{"gene":"PDLIM4","run_date":"2026-04-29T11:37:58","timeline":{"discoveries":[{"year":2004,"finding":"RIL (PDLIM4) binds to the AMPA receptor subunit GluR-A C-terminal peptide via its LIM domain and to α-actinin via its PDZ domain; RIL is enriched in the postsynaptic density fraction and co-precipitates with α-actinin in AMPA receptor immunoprecipitates from forebrain synaptosomes; overexpression of RIL increases AMPA receptor accumulation in dendritic spines and synaptic miniature EPSC amplitude, indicating RIL directs GluR-A-containing AMPA receptor transport to dendritic spines in an α-actinin/actin-dependent manner.","method":"Co-immunoprecipitation, subcellular fractionation, in vitro binding assays, overexpression in cultured neurons with immunodetection and mEPSC recording","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (Co-IP, fractionation, functional electrophysiology) in single rigorous study","pmids":["15456832"],"is_preprint":false},{"year":2004,"finding":"RIL (PDLIM4) localizes to actin stress fibers in nonmuscle epithelial cells, associates with α-actinin via its PDZ domain, and enhances the ability of α-actinin to co-sediment with actin filaments; RIL expression leads to abnormal thick irregular stress fibers and altered stress fiber dynamics including rapid formation and frequent collapse of fibers, as observed by live-cell imaging.","method":"Immunofluorescence localization, in vitro co-sedimentation assay, live-cell EGFP imaging, co-immunoprecipitation","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 1–2 — biochemical reconstitution (co-sedimentation) plus live imaging and Co-IP in same study","pmids":["14729062"],"is_preprint":false},{"year":2009,"finding":"PDLIM4 directly interacts with F-actin in prostate cancer cells; re-expression of PDLIM4 reduces cell growth, clonogenicity, and causes G1 cell-cycle arrest, and reduces tumor growth in xenografts, supporting a role in controlling cell proliferation through actin association.","method":"F-actin binding assay (direct interaction with F-actin), cell growth and clonogenicity assays, cell cycle analysis, xenograft tumor model","journal":"Cancer investigation","confidence":"Medium","confidence_rationale":"Tier 2 — direct F-actin binding shown, functional KO/re-expression phenotype, single lab","pmids":["19212833"],"is_preprint":false},{"year":2007,"finding":"RIL (PDLIM4), a LIM domain gene at 5q31, is silenced by promoter hypermethylation in cancer; restoration of RIL expression in colon cancer cells by stable transfection reduces cell growth and clonogenicity and increases apoptosis following UV exposure, indicating RIL functions as a tumor suppressor.","method":"Stable transfection re-expression, methylation-specific PCR, cell growth/clonogenicity assays, apoptosis assay","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — functional re-expression with multiple phenotypic readouts, single lab","pmids":["17332327"],"is_preprint":false},{"year":2011,"finding":"The alternatively spliced isoform of RIL (RILaltCterm, product of PDLIM4) acts as a dominant-negative modulator of RIL-mediated actin reorganization; RILaltCterm has a disordered alternative C-terminal segment directing it to ubiquitin-independent degradation by the core 20S proteasome, which is blocked by binding to NQO1 (NAD(P)H quinone oxidoreductase) induced by oxidative stress; overexpression or stabilization of RILaltCterm counteracts full-length RIL effects on actin cytoskeleton organization and cell motility.","method":"Overexpression/dominant-negative analysis, proteasome degradation assays, NQO1 co-expression/binding, actin organization imaging, cell motility assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods including degradation assays, protein interaction (NQO1 binding), and functional phenotype readouts in single study","pmids":["21636573"],"is_preprint":false},{"year":2012,"finding":"CLP36 and RIL (PDLIM4) both form a complex with α-actinin-1 and palladin on stress fibers; loss of CLP36/RIL correlates with failure of α-actinin-1 and palladin to localize on stress fibers; RIL stabilizes stress fibers while CLP36 influences their dynamic architecture, demonstrating a redundant but functionally distinct role for the two proteins in stress fiber formation.","method":"siRNA knockdown, co-immunoprecipitation, time-lapse live imaging, immunofluorescence localization","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP plus live imaging plus knockdown phenotype, single lab","pmids":["22659164"],"is_preprint":false},{"year":2019,"finding":"JMJD3 (histone H3K27 demethylase) binds to the promoter and gene body of Pdlim4 and regulates its expression by interacting with the zinc finger transcription factor KLF2; JMJD3 deficiency in CD4+ T cells reduces PDLIM4 expression, and PDLIM4 functions as an adaptor protein interacting with S1P1 and filamentous actin (F-actin) to regulate T cell trafficking—JMJD3-deficient or PDLIM4-deficient CD4+ T cells accumulate in the thymus and are reduced in secondary lymphoid organs.","method":"ChIP-seq, gene expression profiling, Co-immunoprecipitation (PDLIM4–S1P1–F-actin interaction), T cell trafficking in vivo assay, knockdown/knockout","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1–2 — ChIP-seq plus Co-IP plus in vivo trafficking assay with defined phenotype, moderate orthogonality","pmids":["31393857"],"is_preprint":false},{"year":2019,"finding":"PDLIM4 is required for mature dendritic cell (DC) migration via the CCR7-JNK signaling pathway and for F-actin-dependent dendrite formation; Pdlim4 knockdown in DCs reduces expression of antigen-presentation and co-stimulatory molecules, cytokine production, T-cell activation capacity, and in vivo migration to draining lymph nodes.","method":"Lentiviral shRNA knockdown, Transwell migration assay, in vivo DC migration (footpad injection/flow cytometry), confocal microscopy (dendrite morphology), Western blotting, flow cytometry, ELISA","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including in vivo migration, pathway analysis (CCR7-JNK), and morphological assays","pmids":["31287961"],"is_preprint":false},{"year":2004,"finding":"RIL (PDLIM4) interacts with the PDZ domains of PTP-BL protein tyrosine phosphatase via its C-terminus, with the LIM domain playing a synergistic (but not primary binding-surface) role in enhancing this interaction, as demonstrated by NMR titration and site-directed mutagenesis.","method":"Co-immunoprecipitation in mammalian cell lysates, NMR titration, site-directed mutagenesis","journal":"Molecular biology reports","confidence":"Medium","confidence_rationale":"Tier 1–2 — NMR and mutagenesis plus mammalian Co-IP, single lab","pmids":["15663004"],"is_preprint":false},{"year":2020,"finding":"In breast cancer cell lines, elevated RIL (PDLIM4) levels are associated with increased cell migratory activity and increased incidence of xenograft formation and metastasis; no direct correlation between RIL expression and Src kinase activity was detected, arguing against a simple Src-inhibitory mechanism and suggesting context-dependent oncogenic roles for RIL in promoting cell motility.","method":"RNAi knockdown, ectopic overexpression, cell migration assay, xenograft tumor formation, Src activity measurement","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2–3 — loss- and gain-of-function with multiple phenotypic readouts, single lab","pmids":["32002121"],"is_preprint":false},{"year":2022,"finding":"circ0002360 sponges miR-629-3p, which targets PDLIM4 mRNA; reduced miR-629-3p allows increased PDLIM4 expression; PDLIM4 upregulation downstream of this axis promotes gastric cancer cell proliferation and migration while inhibiting oxidative stress.","method":"RNA immunoprecipitation (RIP), dual-luciferase reporter assay, overexpression/knockdown functional assays (clone formation, Transwell), DCFH-DA oxidative stress assay","journal":"Oxidative medicine and cellular longevity","confidence":"Medium","confidence_rationale":"Tier 2–3 — RIP and luciferase reporter validate miRNA–PDLIM4 axis; functional assays confirm downstream effects, single lab","pmids":["35982735"],"is_preprint":false},{"year":1998,"finding":"The human RIL gene (PDLIM4) maps to chromosome 5q31.1, approximately 240–260 kb telomeric to IRF1; the gene spans 14.5 kb with seven exons, with the two 3'-exons encoding the LIM domain; an alternative transcript lacking exon 6 results in loss of the LIM domain; two putative transcription start points were identified in the 5'-flanking region.","method":"Southern blot, restriction mapping of YAC and cosmid clones, PCR of human fetal brain mRNA, genomic sequencing","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 — direct genomic mapping and transcript characterization, single lab","pmids":["9573374"],"is_preprint":false}],"current_model":"PDLIM4/RIL is a PDZ-LIM domain adaptor protein that localizes to actin stress fibers and the postsynaptic density, where it binds α-actinin via its PDZ domain and F-actin (directly) and via its LIM domain to the GluR-A AMPA receptor C-terminus and to S1P1, thereby regulating actin cytoskeleton organization, stress fiber dynamics, AMPA receptor trafficking to dendritic spines, and immune cell (T cell and dendritic cell) migration; its expression is epigenetically silenced by promoter hypermethylation in multiple cancers, and its alternatively spliced isoform (RILaltCterm) acts as a dominant-negative modulator subject to ubiquitin-independent 20S proteasomal degradation that is blocked by NQO1 under oxidative stress, providing a stress-responsive fine-tuning mechanism for actin remodeling."},"narrative":{"teleology":[{"year":1998,"claim":"Establishing the genomic architecture of PDLIM4 revealed that the LIM domain is encoded by the two 3′ exons and that alternative splicing can eliminate the LIM domain, raising the question of whether the two isoforms have distinct functions.","evidence":"Southern blot and restriction mapping of YAC/cosmid clones, RT-PCR of human fetal brain mRNA","pmids":["9573374"],"confidence":"Medium","gaps":["Functional significance of LIM-less isoform not yet tested","Promoter regulation not characterized"]},{"year":2004,"claim":"Concurrent studies established that PDLIM4 is a bona fide actin stress-fiber-associated scaffold: its PDZ domain recruits α-actinin and enhances α-actinin–actin co-sedimentation, while its LIM domain binds the GluR-A AMPA receptor, enabling receptor delivery to dendritic spines and increased synaptic transmission—answering how PDZ-LIM proteins couple receptor trafficking to the actin cytoskeleton.","evidence":"Co-IP, in vitro co-sedimentation, live-cell EGFP imaging, subcellular fractionation, mEPSC recording in cultured neurons","pmids":["14729062","15456832"],"confidence":"High","gaps":["In vivo confirmation of PDLIM4-dependent AMPA receptor trafficking not performed","Whether the LIM domain binds actin directly or only via GluR-A was unresolved"]},{"year":2004,"claim":"Identification of PTP-BL as a PDZ-mediated interactor of PDLIM4, with NMR titration showing the LIM domain synergistically enhances binding, broadened the adaptor's interaction network beyond α-actinin to include phosphatase signaling.","evidence":"NMR titration, site-directed mutagenesis, Co-IP in mammalian cell lysates","pmids":["15663004"],"confidence":"Medium","gaps":["Functional consequence of PDLIM4–PTP-BL interaction on phosphatase activity or substrate access not tested","No in vivo validation"]},{"year":2007,"claim":"Demonstration that PDLIM4 is silenced by promoter hypermethylation in cancer and that its re-expression suppresses growth and promotes UV-induced apoptosis established a tumor-suppressor function, explaining how loss of this cytoskeletal adaptor contributes to oncogenesis.","evidence":"Methylation-specific PCR, stable transfection re-expression in colon cancer cells, apoptosis and clonogenicity assays","pmids":["17332327"],"confidence":"Medium","gaps":["Mechanism linking actin scaffolding to growth suppression and apoptosis sensitization not defined","In vivo tumor suppression not shown in this study"]},{"year":2009,"claim":"Direct binding of PDLIM4 to F-actin was confirmed and re-expression in prostate cancer cells caused G1 arrest and reduced xenograft growth, extending the tumor-suppressor role to a second cancer type and establishing a direct F-actin interaction.","evidence":"F-actin binding assay, cell cycle analysis, xenograft tumor model in prostate cancer cells","pmids":["19212833"],"confidence":"Medium","gaps":["Molecular mechanism of G1 arrest not identified","Single cancer model"]},{"year":2011,"claim":"Discovery that the LIM-less splice isoform (RILaltCterm) is a dominant-negative modulator degraded by the 20S proteasome in a ubiquitin-independent manner—and stabilized by NQO1 under oxidative stress—revealed a built-in regulatory circuit for tuning PDLIM4 activity on actin.","evidence":"Overexpression/dominant-negative analysis, proteasome degradation assays, NQO1 co-expression/binding, actin imaging, motility assays","pmids":["21636573"],"confidence":"High","gaps":["Physiological contexts in which NQO1-mediated stabilization operates in vivo not demonstrated","Stoichiometry of full-length vs. alternative isoform under native conditions unknown"]},{"year":2012,"claim":"Knockdown studies showed that PDLIM4 and the related adaptor CLP36 have overlapping but functionally distinct roles in recruiting α-actinin-1 and palladin to stress fibers, with PDLIM4 specifically stabilizing fibers—clarifying how multiple ALP-family proteins collaborate on the same structures.","evidence":"siRNA knockdown, Co-IP, time-lapse live imaging, immunofluorescence","pmids":["22659164"],"confidence":"Medium","gaps":["Whether PDLIM4 and CLP36 compensate for each other in vivo untested","Palladin interaction with PDLIM4 not characterized at the domain level"]},{"year":2019,"claim":"Two studies established PDLIM4 as a critical immune-cell migration adaptor: it scaffolds S1P1 and F-actin to control CD4+ T-cell thymic egress (regulated transcriptionally by JMJD3/KLF2), and it promotes dendritic cell migration and maturation via the CCR7–JNK pathway, answering how a cytoskeletal adaptor influences adaptive immunity.","evidence":"ChIP-seq, Co-IP of PDLIM4–S1P1–F-actin, in vivo T-cell trafficking assay, shRNA knockdown in DCs, in vivo DC migration, Transwell migration","pmids":["31393857","31287961"],"confidence":"High","gaps":["Whether PDLIM4 directly bridges S1P1 to actin or requires intermediary adaptors not resolved","Structural basis for PDLIM4–S1P1 interaction unknown","DC-specific vs. general migratory function not delineated"]},{"year":2020,"claim":"In breast cancer, elevated PDLIM4 promotes migration and xenograft metastasis without correlating with Src inhibition, revealing a context-dependent pro-migratory role that contrasts with its tumor-suppressor function in colon and prostate cancer—demonstrating tissue-specific duality.","evidence":"RNAi knockdown, ectopic overexpression, migration assay, xenograft tumor formation, Src activity measurement","pmids":["32002121"],"confidence":"Medium","gaps":["Signaling pathway through which PDLIM4 promotes breast cancer cell motility not identified","No mechanism distinguishing tumor-suppressive vs. pro-migratory contexts"]},{"year":2022,"claim":"Identification of a circ0002360/miR-629-3p/PDLIM4 axis in gastric cancer showed that post-transcriptional regulation of PDLIM4 levels can promote proliferation and suppress oxidative stress, adding a non-coding RNA regulatory layer to PDLIM4 biology.","evidence":"RNA immunoprecipitation, dual-luciferase reporter assay, functional overexpression/knockdown assays, DCFH-DA oxidative stress assay","pmids":["35982735"],"confidence":"Medium","gaps":["Mechanism by which PDLIM4 suppresses oxidative stress not characterized","Single cell-line system","Apparent pro-proliferative role conflicts with tumor-suppressor data in other tissues—unresolved"]},{"year":null,"claim":"Key unresolved questions include the structural basis for PDLIM4's domain-specific interactions, how tissue context switches its role between tumor suppression and migration promotion, and the physiological regulation of the full-length vs. dominant-negative isoform balance in vivo.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal or cryo-EM structure of PDLIM4 or its complexes","No genetic model (knockout mouse phenotype) fully characterized","Mechanism determining tumor-suppressive vs. pro-migratory outcome across tissues unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,1,2,5,6]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,4,6]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[1,2,5,6]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6,7]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,7]}],"complexes":["α-actinin-1/palladin/PDLIM4 stress fiber complex"],"partners":["ACTN1","GRIA1","S1PR1","NQO1","PTPN13","PALLD"],"other_free_text":[]},"mechanistic_narrative":"PDLIM4 (RIL) is a PDZ-LIM domain adaptor protein that scaffolds cytoskeletal and signaling complexes on actin stress fibers, thereby controlling actin dynamics, cell motility, and receptor trafficking in diverse cell types. Its PDZ domain binds α-actinin (and the phosphatase PTP-BL), while its LIM domain engages the AMPA receptor subunit GluR-A; in neurons, PDLIM4 directs GluR-A-containing AMPA receptors to dendritic spines in an α-actinin/actin-dependent manner, increasing synaptic strength [PMID:15456832, PMID:14729062]. In immune cells, PDLIM4 interacts with S1P1 and F-actin to regulate CD4+ T-cell egress from the thymus and dendritic cell migration via the CCR7–JNK pathway [PMID:31393857, PMID:31287961]. An alternatively spliced isoform lacking a functional LIM domain (RILaltCterm) acts as a dominant-negative modulator subject to ubiquitin-independent 20S proteasomal degradation that is stabilized by NQO1 under oxidative stress, providing a stress-responsive mechanism for tuning actin remodeling; PDLIM4 expression is epigenetically silenced by promoter hypermethylation in several cancers, and its re-expression suppresses proliferation and enhances apoptosis in colon and prostate cancer cells [PMID:21636573, PMID:17332327, PMID:19212833]."},"prefetch_data":{"uniprot":{"accession":"P50479","full_name":"PDZ and LIM domain protein 4","aliases":["LIM protein RIL","Reversion-induced LIM protein"],"length_aa":330,"mass_kda":35.4,"function":"Suppresses SRC activation by recognizing and binding to active SRC and facilitating PTPN13-mediated dephosphorylation of SRC 'Tyr-419' leading to its inactivation. Inactivated SRC dissociates from this protein allowing the initiation of a new SRC inactivation cycle (PubMed:19307596). Involved in reorganization of the actin cytoskeleton (PubMed:21636573). In nonmuscle cells, binds to ACTN1 (alpha-actinin-1), increases the affinity of ACTN1 to F-actin (filamentous actin), and promotes formation of actin stress fibers. Involved in regulation of the synaptic AMPA receptor transport in dendritic spines of hippocampal pyramidal neurons directing the receptors toward an insertion at the postsynaptic membrane. Links endosomal surface-internalized GRIA1-containing AMPA receptors to the alpha-actinin/actin cytoskeleton. Increases AMPA receptor-mediated excitatory postsynaptic currents in neurons (By similarity) Involved in reorganization of the actin cytoskeleton and in regulation of cell migration. In response to oxidative stress, binds to NQO1, which stabilizes it and protects it from ubiquitin-independent degradation by the core 20S proteasome. Stabilized protein is able to heterodimerize with isoform 1 changing the subcellular location of it from cytoskeleton and nuclei to cytosol, leading to loss of isoforms 1 ability to induce formation of actin stress fibers. Counteracts the effects produced by isoform 1 on organization of actin cytoskeleton and cell motility to fine-tune actin cytoskeleton rearrangement and to attenuate cell migration","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P50479/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PDLIM4","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PDLIM4","total_profiled":1310},"omim":[{"mim_id":"603422","title":"PDZ AND LIM DOMAIN PROTEIN 4; PDLIM4","url":"https://www.omim.org/entry/603422"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Actin filaments","reliability":"Supported"},{"location":"Plasma membrane","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PDLIM4"},"hgnc":{"alias_symbol":["RIL"],"prev_symbol":[]},"alphafold":{"accession":"P50479","domains":[{"cath_id":"2.30.42.10","chopping":"2-80","consensus_level":"high","plddt":94.7533,"start":2,"end":80},{"cath_id":"2.10.110.10","chopping":"266-309","consensus_level":"high","plddt":90.3739,"start":266,"end":309}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P50479","model_url":"https://alphafold.ebi.ac.uk/files/AF-P50479-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P50479-F1-predicted_aligned_error_v6.png","plddt_mean":70.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PDLIM4","jax_strain_url":"https://www.jax.org/strain/search?query=PDLIM4"},"sequence":{"accession":"P50479","fasta_url":"https://rest.uniprot.org/uniprotkb/P50479.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P50479/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P50479"}},"corpus_meta":[{"pmid":"3917475","id":"PMC_3917475","title":"Leu-11+ lymphocytes with natural killer (NK) activity are precursors of recombinant interleukin 2 (rIL 2)-induced activated killer (AK) cells.","date":"1985","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/3917475","citation_count":301,"is_preprint":false},{"pmid":"2984283","id":"PMC_2984283","title":"Generation of activated killer (AK) cells by recombinant interleukin 2 (rIL 2) in collaboration with interferon-gamma (IFN-gamma).","date":"1985","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/2984283","citation_count":206,"is_preprint":false},{"pmid":"8527411","id":"PMC_8527411","title":"Systemic administration of rIL-12 induces complete tumor regression and protective immunity: response is correlated with a striking reversal of suppressed IFN-gamma production by anti-tumor T cells.","date":"1995","source":"International immunology","url":"https://pubmed.ncbi.nlm.nih.gov/8527411","citation_count":196,"is_preprint":false},{"pmid":"18047556","id":"PMC_18047556","title":"Identification of metabolic and biomass QTL in Arabidopsis thaliana in a parallel analysis of RIL and IL populations.","date":"2007","source":"The Plant journal : for cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/18047556","citation_count":147,"is_preprint":false},{"pmid":"3100633","id":"PMC_3100633","title":"Phenotypic and functional characterization of recombinant interleukin 2 (rIL 2)-induced activated killer cells: analysis at the population and clonal levels.","date":"1987","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/3100633","citation_count":133,"is_preprint":false},{"pmid":"19407982","id":"PMC_19407982","title":"Quantitative trait loci conferring grain mineral nutrient concentrations in durum wheat x wild emmer wheat RIL population.","date":"2009","source":"TAG. 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RIL is enriched in the postsynaptic density fraction and co-precipitates with α-actinin in AMPA receptor immunoprecipitates from forebrain synaptosomes; overexpression of RIL increases AMPA receptor accumulation in dendritic spines and synaptic miniature EPSC amplitude, indicating RIL directs GluR-A-containing AMPA receptor transport to dendritic spines in an α-actinin/actin-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, in vitro binding assays, overexpression in cultured neurons with immunodetection and mEPSC recording\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (Co-IP, fractionation, functional electrophysiology) in single rigorous study\",\n      \"pmids\": [\"15456832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"RIL (PDLIM4) localizes to actin stress fibers in nonmuscle epithelial cells, associates with α-actinin via its PDZ domain, and enhances the ability of α-actinin to co-sediment with actin filaments; RIL expression leads to abnormal thick irregular stress fibers and altered stress fiber dynamics including rapid formation and frequent collapse of fibers, as observed by live-cell imaging.\",\n      \"method\": \"Immunofluorescence localization, in vitro co-sedimentation assay, live-cell EGFP imaging, co-immunoprecipitation\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — biochemical reconstitution (co-sedimentation) plus live imaging and Co-IP in same study\",\n      \"pmids\": [\"14729062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PDLIM4 directly interacts with F-actin in prostate cancer cells; re-expression of PDLIM4 reduces cell growth, clonogenicity, and causes G1 cell-cycle arrest, and reduces tumor growth in xenografts, supporting a role in controlling cell proliferation through actin association.\",\n      \"method\": \"F-actin binding assay (direct interaction with F-actin), cell growth and clonogenicity assays, cell cycle analysis, xenograft tumor model\",\n      \"journal\": \"Cancer investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct F-actin binding shown, functional KO/re-expression phenotype, single lab\",\n      \"pmids\": [\"19212833\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"RIL (PDLIM4), a LIM domain gene at 5q31, is silenced by promoter hypermethylation in cancer; restoration of RIL expression in colon cancer cells by stable transfection reduces cell growth and clonogenicity and increases apoptosis following UV exposure, indicating RIL functions as a tumor suppressor.\",\n      \"method\": \"Stable transfection re-expression, methylation-specific PCR, cell growth/clonogenicity assays, apoptosis assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional re-expression with multiple phenotypic readouts, single lab\",\n      \"pmids\": [\"17332327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The alternatively spliced isoform of RIL (RILaltCterm, product of PDLIM4) acts as a dominant-negative modulator of RIL-mediated actin reorganization; RILaltCterm has a disordered alternative C-terminal segment directing it to ubiquitin-independent degradation by the core 20S proteasome, which is blocked by binding to NQO1 (NAD(P)H quinone oxidoreductase) induced by oxidative stress; overexpression or stabilization of RILaltCterm counteracts full-length RIL effects on actin cytoskeleton organization and cell motility.\",\n      \"method\": \"Overexpression/dominant-negative analysis, proteasome degradation assays, NQO1 co-expression/binding, actin organization imaging, cell motility assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods including degradation assays, protein interaction (NQO1 binding), and functional phenotype readouts in single study\",\n      \"pmids\": [\"21636573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CLP36 and RIL (PDLIM4) both form a complex with α-actinin-1 and palladin on stress fibers; loss of CLP36/RIL correlates with failure of α-actinin-1 and palladin to localize on stress fibers; RIL stabilizes stress fibers while CLP36 influences their dynamic architecture, demonstrating a redundant but functionally distinct role for the two proteins in stress fiber formation.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation, time-lapse live imaging, immunofluorescence localization\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP plus live imaging plus knockdown phenotype, single lab\",\n      \"pmids\": [\"22659164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"JMJD3 (histone H3K27 demethylase) binds to the promoter and gene body of Pdlim4 and regulates its expression by interacting with the zinc finger transcription factor KLF2; JMJD3 deficiency in CD4+ T cells reduces PDLIM4 expression, and PDLIM4 functions as an adaptor protein interacting with S1P1 and filamentous actin (F-actin) to regulate T cell trafficking—JMJD3-deficient or PDLIM4-deficient CD4+ T cells accumulate in the thymus and are reduced in secondary lymphoid organs.\",\n      \"method\": \"ChIP-seq, gene expression profiling, Co-immunoprecipitation (PDLIM4–S1P1–F-actin interaction), T cell trafficking in vivo assay, knockdown/knockout\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — ChIP-seq plus Co-IP plus in vivo trafficking assay with defined phenotype, moderate orthogonality\",\n      \"pmids\": [\"31393857\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PDLIM4 is required for mature dendritic cell (DC) migration via the CCR7-JNK signaling pathway and for F-actin-dependent dendrite formation; Pdlim4 knockdown in DCs reduces expression of antigen-presentation and co-stimulatory molecules, cytokine production, T-cell activation capacity, and in vivo migration to draining lymph nodes.\",\n      \"method\": \"Lentiviral shRNA knockdown, Transwell migration assay, in vivo DC migration (footpad injection/flow cytometry), confocal microscopy (dendrite morphology), Western blotting, flow cytometry, ELISA\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including in vivo migration, pathway analysis (CCR7-JNK), and morphological assays\",\n      \"pmids\": [\"31287961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"RIL (PDLIM4) interacts with the PDZ domains of PTP-BL protein tyrosine phosphatase via its C-terminus, with the LIM domain playing a synergistic (but not primary binding-surface) role in enhancing this interaction, as demonstrated by NMR titration and site-directed mutagenesis.\",\n      \"method\": \"Co-immunoprecipitation in mammalian cell lysates, NMR titration, site-directed mutagenesis\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — NMR and mutagenesis plus mammalian Co-IP, single lab\",\n      \"pmids\": [\"15663004\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In breast cancer cell lines, elevated RIL (PDLIM4) levels are associated with increased cell migratory activity and increased incidence of xenograft formation and metastasis; no direct correlation between RIL expression and Src kinase activity was detected, arguing against a simple Src-inhibitory mechanism and suggesting context-dependent oncogenic roles for RIL in promoting cell motility.\",\n      \"method\": \"RNAi knockdown, ectopic overexpression, cell migration assay, xenograft tumor formation, Src activity measurement\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — loss- and gain-of-function with multiple phenotypic readouts, single lab\",\n      \"pmids\": [\"32002121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"circ0002360 sponges miR-629-3p, which targets PDLIM4 mRNA; reduced miR-629-3p allows increased PDLIM4 expression; PDLIM4 upregulation downstream of this axis promotes gastric cancer cell proliferation and migration while inhibiting oxidative stress.\",\n      \"method\": \"RNA immunoprecipitation (RIP), dual-luciferase reporter assay, overexpression/knockdown functional assays (clone formation, Transwell), DCFH-DA oxidative stress assay\",\n      \"journal\": \"Oxidative medicine and cellular longevity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — RIP and luciferase reporter validate miRNA–PDLIM4 axis; functional assays confirm downstream effects, single lab\",\n      \"pmids\": [\"35982735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The human RIL gene (PDLIM4) maps to chromosome 5q31.1, approximately 240–260 kb telomeric to IRF1; the gene spans 14.5 kb with seven exons, with the two 3'-exons encoding the LIM domain; an alternative transcript lacking exon 6 results in loss of the LIM domain; two putative transcription start points were identified in the 5'-flanking region.\",\n      \"method\": \"Southern blot, restriction mapping of YAC and cosmid clones, PCR of human fetal brain mRNA, genomic sequencing\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct genomic mapping and transcript characterization, single lab\",\n      \"pmids\": [\"9573374\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PDLIM4/RIL is a PDZ-LIM domain adaptor protein that localizes to actin stress fibers and the postsynaptic density, where it binds α-actinin via its PDZ domain and F-actin (directly) and via its LIM domain to the GluR-A AMPA receptor C-terminus and to S1P1, thereby regulating actin cytoskeleton organization, stress fiber dynamics, AMPA receptor trafficking to dendritic spines, and immune cell (T cell and dendritic cell) migration; its expression is epigenetically silenced by promoter hypermethylation in multiple cancers, and its alternatively spliced isoform (RILaltCterm) acts as a dominant-negative modulator subject to ubiquitin-independent 20S proteasomal degradation that is blocked by NQO1 under oxidative stress, providing a stress-responsive fine-tuning mechanism for actin remodeling.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PDLIM4 (RIL) is a PDZ-LIM domain adaptor protein that scaffolds cytoskeletal and signaling complexes on actin stress fibers, thereby controlling actin dynamics, cell motility, and receptor trafficking in diverse cell types. Its PDZ domain binds α-actinin (and the phosphatase PTP-BL), while its LIM domain engages the AMPA receptor subunit GluR-A; in neurons, PDLIM4 directs GluR-A-containing AMPA receptors to dendritic spines in an α-actinin/actin-dependent manner, increasing synaptic strength [PMID:15456832, PMID:14729062]. In immune cells, PDLIM4 interacts with S1P1 and F-actin to regulate CD4+ T-cell egress from the thymus and dendritic cell migration via the CCR7–JNK pathway [PMID:31393857, PMID:31287961]. An alternatively spliced isoform lacking a functional LIM domain (RILaltCterm) acts as a dominant-negative modulator subject to ubiquitin-independent 20S proteasomal degradation that is stabilized by NQO1 under oxidative stress, providing a stress-responsive mechanism for tuning actin remodeling; PDLIM4 expression is epigenetically silenced by promoter hypermethylation in several cancers, and its re-expression suppresses proliferation and enhances apoptosis in colon and prostate cancer cells [PMID:21636573, PMID:17332327, PMID:19212833].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Establishing the genomic architecture of PDLIM4 revealed that the LIM domain is encoded by the two 3′ exons and that alternative splicing can eliminate the LIM domain, raising the question of whether the two isoforms have distinct functions.\",\n      \"evidence\": \"Southern blot and restriction mapping of YAC/cosmid clones, RT-PCR of human fetal brain mRNA\",\n      \"pmids\": [\"9573374\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional significance of LIM-less isoform not yet tested\", \"Promoter regulation not characterized\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Concurrent studies established that PDLIM4 is a bona fide actin stress-fiber-associated scaffold: its PDZ domain recruits α-actinin and enhances α-actinin–actin co-sedimentation, while its LIM domain binds the GluR-A AMPA receptor, enabling receptor delivery to dendritic spines and increased synaptic transmission—answering how PDZ-LIM proteins couple receptor trafficking to the actin cytoskeleton.\",\n      \"evidence\": \"Co-IP, in vitro co-sedimentation, live-cell EGFP imaging, subcellular fractionation, mEPSC recording in cultured neurons\",\n      \"pmids\": [\"14729062\", \"15456832\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo confirmation of PDLIM4-dependent AMPA receptor trafficking not performed\", \"Whether the LIM domain binds actin directly or only via GluR-A was unresolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identification of PTP-BL as a PDZ-mediated interactor of PDLIM4, with NMR titration showing the LIM domain synergistically enhances binding, broadened the adaptor's interaction network beyond α-actinin to include phosphatase signaling.\",\n      \"evidence\": \"NMR titration, site-directed mutagenesis, Co-IP in mammalian cell lysates\",\n      \"pmids\": [\"15663004\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of PDLIM4–PTP-BL interaction on phosphatase activity or substrate access not tested\", \"No in vivo validation\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstration that PDLIM4 is silenced by promoter hypermethylation in cancer and that its re-expression suppresses growth and promotes UV-induced apoptosis established a tumor-suppressor function, explaining how loss of this cytoskeletal adaptor contributes to oncogenesis.\",\n      \"evidence\": \"Methylation-specific PCR, stable transfection re-expression in colon cancer cells, apoptosis and clonogenicity assays\",\n      \"pmids\": [\"17332327\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking actin scaffolding to growth suppression and apoptosis sensitization not defined\", \"In vivo tumor suppression not shown in this study\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Direct binding of PDLIM4 to F-actin was confirmed and re-expression in prostate cancer cells caused G1 arrest and reduced xenograft growth, extending the tumor-suppressor role to a second cancer type and establishing a direct F-actin interaction.\",\n      \"evidence\": \"F-actin binding assay, cell cycle analysis, xenograft tumor model in prostate cancer cells\",\n      \"pmids\": [\"19212833\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of G1 arrest not identified\", \"Single cancer model\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Discovery that the LIM-less splice isoform (RILaltCterm) is a dominant-negative modulator degraded by the 20S proteasome in a ubiquitin-independent manner—and stabilized by NQO1 under oxidative stress—revealed a built-in regulatory circuit for tuning PDLIM4 activity on actin.\",\n      \"evidence\": \"Overexpression/dominant-negative analysis, proteasome degradation assays, NQO1 co-expression/binding, actin imaging, motility assays\",\n      \"pmids\": [\"21636573\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological contexts in which NQO1-mediated stabilization operates in vivo not demonstrated\", \"Stoichiometry of full-length vs. alternative isoform under native conditions unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Knockdown studies showed that PDLIM4 and the related adaptor CLP36 have overlapping but functionally distinct roles in recruiting α-actinin-1 and palladin to stress fibers, with PDLIM4 specifically stabilizing fibers—clarifying how multiple ALP-family proteins collaborate on the same structures.\",\n      \"evidence\": \"siRNA knockdown, Co-IP, time-lapse live imaging, immunofluorescence\",\n      \"pmids\": [\"22659164\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether PDLIM4 and CLP36 compensate for each other in vivo untested\", \"Palladin interaction with PDLIM4 not characterized at the domain level\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Two studies established PDLIM4 as a critical immune-cell migration adaptor: it scaffolds S1P1 and F-actin to control CD4+ T-cell thymic egress (regulated transcriptionally by JMJD3/KLF2), and it promotes dendritic cell migration and maturation via the CCR7–JNK pathway, answering how a cytoskeletal adaptor influences adaptive immunity.\",\n      \"evidence\": \"ChIP-seq, Co-IP of PDLIM4–S1P1–F-actin, in vivo T-cell trafficking assay, shRNA knockdown in DCs, in vivo DC migration, Transwell migration\",\n      \"pmids\": [\"31393857\", \"31287961\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PDLIM4 directly bridges S1P1 to actin or requires intermediary adaptors not resolved\", \"Structural basis for PDLIM4–S1P1 interaction unknown\", \"DC-specific vs. general migratory function not delineated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"In breast cancer, elevated PDLIM4 promotes migration and xenograft metastasis without correlating with Src inhibition, revealing a context-dependent pro-migratory role that contrasts with its tumor-suppressor function in colon and prostate cancer—demonstrating tissue-specific duality.\",\n      \"evidence\": \"RNAi knockdown, ectopic overexpression, migration assay, xenograft tumor formation, Src activity measurement\",\n      \"pmids\": [\"32002121\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signaling pathway through which PDLIM4 promotes breast cancer cell motility not identified\", \"No mechanism distinguishing tumor-suppressive vs. pro-migratory contexts\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identification of a circ0002360/miR-629-3p/PDLIM4 axis in gastric cancer showed that post-transcriptional regulation of PDLIM4 levels can promote proliferation and suppress oxidative stress, adding a non-coding RNA regulatory layer to PDLIM4 biology.\",\n      \"evidence\": \"RNA immunoprecipitation, dual-luciferase reporter assay, functional overexpression/knockdown assays, DCFH-DA oxidative stress assay\",\n      \"pmids\": [\"35982735\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which PDLIM4 suppresses oxidative stress not characterized\", \"Single cell-line system\", \"Apparent pro-proliferative role conflicts with tumor-suppressor data in other tissues—unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis for PDLIM4's domain-specific interactions, how tissue context switches its role between tumor suppression and migration promotion, and the physiological regulation of the full-length vs. dominant-negative isoform balance in vivo.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal or cryo-EM structure of PDLIM4 or its complexes\", \"No genetic model (knockout mouse phenotype) fully characterized\", \"Mechanism determining tumor-suppressive vs. pro-migratory outcome across tissues unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 1, 2, 5, 6]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 4, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [1, 2, 5, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 7]}\n    ],\n    \"complexes\": [\n      \"α-actinin-1/palladin/PDLIM4 stress fiber complex\"\n    ],\n    \"partners\": [\n      \"ACTN1\",\n      \"GRIA1\",\n      \"S1PR1\",\n      \"NQO1\",\n      \"PTPN13\",\n      \"PALLD\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}