{"gene":"PDLIM2","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":2007,"finding":"PDLIM2 acts as a nuclear ubiquitin E3 ligase that binds the p65 subunit of NF-κB, promotes p65 polyubiquitination, and targets p65 to discrete intranuclear compartments for proteasomal degradation, thereby terminating NF-κB activation. PDLIM2 deficiency results in larger amounts of nuclear p65, defective p65 ubiquitination, and augmented proinflammatory cytokine production.","method":"Co-immunoprecipitation, ubiquitination assay, PDLIM2-deficient cells/mice with cytokine readout, nuclear localization imaging","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, in vivo ubiquitination assay, KO mice with defined inflammatory phenotype, replicated across multiple subsequent studies","pmids":["17468759"],"is_preprint":false},{"year":2004,"finding":"PDLIM2 directly interacts with α-actinin-1, α-actinin-4, and filamin A (confirmed by pulldown with purified proteins and gel overlay assay), and co-localizes with α-actinins at stress fibers. The PDZ domain mediates cytoskeletal binding.","method":"Co-immunoprecipitation, GST pulldown, gel overlay assay with purified proteins, confocal microscopy in transfected COS-7 cells","journal":"Investigative ophthalmology & visual science","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro binding confirmed with purified proteins (gel overlay + pulldown), multiple orthogonal methods in one study","pmids":["15505042"],"is_preprint":false},{"year":2009,"finding":"PDLIM2 directly binds the HTLV-I Tax oncoprotein, promotes K48-linked polyubiquitination of Tax, and recruits Tax from its functional sites into the nuclear matrix for proteasomal degradation, thereby suppressing Tax-mediated cell transformation and oncogenesis.","method":"Co-immunoprecipitation, ubiquitination assay, nuclear matrix fractionation, in vitro and in vivo transformation/oncogenesis assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, linkage-specific ubiquitination assay, nuclear fractionation, in vivo tumor suppression model","pmids":["19131544"],"is_preprint":false},{"year":2011,"finding":"PDLIM2 acts as a nuclear ubiquitin E3 ligase targeting STAT3 for polyubiquitination and proteasomal degradation, thereby inhibiting TH17 cell development. PDLIM2 deficiency leads to nuclear STAT3 accumulation, enhanced TH17 differentiation, and exacerbated granuloma formation.","method":"Ubiquitination assay, PDLIM2-deficient mice, T-cell differentiation assays, nuclear fractionation","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo ubiquitination assay, KO mice with defined TH17/granuloma phenotype, nuclear accumulation data","pmids":["22155789"],"is_preprint":false},{"year":2010,"finding":"PDLIM2 binds Tax directly via a putative α-helix motif at amino acids 236–254; selective disruption of this motif abolishes Tax shuttling to the nuclear matrix and ubiquitination-mediated degradation. The C-terminal LIM domain is required for PDLIM2 interaction with the nuclear matrix and for Tax repression, while the N-terminal PDZ domain is dispensable for Tax regulation but mediates cytoskeletal binding.","method":"Domain deletion/mutation analysis, co-immunoprecipitation, nuclear matrix fractionation, ubiquitination assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis of specific domain combined with functional rescue, nuclear fractionation, ubiquitination assays, multiple orthogonal methods","pmids":["20838382"],"is_preprint":false},{"year":2010,"finding":"PDLIM2 ubiquitinates STAT1 in an osteopontin (OPN)- and protein kinase C-dependent manner. Serine 137 of PDLIM2 is a PKC phosphorylation site required for STAT1 ubiquitination; phospho-mimetic constructs confirm this role. OPN expression is required for PDLIM2 serine phosphorylation and STAT1 ubiquitination in macrophages.","method":"In vivo and in vitro ubiquitination assays, phospho-mutant/phospho-mimetic constructs, ChIP assay, OPN-knockout mice","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — site-directed mutagenesis of phosphorylation site, in vitro and in vivo ubiquitination assays, KO mouse model","pmids":["20889505"],"is_preprint":false},{"year":2011,"finding":"PDLIM2 acts as an actin-regulating protein in podocyte foot processes, stabilizes stress fibers, and interacts with the actin-associated proteins α-actinin-4 and angiomotin-like-1 as shown by co-immunoprecipitation and yeast two-hybrid analysis.","method":"Co-immunoprecipitation, yeast two-hybrid, immunofluorescence, immunoelectron microscopy","journal":"Kidney international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and yeast two-hybrid for binding partners, in situ localization by immunoelectron microscopy, single lab","pmids":["21814175"],"is_preprint":false},{"year":2011,"finding":"The PDZ domain of PDLIM2 selectively binds the ESEV PDZ-binding motif (PBM) of highly pathogenic avian influenza H5N1 NS1, but not the RSEV PBM of human H1N1 NS1. A crystal structure of the PDLIM2 PDZ domain fused with the C-terminal hexapeptide of HN12-NS1 reveals that residues Arg16 and Lys31 of PDLIM2 are critical for this interaction.","method":"Yeast two-hybrid, GST pulldown, mammalian two-hybrid, bimolecular fluorescence complementation, X-ray crystallography, PDZ domain mutagenesis","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional mutagenesis validation and multiple orthogonal binding assays","pmids":["21625420"],"is_preprint":false},{"year":2008,"finding":"PDLIM2 subcellular localization is regulated by differentiation state: in non-differentiated monocytic THP-1 cells PDLIM2 is predominantly nuclear, whereas PMA-induced differentiation into macrophages shifts PDLIM2 predominantly to the cytoplasm. This cytoplasmic sequestration is associated with cell adhesion and increased nuclear NF-κB activity. The cytoplasmic shift involves PKC/ERK-dependent serine phosphorylation of PDLIM2.","method":"Subcellular fractionation, immunofluorescence, phosphatase treatment, kinase inhibitors, PDLIM2 knockdown/overexpression with NF-κB reporter and adhesion assays","journal":"Journal of leukocyte biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct fractionation and imaging, kinase inhibitor pharmacology, functional readouts (adhesion, NF-κB reporter), single lab","pmids":["19052146"],"is_preprint":false},{"year":2013,"finding":"PDLIM2 associates with CSN5 (a subunit of the COP9 signalosome) and controls the nuclear accumulation and deneddylation activity of the CSN toward cullin 1 and cullin 3 subunits of cullin-RING ubiquitin ligases. PDLIM2 suppression causes loss of directional migration, inability to polarize the cytoskeleton, and reversal of the EMT phenotype, along with altered activity of β-catenin, AP-1, NFκB, IRFs, STATs, JUN, and p53.","method":"Co-immunoprecipitation (PDLIM2-CSN5), deneddylation activity assay, PDLIM2 knockdown with migration/polarity/transcription factor activity readouts","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of PDLIM2-CSN5, enzymatic deneddylation assay, knockdown with defined phenotype, single lab","pmids":["24196835"],"is_preprint":false},{"year":2013,"finding":"PDLIM2 is a direct transcriptional target of 1,25(OH)2D3/VDR signaling; a functional vitamin D response element (VDRE) was identified in the PDLIM2 promoter. 1,25(OH)2D3-induced demethylation of the PDLIM2 promoter enhances its transcription. PDLIM2 is required for vitamin D-induced cell adhesion and for mediating vitamin D suppression of cancer cell migration and invasion.","method":"VDRE reporter assay, ChIP, demethylation analysis, PDLIM2 knockdown with adhesion/migration/invasion readouts","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP for VDRE, promoter reporter assay, KD with functional phenotypes; single lab","pmids":["23584482"],"is_preprint":false},{"year":2014,"finding":"PDLIM2 is required for feedback regulation of the β1-integrin–RhoA signaling axis in 3D breast epithelial acini. PDLIM2 suppression increases β1-integrin, IGF-1R, and RACK1 levels, enhances FAK and cofilin phosphorylation and RhoA-GTPase activity, and disrupts cell polarization and acini formation. Inhibition of FAK or ROCK rescues the polarity defect caused by PDLIM2 suppression.","method":"shRNA knockdown in 3D MCF10A cultures, RhoA GTPase activity assay, FAK/cofilin phosphorylation Western blot, FAK/ROCK inhibitor rescue","journal":"Neoplasia (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RhoA activity assay, kinase phosphorylation, pharmacological rescue in 3D culture system, single lab","pmids":["24863845"],"is_preprint":false},{"year":2019,"finding":"PDLIM2 acts as an E3 ubiquitin ligase that promotes nuclear proteasome-dependent degradation of STAT2 (but not STAT1). Interferon-dependent relocalization of STAT1/2 to the nucleus leads to PDLIM2 ubiquitination of STAT2. CRISPR/Cas9 knockout of PDLIM2 increases STAT2 levels after IFNα treatment, retains STAT2 in the nucleus of HCV-infected cells, and increases resistance to several flaviviruses.","method":"CRISPR/Cas9 knockout, ubiquitination assay, nuclear fractionation, IFN response assay, flavivirus infection assay","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR KO with multiple functional readouts, ubiquitination assay, nuclear fractionation, viral infection model, multiple orthogonal methods","pmids":["31374104"],"is_preprint":false},{"year":2020,"finding":"PDLIM7 heterodimerizes with PDLIM2 to promote synergistic PDLIM2-mediated degradation of p65. Mechanistically, PDLIM7 promotes K63-linked ubiquitination of PDLIM2, and then p62/SQSTM1 binds polyubiquitinated PDLIM2 and the proteasome, facilitating delivery of the NF-κB–PDLIM2 complex to the proteasome for p65 degradation.","method":"Co-immunoprecipitation (PDLIM7-PDLIM2 heterodimer), linkage-specific ubiquitination assay, double knockdown with NF-κB/cytokine readouts","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, linkage-specific ubiquitination, double-KD epistasis, single lab","pmids":["32849529"],"is_preprint":false},{"year":2019,"finding":"PDLIM2 cytoplasmic retention is controlled by cell adhesion, and nuclear translocation is stimulated by IGF-1 or TGFβ. Cytoplasmic PDLIM2 associates with active β-catenin, and ectopic PDLIM2 expression increases β-catenin levels and its transcriptional activity.","method":"Subcellular fractionation, co-immunoprecipitation (PDLIM2–β-catenin), β-catenin reporter assay, IGF-1/TGFβ stimulation","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct fractionation, Co-IP, reporter assay, growth factor stimulation experiments; single lab","pmids":["30885980"],"is_preprint":false},{"year":2021,"finding":"PDLIM2 downregulation in alveolar macrophages is driven by ROS-activated transcription repressor BACH1. PDLIM2 downregulation leads to constitutive STAT3 activation, driving pro-tumorigenic AM polarization, differentiation from attracted monocytes, suppression of CTLs, and decreased AM phagocytosis. This defines a ROS/BACH1/PDLIM2/STAT3 signaling axis.","method":"Conditional PDLIM2 KO mice, ROS stimulation, BACH1 ChIP/reporter assay, flow cytometry (AM polarization), phagocytosis assay, CTL suppression assay","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO mice with multiple cellular phenotypes, BACH1 ChIP establishing pathway, phagocytosis and T-cell functional assays, multiple orthogonal methods","pmids":["33539325"],"is_preprint":false},{"year":2019,"finding":"Through nuclear repression of NF-κB/RelA and STAT3, PDLIM2 increases expression of antigen-presentation genes and T-cell activation genes while repressing multidrug resistance genes, rendering cancer cells vulnerable to immune attack and therapies. Global or lung epithelial-specific PDLIM2 deletion in mice causes increased lung cancer development, chemoresistance, and complete resistance to anti-PD-1.","method":"Conditional/global KO mice, gene expression profiling, anti-PD-1 treatment, chemotherapy treatment, epigenetic restoration","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple conditional KO models, in vivo therapeutic experiments, gene expression analysis, multiple orthogonal approaches","pmids":["31757943"],"is_preprint":false},{"year":2022,"finding":"PDLIM2 acts as an E3 ubiquitin ligase that ubiquitinates PFKL (phosphofructokinase, liver type), promoting its degradation. In LSCC cells, PDLIM2 inhibits cell proliferation and glycolysis, and M2 macrophage-derived exosomes deliver miR-222-3p to suppress PDLIM2 expression, leading to elevated PFKL and enhanced glycolysis.","method":"Ubiquitination assay (PDLIM2–PFKL), Seahorse metabolic assay, miRNA luciferase reporter, PDLIM2 overexpression/knockdown, in vivo xenograft","journal":"Neoplasma","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination assay for specific substrate PFKL, metabolic assay, in vivo model; single lab","pmids":["35723199"],"is_preprint":false},{"year":2024,"finding":"PDLIM2 acts as a ubiquitin ligase enhancer (E5) that stabilizes ROC1 (an essential component of SCF ubiquitin ligases) and chaperones the ROC1-SCFβ-TrCP ubiquitin ligase complex to ubiquitinate nuclear NF-κB RelA for proteasomal degradation. Silencing of ROC1, Cullin 1, or β-TrCP blocks RelA ubiquitination and degradation by PDLIM2.","method":"Co-immunoprecipitation, RNAi knockdown of ROC1/Cullin1/β-TrCP, ubiquitination assay, nuclear fractionation","journal":"Cell & bioscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, epistatic RNAi knockdowns of multiple pathway components, ubiquitination assay; single lab","pmids":["39080804"],"is_preprint":false},{"year":2021,"finding":"PDLIM2 is required for M2 macrophage polarization induced by IL-4, including expression of M2 phenotypic markers, cell adhesion, and cell migration. PDLIM2 is also required for naïve macrophage migration. M1 macrophage activity induced by TLR4, TLR3, or IFNγ was less dependent on PDLIM2.","method":"PDLIM2 knockout bone marrow-derived macrophage cultures, M2 polarization assay (IL-4 stimulation), M1 polarization assay, migration assay","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO bone marrow macrophages with M1/M2 polarization assays and migration readout; single lab","pmids":["36531051"],"is_preprint":false},{"year":2021,"finding":"PDLIM2 interacts with TRIM27 and facilitates K27-linked polyubiquitination-mediated proteasomal degradation of TRIM27, thereby attenuating STAT3 signaling. PBXIP1 overexpression in HCC promotes polyubiquitination of PDLIM2 via the ubiquitin-proteasome system, destabilizing PDLIM2.","method":"Co-immunoprecipitation (PDLIM2–TRIM27), linkage-specific ubiquitination assay, PBXIP1 overexpression/KD, STAT3 signaling readout","journal":"European journal of medical research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and K27-specific ubiquitination assay for novel substrate TRIM27, upstream regulator identified; single lab","pmids":["41340074"],"is_preprint":false},{"year":2021,"finding":"PDLIM2 regulates bacterial (E. coli) and fungal (C. neoformans) traversal and exocytosis in brain microvascular endothelial cells. PDLIM2 knockdown specifically impairs microbial transcytosis and egression (but not invasion). Among 210 proximity-biotinylated PDLIM2 interactors identified by BioID2, MPRIP knockdown mimics the PDLIM2 knockdown phenotype, placing MPRIP as a PDLIM2-interacting effector in this process. Calcium ionophore rescues the exocytosis defect.","method":"shRNA knockdown, BioID2 proximity labeling, transcytosis/invasion/egression assays, MPRIP knockdown, calcium ionophore rescue","journal":"Infection and immunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proximity proteomics with functional validation via secondary KD, specific transcytosis assay with rescue; single lab","pmids":["34228504"],"is_preprint":false},{"year":2024,"finding":"PDLIM2 downregulation leads to NF-κB activation, impaired expression of succinate dehydrogenase (SDH) genes, mitochondrial dysfunction, accumulation of succinate and other oncometabolites, buildup of mitochondrial ROS (mtROS), and activation of HIF-1α. HIF-1α inhibition (PX-478) significantly reduces PDLIM2 knockdown-promoted tumor growth in vivo, placing HIF-1α downstream of PDLIM2 loss.","method":"Seahorse metabolic assay, LC-MS oncometabolite analysis, flow cytometry (mtROS), DNA microarray, Lewis lung carcinoma mouse model with HIF-1α inhibitor treatment","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — metabolic assays, LC-MS, in vivo pharmacological rescue; single lab","pmids":["38880883"],"is_preprint":false},{"year":2024,"finding":"CircPTPN12 interacts with the PDZ domain of PDLIM2 and facilitates p65 ubiquitination by PDLIM2. CircPTPN12 also promotes the deubiquitination of PDLIM2 itself by bolstering the PDLIM2/OTUD6B complex, thereby stabilizing PDLIM2.","method":"RNA immunoprecipitation, biotin-coupled probe pulldown, FISH, RNA sequencing, ubiquitination assay","journal":"Molecular cancer","confidence":"Low","confidence_rationale":"Tier 3 / Weak — circRNA study where PDLIM2 mechanistic role (PDZ domain binding, ubiquitination) is shown by pulldown and ubiquitination assay but the primary focus is on the circRNA; single lab, indirect for canonical PDLIM2 protein mechanism","pmids":["38992675"],"is_preprint":false}],"current_model":"PDLIM2 is a PDZ-LIM domain-containing protein that functions dually as a cytoskeletal adaptor (binding α-actinins and filamin A via its PDZ domain) and a nuclear ubiquitin E3 ligase enhancer (E5) that stabilizes the ROC1-SCFβ-TrCP complex to polyubiquitinate nuclear NF-κB RelA/p65, and directly ubiquitinates STAT3 and STAT2, targeting all three transcription factors for intranuclear proteasomal degradation; its LIM domain anchors it to the nuclear matrix, its subcellular localization is regulated by PKC/ERK-dependent serine phosphorylation, and its activity is modulated by PDLIM7 heterodimerization and by upstream signals including OPN, BACH1, and viral infection, enabling PDLIM2 to serve as a critical terminator of NF-κB and STAT-driven inflammatory and oncogenic signaling."},"narrative":{"mechanistic_narrative":"PDLIM2 is a PDZ-LIM domain protein that operates at the interface of the cytoskeleton and the nucleus, functioning as a nuclear ubiquitin-ligase system that terminates inflammatory and oncogenic transcription-factor signaling [PMID:17468759, PMID:22155789]. In the nucleus, its LIM domain anchors it to the nuclear matrix, where it binds the NF-κB subunit p65/RelA, promotes its polyubiquitination, and sequesters it into intranuclear compartments for proteasomal degradation, thereby switching off NF-κB activity [PMID:17468759, PMID:20838382]. PDLIM2 enforces this degradation not by acting alone but as a ubiquitin-ligase enhancer (E5) that stabilizes ROC1 and chaperones the ROC1–SCFβ-TrCP cullin-RING ligase complex onto nuclear RelA [PMID:39080804]. The same intranuclear degradation mechanism targets the STAT family: PDLIM2 ubiquitinates STAT3 to restrain TH17 differentiation [PMID:22155789], STAT1 in an osteopontin/PKC-dependent manner [PMID:20889505], and STAT2 to limit interferon signaling and confer antiviral resistance [PMID:31374104]. It also degrades transforming proteins, K48-ubiquitinating the HTLV-I Tax oncoprotein to suppress cell transformation [PMID:19131544]. Through its PDZ domain PDLIM2 binds the cytoskeletal cross-linkers α-actinin-1/-4 and filamin A and co-localizes at stress fibers, linking it to actin organization, cell adhesion, and directional migration [PMID:15505042, PMID:21814175]. Its subcellular partitioning is regulated by differentiation- and adhesion-coupled PKC/ERK-dependent serine phosphorylation, which drives cytoplasmic sequestration and consequent nuclear NF-κB activity [PMID:19052146]. By coupling these activities, PDLIM2 acts as a tumor suppressor whose loss—driven by ROS/BACH1-mediated repression or miRNA delivery—promotes constitutive STAT3 and NF-κB activation, immune evasion, chemoresistance, and metabolic reprogramming [PMID:33539325, PMID:31757943, PMID:38880883].","teleology":[{"year":2004,"claim":"Established PDLIM2's first molecular identity as a cytoskeletal adaptor, defining the PDZ domain as the cytoskeleton-binding module before any nuclear role was known.","evidence":"GST pulldown and gel overlay with purified α-actinin-1/-4 and filamin A, plus confocal co-localization at stress fibers in COS-7 cells","pmids":["15505042"],"confidence":"High","gaps":["Did not address any nuclear or ubiquitin-ligase function","Functional consequence of cytoskeletal binding not tested in physiological cells"]},{"year":2007,"claim":"Revealed PDLIM2 as a nuclear E3 ligase terminator of NF-κB, answering how nuclear p65 is cleared to resolve inflammation.","evidence":"Reciprocal Co-IP, in vivo p65 ubiquitination assay, and PDLIM2-deficient cells/mice with proinflammatory cytokine readouts","pmids":["17468759"],"confidence":"High","gaps":["Did not identify the cullin-RING machinery PDLIM2 recruits","Mechanism of intranuclear compartment targeting unresolved"]},{"year":2008,"claim":"Showed PDLIM2 localization is dynamically partitioned between nucleus and cytoplasm by signaling, explaining how its NF-κB-suppressive activity is switched off.","evidence":"Subcellular fractionation, kinase inhibitor pharmacology, and phosphatase treatment in THP-1 monocyte/macrophage differentiation with NF-κB reporter","pmids":["19052146"],"confidence":"Medium","gaps":["Specific phosphorylated residues not mapped here","Single cell-line model"]},{"year":2009,"claim":"Extended the degradation mechanism to a viral oncoprotein, establishing PDLIM2 as a tumor suppressor that clears HTLV-I Tax.","evidence":"Reciprocal Co-IP, K48-linkage-specific ubiquitination assay, nuclear matrix fractionation, and in vivo transformation/oncogenesis assays","pmids":["19131544"],"confidence":"High","gaps":["E3 cofactors for Tax ubiquitination not defined","Did not address endogenous substrates beyond Tax"]},{"year":2010,"claim":"Defined the domain logic of PDLIM2 function—LIM/nuclear-matrix anchoring versus PDZ/cytoskeletal binding—and showed PKC-phosphorylation of Ser137 licenses STAT1 ubiquitination downstream of osteopontin.","evidence":"Domain deletion and Tax-binding motif mutagenesis with nuclear fractionation; phospho-mutant/phospho-mimetic constructs plus OPN-knockout mice for STAT1","pmids":["20838382","20889505"],"confidence":"High","gaps":["Kinase acting directly on Ser137 in vivo not isolated","How OPN signaling reaches PDLIM2 not fully traced"]},{"year":2011,"claim":"Broadened the substrate repertoire to STAT3 and connected PDLIM2 to actin/podocyte biology and to PDZ-dependent recognition of a pathogen ligand.","evidence":"PDLIM2-deficient mice with TH17/granuloma phenotypes (STAT3); Co-IP/yeast two-hybrid with α-actinin-4 and angiomotin-like-1 in podocytes; crystal structure of the PDZ domain bound to H5N1 NS1 ESEV motif with mutagenesis","pmids":["22155789","21814175","21625420"],"confidence":"High","gaps":["Whether NS1 binding alters PDLIM2 enzymatic function untested","Podocyte data confidence Medium and single-lab"]},{"year":2013,"claim":"Linked PDLIM2 to upstream ubiquitin-system regulation (COP9 signalosome) and to its own transcriptional induction by vitamin D, integrating it into migration, polarity, and EMT control.","evidence":"PDLIM2-CSN5 Co-IP with cullin deneddylation assays and knockdown migration/polarity readouts; VDRE reporter, ChIP, and promoter demethylation analysis","pmids":["24196835","23584482"],"confidence":"Medium","gaps":["Direct enzymatic relationship between PDLIM2 and CSN deneddylation not reconstituted","Both single-lab"]},{"year":2014,"claim":"Placed PDLIM2 in a β1-integrin–RhoA feedback loop governing epithelial polarity, mechanistically connecting its cytoskeletal role to morphogenesis.","evidence":"shRNA knockdown in 3D MCF10A acini with RhoA GTPase activity assays, FAK/cofilin phosphorylation, and FAK/ROCK inhibitor rescue","pmids":["24863845"],"confidence":"Medium","gaps":["Whether the effect requires PDLIM2 ligase activity unresolved","Single 3D culture system"]},{"year":2019,"claim":"Consolidated PDLIM2 as a tumor suppressor coupling NF-κB/STAT3 repression to anti-tumor immunity, added STAT2/antiviral function, and defined cytoplasmic β-catenin association.","evidence":"Conditional/global KO mice with anti-PD-1 and chemotherapy treatments and expression profiling; CRISPR KO with STAT2 ubiquitination and flavivirus assays; fractionation/Co-IP/β-catenin reporter with IGF-1/TGFβ stimulation","pmids":["31757943","31374104","30885980"],"confidence":"High","gaps":["Distinction between PDLIM2's nuclear suppressor and cytoplasmic β-catenin-promoting roles not mechanistically reconciled","β-catenin association data Medium-confidence single-lab"]},{"year":2020,"claim":"Identified PDLIM7 heterodimerization and a p62/SQSTM1-mediated proteasome-delivery route as a regulatory layer amplifying PDLIM2-driven p65 degradation.","evidence":"PDLIM7-PDLIM2 Co-IP, K63-linkage-specific ubiquitination of PDLIM2, and double-knockdown epistasis with NF-κB/cytokine readouts","pmids":["32849529"],"confidence":"Medium","gaps":["E3 producing K63 chains on PDLIM2 not identified","Single lab"]},{"year":2021,"claim":"Embedded PDLIM2 loss in disease-relevant axes (ROS/BACH1 repression driving STAT3-dependent macrophage reprogramming), defined its requirement for M2 polarization, identified TRIM27 as a substrate, and implicated it in microbial transcytosis.","evidence":"Conditional KO mice with BACH1 ChIP and AM phenotyping; KO macrophages with M1/M2 polarization and migration assays; PDLIM2-TRIM27 Co-IP with K27-ubiquitination; BioID2 proximity proteomics with MPRIP validation in endothelial transcytosis","pmids":["33539325","36531051","41340074","34228504"],"confidence":"High","gaps":["TRIM27 and transcytosis findings are Medium-confidence single-lab","How the BioID2 interactome connects to ligase activity largely unmapped"]},{"year":2022,"claim":"Expanded the substrate set into metabolism, showing PDLIM2 ubiquitinates the glycolytic enzyme PFKL and that tumor-derived exosomal miR-222-3p suppresses PDLIM2 to enhance glycolysis.","evidence":"PDLIM2-PFKL ubiquitination assay, Seahorse metabolic assay, miRNA luciferase reporter, and xenograft in LSCC","pmids":["35723199"],"confidence":"Medium","gaps":["Whether PFKL ubiquitination occurs in the nucleus or cytoplasm unclear","Single lab"]},{"year":2024,"claim":"Resolved the cullin-RING machinery PDLIM2 employs (E5 enhancer of ROC1-SCFβ-TrCP), connected PDLIM2 loss to mitochondrial/oncometabolite/HIF-1α reprogramming, and added circPTPN12 as a PDZ-binding stabilizer.","evidence":"Co-IP and epistatic RNAi of ROC1/Cullin1/β-TrCP with RelA ubiquitination assays; Seahorse, LC-MS oncometabolites, and Lewis lung carcinoma model with HIF-1α inhibitor; RIP/pulldown/ubiquitination for circPTPN12-OTUD6B","pmids":["39080804","38880883","38992675"],"confidence":"Medium","gaps":["circPTPN12 finding is Low-confidence and focused on the circRNA","Structural basis of ROC1-SCFβ-TrCP chaperoning not determined"]},{"year":null,"claim":"How a single protein reconciles cytoplasmic cytoskeletal/β-catenin-promoting roles with nuclear tumor-suppressive ubiquitin ligase activity, and how phosphorylation-driven trafficking dictates which program dominates, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of the full-length protein engaged with its cullin-RING partners","Direct kinases controlling localization not definitively identified","Substrate selection rules across NF-κB/STAT/Tax/PFKL/TRIM27 not unified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2,3,5,12,17,20]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,12,18]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[1,6]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[18,13]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[18,9]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,3,8,12]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[2,4]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[8,14]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[1,6]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,3,5,12,16,19]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,2,3,12,18]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,11,14]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,15,16,17,22]}],"complexes":["ROC1-SCFβ-TrCP ubiquitin ligase complex","PDLIM2-PDLIM7 heterodimer"],"partners":["RELA","ACTN4","FLNA","PDLIM7","ROC1","CSN5","TRIM27","CTNNB1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96JY6","full_name":"PDZ and LIM domain protein 2","aliases":["PDZ-LIM protein mystique"],"length_aa":352,"mass_kda":37.5,"function":"Probable adapter protein located at the actin cytoskeleton that promotes cell attachment. Necessary for the migratory capacity of epithelial cells. Overexpression enhances cell adhesion to collagen and fibronectin and suppresses anchorage independent growth. May contribute to tumor cell migratory capacity","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q96JY6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PDLIM2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PDLIM2","total_profiled":1310},"omim":[{"mim_id":"609722","title":"PDZ AND LIM DOMAIN PROTEIN 2; PDLIM2","url":"https://www.omim.org/entry/609722"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Actin filaments","reliability":"Supported"},{"location":"Focal adhesion sites","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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PDLIM2 deficiency results in larger amounts of nuclear p65, defective p65 ubiquitination, and augmented proinflammatory cytokine production.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, PDLIM2-deficient cells/mice with cytokine readout, nuclear localization imaging\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, in vivo ubiquitination assay, KO mice with defined inflammatory phenotype, replicated across multiple subsequent studies\",\n      \"pmids\": [\"17468759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"PDLIM2 directly interacts with α-actinin-1, α-actinin-4, and filamin A (confirmed by pulldown with purified proteins and gel overlay assay), and co-localizes with α-actinins at stress fibers. The PDZ domain mediates cytoskeletal binding.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown, gel overlay assay with purified proteins, confocal microscopy in transfected COS-7 cells\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro binding confirmed with purified proteins (gel overlay + pulldown), multiple orthogonal methods in one study\",\n      \"pmids\": [\"15505042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PDLIM2 directly binds the HTLV-I Tax oncoprotein, promotes K48-linked polyubiquitination of Tax, and recruits Tax from its functional sites into the nuclear matrix for proteasomal degradation, thereby suppressing Tax-mediated cell transformation and oncogenesis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, nuclear matrix fractionation, in vitro and in vivo transformation/oncogenesis assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, linkage-specific ubiquitination assay, nuclear fractionation, in vivo tumor suppression model\",\n      \"pmids\": [\"19131544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PDLIM2 acts as a nuclear ubiquitin E3 ligase targeting STAT3 for polyubiquitination and proteasomal degradation, thereby inhibiting TH17 cell development. PDLIM2 deficiency leads to nuclear STAT3 accumulation, enhanced TH17 differentiation, and exacerbated granuloma formation.\",\n      \"method\": \"Ubiquitination assay, PDLIM2-deficient mice, T-cell differentiation assays, nuclear fractionation\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo ubiquitination assay, KO mice with defined TH17/granuloma phenotype, nuclear accumulation data\",\n      \"pmids\": [\"22155789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PDLIM2 binds Tax directly via a putative α-helix motif at amino acids 236–254; selective disruption of this motif abolishes Tax shuttling to the nuclear matrix and ubiquitination-mediated degradation. The C-terminal LIM domain is required for PDLIM2 interaction with the nuclear matrix and for Tax repression, while the N-terminal PDZ domain is dispensable for Tax regulation but mediates cytoskeletal binding.\",\n      \"method\": \"Domain deletion/mutation analysis, co-immunoprecipitation, nuclear matrix fractionation, ubiquitination assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis of specific domain combined with functional rescue, nuclear fractionation, ubiquitination assays, multiple orthogonal methods\",\n      \"pmids\": [\"20838382\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PDLIM2 ubiquitinates STAT1 in an osteopontin (OPN)- and protein kinase C-dependent manner. Serine 137 of PDLIM2 is a PKC phosphorylation site required for STAT1 ubiquitination; phospho-mimetic constructs confirm this role. OPN expression is required for PDLIM2 serine phosphorylation and STAT1 ubiquitination in macrophages.\",\n      \"method\": \"In vivo and in vitro ubiquitination assays, phospho-mutant/phospho-mimetic constructs, ChIP assay, OPN-knockout mice\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — site-directed mutagenesis of phosphorylation site, in vitro and in vivo ubiquitination assays, KO mouse model\",\n      \"pmids\": [\"20889505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PDLIM2 acts as an actin-regulating protein in podocyte foot processes, stabilizes stress fibers, and interacts with the actin-associated proteins α-actinin-4 and angiomotin-like-1 as shown by co-immunoprecipitation and yeast two-hybrid analysis.\",\n      \"method\": \"Co-immunoprecipitation, yeast two-hybrid, immunofluorescence, immunoelectron microscopy\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and yeast two-hybrid for binding partners, in situ localization by immunoelectron microscopy, single lab\",\n      \"pmids\": [\"21814175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The PDZ domain of PDLIM2 selectively binds the ESEV PDZ-binding motif (PBM) of highly pathogenic avian influenza H5N1 NS1, but not the RSEV PBM of human H1N1 NS1. A crystal structure of the PDLIM2 PDZ domain fused with the C-terminal hexapeptide of HN12-NS1 reveals that residues Arg16 and Lys31 of PDLIM2 are critical for this interaction.\",\n      \"method\": \"Yeast two-hybrid, GST pulldown, mammalian two-hybrid, bimolecular fluorescence complementation, X-ray crystallography, PDZ domain mutagenesis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional mutagenesis validation and multiple orthogonal binding assays\",\n      \"pmids\": [\"21625420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PDLIM2 subcellular localization is regulated by differentiation state: in non-differentiated monocytic THP-1 cells PDLIM2 is predominantly nuclear, whereas PMA-induced differentiation into macrophages shifts PDLIM2 predominantly to the cytoplasm. This cytoplasmic sequestration is associated with cell adhesion and increased nuclear NF-κB activity. The cytoplasmic shift involves PKC/ERK-dependent serine phosphorylation of PDLIM2.\",\n      \"method\": \"Subcellular fractionation, immunofluorescence, phosphatase treatment, kinase inhibitors, PDLIM2 knockdown/overexpression with NF-κB reporter and adhesion assays\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct fractionation and imaging, kinase inhibitor pharmacology, functional readouts (adhesion, NF-κB reporter), single lab\",\n      \"pmids\": [\"19052146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PDLIM2 associates with CSN5 (a subunit of the COP9 signalosome) and controls the nuclear accumulation and deneddylation activity of the CSN toward cullin 1 and cullin 3 subunits of cullin-RING ubiquitin ligases. PDLIM2 suppression causes loss of directional migration, inability to polarize the cytoskeleton, and reversal of the EMT phenotype, along with altered activity of β-catenin, AP-1, NFκB, IRFs, STATs, JUN, and p53.\",\n      \"method\": \"Co-immunoprecipitation (PDLIM2-CSN5), deneddylation activity assay, PDLIM2 knockdown with migration/polarity/transcription factor activity readouts\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of PDLIM2-CSN5, enzymatic deneddylation assay, knockdown with defined phenotype, single lab\",\n      \"pmids\": [\"24196835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PDLIM2 is a direct transcriptional target of 1,25(OH)2D3/VDR signaling; a functional vitamin D response element (VDRE) was identified in the PDLIM2 promoter. 1,25(OH)2D3-induced demethylation of the PDLIM2 promoter enhances its transcription. PDLIM2 is required for vitamin D-induced cell adhesion and for mediating vitamin D suppression of cancer cell migration and invasion.\",\n      \"method\": \"VDRE reporter assay, ChIP, demethylation analysis, PDLIM2 knockdown with adhesion/migration/invasion readouts\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP for VDRE, promoter reporter assay, KD with functional phenotypes; single lab\",\n      \"pmids\": [\"23584482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PDLIM2 is required for feedback regulation of the β1-integrin–RhoA signaling axis in 3D breast epithelial acini. PDLIM2 suppression increases β1-integrin, IGF-1R, and RACK1 levels, enhances FAK and cofilin phosphorylation and RhoA-GTPase activity, and disrupts cell polarization and acini formation. Inhibition of FAK or ROCK rescues the polarity defect caused by PDLIM2 suppression.\",\n      \"method\": \"shRNA knockdown in 3D MCF10A cultures, RhoA GTPase activity assay, FAK/cofilin phosphorylation Western blot, FAK/ROCK inhibitor rescue\",\n      \"journal\": \"Neoplasia (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RhoA activity assay, kinase phosphorylation, pharmacological rescue in 3D culture system, single lab\",\n      \"pmids\": [\"24863845\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PDLIM2 acts as an E3 ubiquitin ligase that promotes nuclear proteasome-dependent degradation of STAT2 (but not STAT1). Interferon-dependent relocalization of STAT1/2 to the nucleus leads to PDLIM2 ubiquitination of STAT2. CRISPR/Cas9 knockout of PDLIM2 increases STAT2 levels after IFNα treatment, retains STAT2 in the nucleus of HCV-infected cells, and increases resistance to several flaviviruses.\",\n      \"method\": \"CRISPR/Cas9 knockout, ubiquitination assay, nuclear fractionation, IFN response assay, flavivirus infection assay\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR KO with multiple functional readouts, ubiquitination assay, nuclear fractionation, viral infection model, multiple orthogonal methods\",\n      \"pmids\": [\"31374104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PDLIM7 heterodimerizes with PDLIM2 to promote synergistic PDLIM2-mediated degradation of p65. Mechanistically, PDLIM7 promotes K63-linked ubiquitination of PDLIM2, and then p62/SQSTM1 binds polyubiquitinated PDLIM2 and the proteasome, facilitating delivery of the NF-κB–PDLIM2 complex to the proteasome for p65 degradation.\",\n      \"method\": \"Co-immunoprecipitation (PDLIM7-PDLIM2 heterodimer), linkage-specific ubiquitination assay, double knockdown with NF-κB/cytokine readouts\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, linkage-specific ubiquitination, double-KD epistasis, single lab\",\n      \"pmids\": [\"32849529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PDLIM2 cytoplasmic retention is controlled by cell adhesion, and nuclear translocation is stimulated by IGF-1 or TGFβ. Cytoplasmic PDLIM2 associates with active β-catenin, and ectopic PDLIM2 expression increases β-catenin levels and its transcriptional activity.\",\n      \"method\": \"Subcellular fractionation, co-immunoprecipitation (PDLIM2–β-catenin), β-catenin reporter assay, IGF-1/TGFβ stimulation\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct fractionation, Co-IP, reporter assay, growth factor stimulation experiments; single lab\",\n      \"pmids\": [\"30885980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PDLIM2 downregulation in alveolar macrophages is driven by ROS-activated transcription repressor BACH1. PDLIM2 downregulation leads to constitutive STAT3 activation, driving pro-tumorigenic AM polarization, differentiation from attracted monocytes, suppression of CTLs, and decreased AM phagocytosis. This defines a ROS/BACH1/PDLIM2/STAT3 signaling axis.\",\n      \"method\": \"Conditional PDLIM2 KO mice, ROS stimulation, BACH1 ChIP/reporter assay, flow cytometry (AM polarization), phagocytosis assay, CTL suppression assay\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO mice with multiple cellular phenotypes, BACH1 ChIP establishing pathway, phagocytosis and T-cell functional assays, multiple orthogonal methods\",\n      \"pmids\": [\"33539325\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Through nuclear repression of NF-κB/RelA and STAT3, PDLIM2 increases expression of antigen-presentation genes and T-cell activation genes while repressing multidrug resistance genes, rendering cancer cells vulnerable to immune attack and therapies. Global or lung epithelial-specific PDLIM2 deletion in mice causes increased lung cancer development, chemoresistance, and complete resistance to anti-PD-1.\",\n      \"method\": \"Conditional/global KO mice, gene expression profiling, anti-PD-1 treatment, chemotherapy treatment, epigenetic restoration\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple conditional KO models, in vivo therapeutic experiments, gene expression analysis, multiple orthogonal approaches\",\n      \"pmids\": [\"31757943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PDLIM2 acts as an E3 ubiquitin ligase that ubiquitinates PFKL (phosphofructokinase, liver type), promoting its degradation. In LSCC cells, PDLIM2 inhibits cell proliferation and glycolysis, and M2 macrophage-derived exosomes deliver miR-222-3p to suppress PDLIM2 expression, leading to elevated PFKL and enhanced glycolysis.\",\n      \"method\": \"Ubiquitination assay (PDLIM2–PFKL), Seahorse metabolic assay, miRNA luciferase reporter, PDLIM2 overexpression/knockdown, in vivo xenograft\",\n      \"journal\": \"Neoplasma\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination assay for specific substrate PFKL, metabolic assay, in vivo model; single lab\",\n      \"pmids\": [\"35723199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PDLIM2 acts as a ubiquitin ligase enhancer (E5) that stabilizes ROC1 (an essential component of SCF ubiquitin ligases) and chaperones the ROC1-SCFβ-TrCP ubiquitin ligase complex to ubiquitinate nuclear NF-κB RelA for proteasomal degradation. Silencing of ROC1, Cullin 1, or β-TrCP blocks RelA ubiquitination and degradation by PDLIM2.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown of ROC1/Cullin1/β-TrCP, ubiquitination assay, nuclear fractionation\",\n      \"journal\": \"Cell & bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, epistatic RNAi knockdowns of multiple pathway components, ubiquitination assay; single lab\",\n      \"pmids\": [\"39080804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PDLIM2 is required for M2 macrophage polarization induced by IL-4, including expression of M2 phenotypic markers, cell adhesion, and cell migration. PDLIM2 is also required for naïve macrophage migration. M1 macrophage activity induced by TLR4, TLR3, or IFNγ was less dependent on PDLIM2.\",\n      \"method\": \"PDLIM2 knockout bone marrow-derived macrophage cultures, M2 polarization assay (IL-4 stimulation), M1 polarization assay, migration assay\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO bone marrow macrophages with M1/M2 polarization assays and migration readout; single lab\",\n      \"pmids\": [\"36531051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PDLIM2 interacts with TRIM27 and facilitates K27-linked polyubiquitination-mediated proteasomal degradation of TRIM27, thereby attenuating STAT3 signaling. PBXIP1 overexpression in HCC promotes polyubiquitination of PDLIM2 via the ubiquitin-proteasome system, destabilizing PDLIM2.\",\n      \"method\": \"Co-immunoprecipitation (PDLIM2–TRIM27), linkage-specific ubiquitination assay, PBXIP1 overexpression/KD, STAT3 signaling readout\",\n      \"journal\": \"European journal of medical research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and K27-specific ubiquitination assay for novel substrate TRIM27, upstream regulator identified; single lab\",\n      \"pmids\": [\"41340074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PDLIM2 regulates bacterial (E. coli) and fungal (C. neoformans) traversal and exocytosis in brain microvascular endothelial cells. PDLIM2 knockdown specifically impairs microbial transcytosis and egression (but not invasion). Among 210 proximity-biotinylated PDLIM2 interactors identified by BioID2, MPRIP knockdown mimics the PDLIM2 knockdown phenotype, placing MPRIP as a PDLIM2-interacting effector in this process. Calcium ionophore rescues the exocytosis defect.\",\n      \"method\": \"shRNA knockdown, BioID2 proximity labeling, transcytosis/invasion/egression assays, MPRIP knockdown, calcium ionophore rescue\",\n      \"journal\": \"Infection and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proximity proteomics with functional validation via secondary KD, specific transcytosis assay with rescue; single lab\",\n      \"pmids\": [\"34228504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PDLIM2 downregulation leads to NF-κB activation, impaired expression of succinate dehydrogenase (SDH) genes, mitochondrial dysfunction, accumulation of succinate and other oncometabolites, buildup of mitochondrial ROS (mtROS), and activation of HIF-1α. HIF-1α inhibition (PX-478) significantly reduces PDLIM2 knockdown-promoted tumor growth in vivo, placing HIF-1α downstream of PDLIM2 loss.\",\n      \"method\": \"Seahorse metabolic assay, LC-MS oncometabolite analysis, flow cytometry (mtROS), DNA microarray, Lewis lung carcinoma mouse model with HIF-1α inhibitor treatment\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — metabolic assays, LC-MS, in vivo pharmacological rescue; single lab\",\n      \"pmids\": [\"38880883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CircPTPN12 interacts with the PDZ domain of PDLIM2 and facilitates p65 ubiquitination by PDLIM2. CircPTPN12 also promotes the deubiquitination of PDLIM2 itself by bolstering the PDLIM2/OTUD6B complex, thereby stabilizing PDLIM2.\",\n      \"method\": \"RNA immunoprecipitation, biotin-coupled probe pulldown, FISH, RNA sequencing, ubiquitination assay\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — circRNA study where PDLIM2 mechanistic role (PDZ domain binding, ubiquitination) is shown by pulldown and ubiquitination assay but the primary focus is on the circRNA; single lab, indirect for canonical PDLIM2 protein mechanism\",\n      \"pmids\": [\"38992675\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PDLIM2 is a PDZ-LIM domain-containing protein that functions dually as a cytoskeletal adaptor (binding α-actinins and filamin A via its PDZ domain) and a nuclear ubiquitin E3 ligase enhancer (E5) that stabilizes the ROC1-SCFβ-TrCP complex to polyubiquitinate nuclear NF-κB RelA/p65, and directly ubiquitinates STAT3 and STAT2, targeting all three transcription factors for intranuclear proteasomal degradation; its LIM domain anchors it to the nuclear matrix, its subcellular localization is regulated by PKC/ERK-dependent serine phosphorylation, and its activity is modulated by PDLIM7 heterodimerization and by upstream signals including OPN, BACH1, and viral infection, enabling PDLIM2 to serve as a critical terminator of NF-κB and STAT-driven inflammatory and oncogenic signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PDLIM2 is a PDZ-LIM domain protein that operates at the interface of the cytoskeleton and the nucleus, functioning as a nuclear ubiquitin-ligase system that terminates inflammatory and oncogenic transcription-factor signaling [#0, #3]. In the nucleus, its LIM domain anchors it to the nuclear matrix, where it binds the NF-\\u03baB subunit p65/RelA, promotes its polyubiquitination, and sequesters it into intranuclear compartments for proteasomal degradation, thereby switching off NF-\\u03baB activity [#0, #4]. PDLIM2 enforces this degradation not by acting alone but as a ubiquitin-ligase enhancer (E5) that stabilizes ROC1 and chaperones the ROC1\\u2013SCF\\u03b2-TrCP cullin-RING ligase complex onto nuclear RelA [#18]. The same intranuclear degradation mechanism targets the STAT family: PDLIM2 ubiquitinates STAT3 to restrain TH17 differentiation [#3], STAT1 in an osteopontin/PKC-dependent manner [#5], and STAT2 to limit interferon signaling and confer antiviral resistance [#12]. It also degrades transforming proteins, K48-ubiquitinating the HTLV-I Tax oncoprotein to suppress cell transformation [#2]. Through its PDZ domain PDLIM2 binds the cytoskeletal cross-linkers \\u03b1-actinin-1/-4 and filamin A and co-localizes at stress fibers, linking it to actin organization, cell adhesion, and directional migration [#1, #6]. Its subcellular partitioning is regulated by differentiation- and adhesion-coupled PKC/ERK-dependent serine phosphorylation, which drives cytoplasmic sequestration and consequent nuclear NF-\\u03baB activity [#8]. By coupling these activities, PDLIM2 acts as a tumor suppressor whose loss\\u2014driven by ROS/BACH1-mediated repression or miRNA delivery\\u2014promotes constitutive STAT3 and NF-\\u03baB activation, immune evasion, chemoresistance, and metabolic reprogramming [#15, #16, #22].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established PDLIM2's first molecular identity as a cytoskeletal adaptor, defining the PDZ domain as the cytoskeleton-binding module before any nuclear role was known.\",\n      \"evidence\": \"GST pulldown and gel overlay with purified \\u03b1-actinin-1/-4 and filamin A, plus confocal co-localization at stress fibers in COS-7 cells\",\n      \"pmids\": [\"15505042\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address any nuclear or ubiquitin-ligase function\", \"Functional consequence of cytoskeletal binding not tested in physiological cells\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Revealed PDLIM2 as a nuclear E3 ligase terminator of NF-\\u03baB, answering how nuclear p65 is cleared to resolve inflammation.\",\n      \"evidence\": \"Reciprocal Co-IP, in vivo p65 ubiquitination assay, and PDLIM2-deficient cells/mice with proinflammatory cytokine readouts\",\n      \"pmids\": [\"17468759\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the cullin-RING machinery PDLIM2 recruits\", \"Mechanism of intranuclear compartment targeting unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed PDLIM2 localization is dynamically partitioned between nucleus and cytoplasm by signaling, explaining how its NF-\\u03baB-suppressive activity is switched off.\",\n      \"evidence\": \"Subcellular fractionation, kinase inhibitor pharmacology, and phosphatase treatment in THP-1 monocyte/macrophage differentiation with NF-\\u03baB reporter\",\n      \"pmids\": [\"19052146\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific phosphorylated residues not mapped here\", \"Single cell-line model\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Extended the degradation mechanism to a viral oncoprotein, establishing PDLIM2 as a tumor suppressor that clears HTLV-I Tax.\",\n      \"evidence\": \"Reciprocal Co-IP, K48-linkage-specific ubiquitination assay, nuclear matrix fractionation, and in vivo transformation/oncogenesis assays\",\n      \"pmids\": [\"19131544\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 cofactors for Tax ubiquitination not defined\", \"Did not address endogenous substrates beyond Tax\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined the domain logic of PDLIM2 function\\u2014LIM/nuclear-matrix anchoring versus PDZ/cytoskeletal binding\\u2014and showed PKC-phosphorylation of Ser137 licenses STAT1 ubiquitination downstream of osteopontin.\",\n      \"evidence\": \"Domain deletion and Tax-binding motif mutagenesis with nuclear fractionation; phospho-mutant/phospho-mimetic constructs plus OPN-knockout mice for STAT1\",\n      \"pmids\": [\"20838382\", \"20889505\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase acting directly on Ser137 in vivo not isolated\", \"How OPN signaling reaches PDLIM2 not fully traced\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Broadened the substrate repertoire to STAT3 and connected PDLIM2 to actin/podocyte biology and to PDZ-dependent recognition of a pathogen ligand.\",\n      \"evidence\": \"PDLIM2-deficient mice with TH17/granuloma phenotypes (STAT3); Co-IP/yeast two-hybrid with \\u03b1-actinin-4 and angiomotin-like-1 in podocytes; crystal structure of the PDZ domain bound to H5N1 NS1 ESEV motif with mutagenesis\",\n      \"pmids\": [\"22155789\", \"21814175\", \"21625420\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether NS1 binding alters PDLIM2 enzymatic function untested\", \"Podocyte data confidence Medium and single-lab\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Linked PDLIM2 to upstream ubiquitin-system regulation (COP9 signalosome) and to its own transcriptional induction by vitamin D, integrating it into migration, polarity, and EMT control.\",\n      \"evidence\": \"PDLIM2-CSN5 Co-IP with cullin deneddylation assays and knockdown migration/polarity readouts; VDRE reporter, ChIP, and promoter demethylation analysis\",\n      \"pmids\": [\"24196835\", \"23584482\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct enzymatic relationship between PDLIM2 and CSN deneddylation not reconstituted\", \"Both single-lab\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Placed PDLIM2 in a \\u03b21-integrin\\u2013RhoA feedback loop governing epithelial polarity, mechanistically connecting its cytoskeletal role to morphogenesis.\",\n      \"evidence\": \"shRNA knockdown in 3D MCF10A acini with RhoA GTPase activity assays, FAK/cofilin phosphorylation, and FAK/ROCK inhibitor rescue\",\n      \"pmids\": [\"24863845\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the effect requires PDLIM2 ligase activity unresolved\", \"Single 3D culture system\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Consolidated PDLIM2 as a tumor suppressor coupling NF-\\u03baB/STAT3 repression to anti-tumor immunity, added STAT2/antiviral function, and defined cytoplasmic \\u03b2-catenin association.\",\n      \"evidence\": \"Conditional/global KO mice with anti-PD-1 and chemotherapy treatments and expression profiling; CRISPR KO with STAT2 ubiquitination and flavivirus assays; fractionation/Co-IP/\\u03b2-catenin reporter with IGF-1/TGF\\u03b2 stimulation\",\n      \"pmids\": [\"31757943\", \"31374104\", \"30885980\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Distinction between PDLIM2's nuclear suppressor and cytoplasmic \\u03b2-catenin-promoting roles not mechanistically reconciled\", \"\\u03b2-catenin association data Medium-confidence single-lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified PDLIM7 heterodimerization and a p62/SQSTM1-mediated proteasome-delivery route as a regulatory layer amplifying PDLIM2-driven p65 degradation.\",\n      \"evidence\": \"PDLIM7-PDLIM2 Co-IP, K63-linkage-specific ubiquitination of PDLIM2, and double-knockdown epistasis with NF-\\u03baB/cytokine readouts\",\n      \"pmids\": [\"32849529\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 producing K63 chains on PDLIM2 not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Embedded PDLIM2 loss in disease-relevant axes (ROS/BACH1 repression driving STAT3-dependent macrophage reprogramming), defined its requirement for M2 polarization, identified TRIM27 as a substrate, and implicated it in microbial transcytosis.\",\n      \"evidence\": \"Conditional KO mice with BACH1 ChIP and AM phenotyping; KO macrophages with M1/M2 polarization and migration assays; PDLIM2-TRIM27 Co-IP with K27-ubiquitination; BioID2 proximity proteomics with MPRIP validation in endothelial transcytosis\",\n      \"pmids\": [\"33539325\", \"36531051\", \"41340074\", \"34228504\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"TRIM27 and transcytosis findings are Medium-confidence single-lab\", \"How the BioID2 interactome connects to ligase activity largely unmapped\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Expanded the substrate set into metabolism, showing PDLIM2 ubiquitinates the glycolytic enzyme PFKL and that tumor-derived exosomal miR-222-3p suppresses PDLIM2 to enhance glycolysis.\",\n      \"evidence\": \"PDLIM2-PFKL ubiquitination assay, Seahorse metabolic assay, miRNA luciferase reporter, and xenograft in LSCC\",\n      \"pmids\": [\"35723199\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether PFKL ubiquitination occurs in the nucleus or cytoplasm unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved the cullin-RING machinery PDLIM2 employs (E5 enhancer of ROC1-SCF\\u03b2-TrCP), connected PDLIM2 loss to mitochondrial/oncometabolite/HIF-1\\u03b1 reprogramming, and added circPTPN12 as a PDZ-binding stabilizer.\",\n      \"evidence\": \"Co-IP and epistatic RNAi of ROC1/Cullin1/\\u03b2-TrCP with RelA ubiquitination assays; Seahorse, LC-MS oncometabolites, and Lewis lung carcinoma model with HIF-1\\u03b1 inhibitor; RIP/pulldown/ubiquitination for circPTPN12-OTUD6B\",\n      \"pmids\": [\"39080804\", \"38880883\", \"38992675\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"circPTPN12 finding is Low-confidence and focused on the circRNA\", \"Structural basis of ROC1-SCF\\u03b2-TrCP chaperoning not determined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single protein reconciles cytoplasmic cytoskeletal/\\u03b2-catenin-promoting roles with nuclear tumor-suppressive ubiquitin ligase activity, and how phosphorylation-driven trafficking dictates which program dominates, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of the full-length protein engaged with its cullin-RING partners\", \"Direct kinases controlling localization not definitively identified\", \"Substrate selection rules across NF-\\u03baB/STAT/Tax/PFKL/TRIM27 not unified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2, 3, 5, 12, 17, 20]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 12, 18]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [1, 6]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [18, 13]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [18, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 3, 8, 12]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [8, 14]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [1, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 3, 5, 12, 16, 19]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 2, 3, 12, 18]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 11, 14]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 15, 16, 17, 22]}\n    ],\n    \"complexes\": [\n      \"ROC1-SCF\\u03b2-TrCP ubiquitin ligase complex\",\n      \"PDLIM2-PDLIM7 heterodimer\"\n    ],\n    \"partners\": [\n      \"RELA\",\n      \"ACTN4\",\n      \"FLNA\",\n      \"PDLIM7\",\n      \"ROC1\",\n      \"CSN5\",\n      \"TRIM27\",\n      \"CTNNB1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}