecipitation, siRNA double knockdown, cytokine measurement, proteasome inhibitor experiments\",\n      \"journal\": \"Frontiers in Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct in vitro ubiquitination assay, reciprocal co-IP, genetic double-knockdown with functional readout (cytokine production), mechanistic epistasis established\",\n      \"pmids\": [\"32849529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PDLIM7 mediates nuclear translocation of YAP1 in prostate cancer cells. TPM2 competes with YAP1 for binding to PDLIM7 through its PDZ-binding motif, thereby blocking PDLIM7-dependent nuclear transport of YAP1 and resulting in cytoplasmic sequestration, S127 phosphorylation, and inactivation/degradation of YAP1 and suppression of its downstream target genes.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, Western blotting, in vitro and in vivo tumor growth assays, PDZ-binding motif mutagenesis\",\n      \"journal\": \"Cell & Bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP, competition assay, mutagenesis of PDZ-binding motif, in vivo xenograft validation; single lab\",\n      \"pmids\": [\"36823643\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PDLIM7 (Enigma) is a scaffold/E3 ubiquitin ligase that, through its PDZ domain (binding α-actinin and transcription factors such as Tbx5 and YAP1) and LIM domains (binding signaling proteins including MDM2 and APS), coordinates actin cytoskeletal organization, mechanotransduction (recruiting to stress fibers/integrin adhesions to drive YAP nuclear localization), p53 regulation (stabilizing MDM2 to promote p53 ubiquitination and degradation via an SRF-induced pathway), NF-κB suppression (directly ubiquitinating p65 and facilitating PDLIM2/p62-mediated proteasomal degradation), and is itself a substrate of the E3 ligase Nedd4-1 in skeletal muscle (ubiquitinated via PY motif–WW domain interaction, contributing to denervation atrophy).\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PDLIM7 (Enigma) is a multidomain cytoskeletal scaffold and E3 ubiquitin ligase that couples actin-based architecture and integrin adhesions to transcriptional and signaling outputs [#3, #7]. Through its PDZ domain it binds \\u03b1-actinin to localize at F-actin stress fibers and integrin adhesions, while its LIM domains and PY motif engage signaling and effector proteins, allowing it to organize the actin cytoskeleton and maintain contractile cell phenotypes [#3, #6, #7]. In mechanotransduction, force recruits PDLIM7 from the cytoplasm to adhesions where it binds YAP via the YAP C-terminal PDZ-binding motif to drive YAP/TAZ nuclear localization and TEAD-dependent transcription [#7]; this interface is competitively antagonized by TPM2, which displaces YAP and promotes its cytoplasmic sequestration and inactivation [#10]. PDLIM7 also controls developmental transcription factor activity, regulating nuclear/cytoplasmic shuttling of Tbx5 at the cardiac atrio-ventricular boundary [#2]. As an E3 ligase, PDLIM7 stabilizes MDM2 by inhibiting its self-ubiquitination, thereby enhancing MDM2-directed p53 ubiquitination and degradation in a serum/SRF-induced pathway, and modulates MDM2 turnover during CDK4/6-inhibitor-induced senescence [#4, #8]. It additionally polyubiquitinates the NF-\\u03baB p65 subunit and heterodimerizes with PDLIM2, using p62/SQSTM1 to bridge ubiquitinated PDLIM2 to the proteasome and suppress proinflammatory cytokine production [#9]. PDLIM7 is itself a substrate of the E3 ligase Nedd4-1, ubiquitinated through a PY-motif\\u2013WW-domain interaction, linking its turnover to denervation-associated skeletal muscle atrophy [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established PDLIM7 as a localization scaffold linking a receptor tyrosine kinase to subcellular positioning required for mitogenic signaling.\",\n      \"evidence\": \"Co-IP, dominant-negative and chimeric coexpression, and subcellular localization studies of Ret/ptc2\",\n      \"pmids\": [\"9528800\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the structural basis of LIM-domain binding to the tyrosine 586 site\", \"Relevance beyond Ret/ptc2 signaling not addressed\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Connected PDLIM7 to insulin-responsive actin remodeling by identifying LIM-domain binding to the APS NPTY motif.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP in HEK293, immunofluorescence colocalization, and NPTY-motif mutagenesis\",\n      \"pmids\": [\"15946664\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vitro reconstitution of the APS/Enigma complex\", \"Functional consequence for insulin signaling outputs not quantified\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrated in vivo that PDLIM7 controls a transcription factor's nucleocytoplasmic shuttling, governing Tbx5 activity during heart development.\",\n      \"evidence\": \"Zebrafish morpholino knockdown with epistasis and target-gene expression analysis (nppa, tbx2b)\",\n      \"pmids\": [\"19895804\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct PDLIM7\\u2013Tbx5 binding interface not mapped\", \"Mechanism of shuttling control not biochemically defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Consolidated the domain logic of the ALP/Enigma family, assigning \\u03b1-actinin binding to the PDZ domain and signaling-protein binding to LIM domains in muscle scaffolding.\",\n      \"evidence\": \"Review synthesizing prior binding and functional studies\",\n      \"pmids\": [\"20042479\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Review-level synthesis, not new primary data\", \"PDLIM7-specific contributions not separated from paralogs\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined PDLIM7 as a positive regulator of MDM2 that suppresses p53, revealing an SRF-driven mitogenic survival pathway.\",\n      \"evidence\": \"In vitro ubiquitination assays, co-IP, apoptosis assays, mouse xenografts, and SRF binding assays\",\n      \"pmids\": [\"21060154\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PDLIM7 directly ubiquitinates any substrate here versus modulating MDM2 not fully resolved\", \"Structural basis of MDM2\\u2013p53 ternary complex formation undefined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified PDLIM7 as a Nedd4-1 substrate, placing its own turnover under E3-ligase control relevant to muscle atrophy.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, PY-motif domain mapping, and Nedd4-1 muscle-specific knockout mice\",\n      \"pmids\": [\"26556890\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of PDLIM7 loss for atrophy not directly demonstrated by PDLIM7 manipulation\", \"Ubiquitin chain topology on PDLIM7 not characterized\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed PDLIM7 maintains the contractile smooth muscle phenotype through cytoskeletal organization, restraining proliferation.\",\n      \"evidence\": \"siRNA knockdown in cultured SMCs with cytoskeleton imaging, spreading and proliferation assays, and H3K27ac ChIP-seq\",\n      \"pmids\": [\"27470516\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, cultured cells only\", \"Direct molecular link between cytoskeletal disruption and marker downregulation not established\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established PDLIM7 as a force-recruited adaptor driving YAP/TAZ nuclear localization and TEAD transcription via \\u03b1-actinin and the YAP PDZ-binding motif.\",\n      \"evidence\": \"siRNA knockdown, co-IP, live-cell imaging, force application, and reporter assays\",\n      \"pmids\": [\"30404826\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How PDLIM7 promotes YAP nuclear import mechanistically not resolved\", \"Redundancy with PDLIM5 not fully dissected\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended PDLIM7's MDM2 regulation to a senescence context, implicating it in CDK4/6-inhibitor-induced MDM2 downregulation.\",\n      \"evidence\": \"CDK4/6 inhibitor treatment, Western blotting, and knockdown in human cell lines\",\n      \"pmids\": [\"29789718\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direction of MDM2 regulation here differs in context from stabilization model; reconciliation not provided\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated PDLIM7 acts as a direct E3 ligase against NF-\\u03baB p65 and partners with PDLIM2/p62 to suppress inflammatory signaling.\",\n      \"evidence\": \"In vitro ubiquitination, co-IP, siRNA double knockdown, cytokine measurement, and proteasome inhibition\",\n      \"pmids\": [\"32849529\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Catalytic domain of PDLIM7 responsible for ligase activity not mapped\", \"In vivo physiological role in inflammation not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed competitive regulation of the PDLIM7\\u2013YAP1 axis by TPM2 in prostate cancer, controlling YAP1 nuclear transport and stability.\",\n      \"evidence\": \"Co-IP, competition and PDZ-binding motif mutagenesis, immunofluorescence, and in vivo tumor assays\",\n      \"pmids\": [\"36823643\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Generality beyond prostate cancer cells not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PDLIM7's scaffolding and intrinsic E3-ligase activities are mechanistically coordinated, and which catalytic determinants drive its ubiquitination of substrates, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the catalytic/substrate-binding interface\", \"Context-dependent opposing effects on MDM2 not reconciled\", \"In vivo physiological roles of the ligase functions largely untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [4, 9]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [4, 9]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 7, 10]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [3, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 10]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [4, 5, 9]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MDM2\", \"YAP1\", \"ACTN\", \"PDLIM2\", \"NEDD4\", \"RELA\", \"TBX5\", \"SH2B2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}