{"gene":"ISLR","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":1997,"finding":"ISLR was identified as a novel protein containing a leucine-rich repeat (LRR) with conserved flanking sequences and a C2-type immunoglobulin-like domain, mapped to human chromosome 15q23-q24, consistent with a role in protein-protein interaction or cell adhesion.","method":"cDNA cloning, domain analysis, Northern blot, fluorescence in situ hybridization","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, structural/domain characterization by cloning and mapping, no functional assay","pmids":["9325048"],"is_preprint":false},{"year":1999,"finding":"The ISLR gene produces two transcript isoforms (ISLR-1 and ISLR-2) from different first exons but encoding an identical protein; the mouse ortholog Islr is expressed in retinal ganglion cells, inner nuclear layer, and photoreceptor inner segments.","method":"cDNA library screening, genomic sequencing, in situ hybridization, radiation hybrid mapping","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, direct sequencing and localization by ISH","pmids":["10512678"],"is_preprint":false},{"year":2020,"finding":"ISLR (Meflin) in cancer-associated fibroblasts promotes BMP signaling (opposing the BMP inhibitor GREM1), and fibroblast Islr overexpression or AAV8-mediated Islr delivery to hepatocytes increased BMP signaling and improved survival in a mouse model of CRC hepatic metastasis; GREM1 and ISLR are regulated by TGF-β and FOXL1.","method":"Mouse CRC hepatic metastasis model, AAV8 gene delivery, CRC tumoroids, in situ hybridization, signaling assays","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (in vivo mouse model, organoids, gene delivery), functional BMP signaling readout, replicated across systems","pmids":["33197448"],"is_preprint":false},{"year":2020,"finding":"Stromal ISLR, induced by ETS1, is secreted and inhibits epithelial Hippo signaling to activate YAP in epithelial cells, promoting intestinal regeneration and tumorigenesis; stromal-specific Islr deletion in mice markedly impaired intestinal regeneration and suppressed colon tumorigenesis.","method":"Conditional knockout mouse model, intestinal regeneration assays, colon tumorigenesis model, epistasis with Hippo-YAP pathway","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function in vivo with defined phenotypic and pathway readout (YAP activation), ETS1 upstream regulation confirmed, multiple orthogonal methods","pmids":["32128839"],"is_preprint":false},{"year":2020,"finding":"ISLR regulates skeletal muscle atrophy via the IGF1-PI3K/Akt-FOXO signaling pathway; ISLR silencing increased expression of atrophy-related genes atrogin-1 and MuRF-1 and increased caspase-8 and caspase-9, while ISLR overexpression rescued dexamethasone-induced atrophy in myoblasts.","method":"siRNA knockdown, overexpression in myoblasts, Western blot, dexamethasone atrophy model","journal":"Cell and tissue research","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single lab, knockdown/overexpression in cell culture with signaling readouts, no in vivo validation or reconstitution","pmids":["32696215"],"is_preprint":false},{"year":2021,"finding":"ISLR silencing in NSCLC cells inhibited proliferation, EMT, migration, invasion, and glycolysis by inactivating the IL-6/JAK/STAT3 pathway; ISLR knockdown inhibited IL-6-induced tumor progression.","method":"siRNA knockdown, overexpression, Western blot, GSEA, IL-6 pathway activator rescue experiment","journal":"International journal of molecular medicine","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single lab, cell-based knockdown/OE with pathway validation by pathway activator rescue","pmids":["34713300"],"is_preprint":false},{"year":2022,"finding":"Islr interacts with NADH:Ubiquinone Oxidoreductase Core Subunit S2 (Ndufs2) in brown adipose tissue and functions as a brake on IL-6 signaling, preventing IL-6 from promoting BAT mitochondrial activity and thermogenesis; Islr loss in BAT improved mitochondrial function and energy expenditure.","method":"Islr knockout mouse model, cardiotoxin injury model, protein interaction assay, metabolic/thermogenesis measurements","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, in vivo knockout with metabolic readouts and protein interaction, but single study","pmids":["36077405"],"is_preprint":false},{"year":2022,"finding":"ISLR activates the EMT signaling pathway to promote colon cancer cell proliferation, migration, and invasion; inhibition of EMT suppressed the growth-promoting effect of ISLR overexpression.","method":"siRNA knockdown, overexpression, KEGG pathway enrichment, Western blot, functional cell assays","journal":"Anti-cancer drugs","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, cell-based assays with pathway inferred from KEGG, limited mechanistic dissection","pmids":["34520435"],"is_preprint":false},{"year":2023,"finding":"ISLR mediates ubiquitin-independent proteasomal degradation of insulin receptor alpha (Insrα) by specifically interacting with proteasome subunit alpha type 4 (Psma4); Islr knockout increased Insrα levels and enhanced insulin sensitivity in adipocytes and in vivo in obese mice.","method":"Co-immunoprecipitation, Islr knockout mouse model, siRNA knockdown in white adipose tissue, Western blot, metabolic assays","journal":"The international journal of biochemistry & cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP defining interaction with Psma4, in vivo knockout and siRNA knockdown with functional insulin sensitivity readout, multiple orthogonal methods in single lab","pmids":["37116777"],"is_preprint":false},{"year":2023,"finding":"ISLR interacts with MGAT5 (N-acetylglucosaminyltransferase V) in gastric cancer cells, and MGAT5 overexpression reversed the effects of ISLR knockdown on tumor cell viability, proliferation, migration, invasion, and EMT.","method":"Co-immunoprecipitation, siRNA knockdown, MGAT5 overexpression rescue, Western blot, functional cell assays","journal":"Iranian journal of basic medical sciences","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single lab, Co-IP for interaction plus functional rescue, limited mechanistic depth","pmids":["37427332"],"is_preprint":false},{"year":2024,"finding":"Islr binds to and promotes degradation of SPARC (secreted protein acidic and rich in cysteine), which activates p-ERK1/2 signaling required for asymmetric division of satellite cells; Islr deletion reduced muscle regeneration by decreasing the satellite cell pool and promoting asymmetric division.","method":"Islr conditional knockout in mice, protein interaction assay (binding to SPARC), Western blot for p-ERK1/2, muscle regeneration assays","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vivo knockout with mechanistic pathway (SPARC/p-ERK1/2) and direct binding shown, single lab","pmids":["38597911"],"is_preprint":false},{"year":2024,"finding":"ISLR functions as a redox sensor, perceiving reactive oxygen species (ROS) through its cysteine residue 19, and then undergoes rapid degradation via the autophagy-lysosome pathway; reduced ISLR promotes tetramerization of PKM2, enhancing pyruvate kinase activity and glycolysis to increase antioxidant capacity.","method":"ROS stimulation, cysteine mutagenesis (C19), autophagy-lysosome pathway inhibition, PKM2 activity assay, PKM2 tetramerization assay","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — active-site mutagenesis (C19), in vitro enzymatic activity assay for PKM2, and pathway mechanistic follow-up in single lab","pmids":["38786060"],"is_preprint":false},{"year":2025,"finding":"ISLR directly interacts with CD74 and regulates its transcriptional activity in TNBC cells, modulating the MIF/CD74 signaling pathway; ISLR knockdown decreased IL-10 and TGF-β secretion and promoted CD8+ T cell infiltration, and radiotherapy reduced ISLR expression.","method":"Co-immunoprecipitation/interaction assay, siRNA knockdown, overexpression, cytokine assay, xenograft mouse model with RT and PD-1 blockade","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single lab, direct interaction with CD74 established by binding assay, functional in vivo rescue, but limited mechanistic dissection of transcriptional activity","pmids":["40517736"],"is_preprint":false}],"current_model":"ISLR (Meflin) is a secreted/cell-surface LRR-immunoglobulin superfamily protein expressed in fibroblasts and mesenchymal stromal cells that acts as a pleiotropic signaling regulator: it promotes BMP signaling in stromal cells to restrain colorectal cancer, inhibits epithelial Hippo/YAP signaling downstream of ETS1 to drive intestinal regeneration, mediates ubiquitin-independent proteasomal degradation of insulin receptor alpha via interaction with Psma4, promotes degradation of SPARC to activate ERK1/2-dependent satellite cell asymmetric division, acts as a redox sensor whose ROS-triggered autophagic degradation relieves suppression of PKM2 tetramerization, and interacts with CD74 to modulate MIF/CD74-mediated immune evasion."},"narrative":{"mechanistic_narrative":"ISLR (Meflin) is a secreted/cell-surface leucine-rich-repeat and immunoglobulin-domain protein, originally identified by cDNA cloning as a putative protein-interaction/adhesion molecule [PMID:9325048], that functions as a pleiotropic regulator of stromal and mesenchymal signaling. In the intestinal and tumor stroma it controls two paracrine axes: it promotes BMP signaling in cancer-associated fibroblasts, opposing the BMP inhibitor GREM1 and restraining colorectal cancer hepatic metastasis [PMID:33197448], while as an ETS1-induced secreted factor it inhibits epithelial Hippo signaling to activate YAP, driving intestinal regeneration and tumorigenesis [PMID:32128839]. ISLR also acts through direct protein partners to control protein turnover and signaling: it mediates ubiquitin-independent proteasomal degradation of insulin receptor alpha via interaction with the proteasome subunit Psma4, thereby limiting insulin sensitivity [PMID:37116777], and binds and promotes degradation of SPARC to license p-ERK1/2-dependent asymmetric division of muscle satellite cells [PMID:38597911]. As a redox sensor, ISLR perceives ROS through cysteine 19 and undergoes autophagy-lysosomal degradation, relieving its suppression of PKM2 tetramerization and thereby enhancing glycolysis and antioxidant capacity [PMID:38786060]. Additional interactions with CD74 modulate MIF/CD74 immune signaling and CD8+ T-cell infiltration [PMID:40517736]. Across cancer cell models ISLR has been linked to proliferation, EMT, and migration through IL-6/JAK/STAT3 and EMT programs [PMID:34713300].","teleology":[{"year":1997,"claim":"Established ISLR as a distinct gene product with a defined domain architecture, framing it as a candidate protein-interaction or adhesion molecule.","evidence":"cDNA cloning, domain analysis, and chromosomal mapping to 15q23-q24","pmids":["9325048"],"confidence":"Medium","gaps":["No functional assay or binding partner identified","Cellular localization of the protein not determined"]},{"year":1999,"claim":"Defined the gene's transcript structure and tissue expression, showing two isoforms encoding an identical protein and ortholog expression in retinal neurons.","evidence":"cDNA library screening, genomic sequencing, and in situ hybridization in mouse","pmids":["10512678"],"confidence":"Medium","gaps":["Functional role in retina not tested","No mechanism linking expression to phenotype"]},{"year":2020,"claim":"Showed that stromal ISLR shapes epithelial fate through two paracrine pathways — promoting BMP signaling against GREM1 to restrain CRC metastasis, and inhibiting Hippo to activate YAP for intestinal regeneration.","evidence":"Mouse CRC hepatic metastasis and intestinal regeneration models, conditional knockout, AAV8 delivery, tumoroids, and pathway epistasis","pmids":["33197448","32128839"],"confidence":"High","gaps":["Molecular receptor/binding mechanism by which secreted ISLR alters BMP or Hippo signaling not defined","How a single protein produces opposing pro- and anti-tumor effects across contexts unresolved"]},{"year":2020,"claim":"Implicated ISLR in skeletal muscle homeostasis via IGF1-PI3K/Akt-FOXO signaling controlling atrophy programs.","evidence":"siRNA knockdown and overexpression in myoblasts with dexamethasone atrophy model and Western blot","pmids":["32696215"],"confidence":"Medium","gaps":["No in vivo validation","Direct molecular target in the pathway not identified"]},{"year":2021,"claim":"Linked ISLR to NSCLC tumor progression and glycolysis through the IL-6/JAK/STAT3 pathway.","evidence":"siRNA knockdown, overexpression, GSEA, and IL-6 pathway-activator rescue in NSCLC cells","pmids":["34713300"],"confidence":"Medium","gaps":["Mechanism connecting ISLR to STAT3 activation not defined","Cell-line only, no in vivo confirmation"]},{"year":2022,"claim":"Identified an intracellular partner (Ndufs2) and a role as a brake on IL-6-driven thermogenesis in brown adipose tissue.","evidence":"Islr knockout mouse, protein interaction assay, and metabolic/thermogenesis measurements","pmids":["36077405"],"confidence":"Medium","gaps":["Direct vs indirect nature of Ndufs2 interaction not resolved","Single study"]},{"year":2023,"claim":"Defined a direct mechanism for ISLR in metabolism: it interacts with the proteasome subunit Psma4 to drive ubiquitin-independent degradation of insulin receptor alpha, limiting insulin sensitivity.","evidence":"Co-immunoprecipitation, Islr knockout mouse, adipose siRNA knockdown, and metabolic assays","pmids":["37116777"],"confidence":"High","gaps":["Structural basis of Psma4 recognition and substrate hand-off not defined","Whether the same mechanism operates outside adipocytes unknown"]},{"year":2023,"claim":"Identified MGAT5 as an ISLR partner mediating its pro-tumor effects in gastric cancer.","evidence":"Co-immunoprecipitation, siRNA knockdown, and MGAT5 overexpression rescue in gastric cancer cells","pmids":["37427332"],"confidence":"Medium","gaps":["Functional consequence of the interaction at the molecular level unclear","No reciprocal validation or in vivo test"]},{"year":2024,"claim":"Showed ISLR controls muscle satellite cell fate by binding and degrading SPARC to enable p-ERK1/2-dependent asymmetric division.","evidence":"Islr conditional knockout, SPARC binding assay, p-ERK1/2 Western blot, and muscle regeneration assays","pmids":["38597911"],"confidence":"Medium","gaps":["Mechanism of SPARC degradation not defined","Single lab"]},{"year":2024,"claim":"Established ISLR as a ROS sensor whose cysteine-19-dependent autophagic degradation relieves suppression of PKM2 tetramerization, coupling redox state to glycolysis.","evidence":"ROS stimulation, C19 cysteine mutagenesis, autophagy-lysosome inhibition, and PKM2 activity/tetramerization assays","pmids":["38786060"],"confidence":"Medium","gaps":["Direct vs indirect effect on PKM2 not fully resolved","Single study"]},{"year":2025,"claim":"Connected ISLR to tumor immune evasion via direct CD74 interaction modulating MIF/CD74 signaling and CD8+ T-cell infiltration.","evidence":"Co-immunoprecipitation, knockdown/overexpression, cytokine assays, and TNBC xenograft with radiotherapy and PD-1 blockade","pmids":["40517736"],"confidence":"Medium","gaps":["Mechanism by which ISLR regulates CD74 transcriptional activity undefined","Limited mechanistic dissection"]},{"year":null,"claim":"How a single secreted LRR-Ig protein engages such diverse, often opposing partners (BMP/GREM1, YAP, Psma4, SPARC, PKM2, CD74) through a unified biochemical activity remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model linking domain architecture to its multiple interactions","Whether secreted and intracellular pools represent distinct functional forms unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[8,10]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[11]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[2,3]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,3]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,3,12]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[8]}],"complexes":[],"partners":["PSMA4","SPARC","CD74","MGAT5","NDUFS2","PKM2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O14498","full_name":"Immunoglobulin superfamily containing leucine-rich repeat protein","aliases":[],"length_aa":428,"mass_kda":46.0,"function":"","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/O14498/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ISLR","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/ISLR","total_profiled":1310},"omim":[{"mim_id":"602059","title":"IMMUNOGLOBULIN SUPERFAMILY CONTAINING LEUCINE-RICH REPEAT; ISLR","url":"https://www.omim.org/entry/602059"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Golgi apparatus","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"cervix","ntpm":214.1}],"url":"https://www.proteinatlas.org/search/ISLR"},"hgnc":{"alias_symbol":["HsT17563"],"prev_symbol":[]},"alphafold":{"accession":"O14498","domains":[{"cath_id":"3.80.10.10","chopping":"15-224","consensus_level":"medium","plddt":95.9679,"start":15,"end":224},{"cath_id":"2.60.40.10","chopping":"232-345","consensus_level":"high","plddt":86.1766,"start":232,"end":345}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O14498","model_url":"https://alphafold.ebi.ac.uk/files/AF-O14498-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O14498-F1-predicted_aligned_error_v6.png","plddt_mean":80.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ISLR","jax_strain_url":"https://www.jax.org/strain/search?query=ISLR"},"sequence":{"accession":"O14498","fasta_url":"https://rest.uniprot.org/uniprotkb/O14498.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O14498/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O14498"}},"corpus_meta":[{"pmid":"33197448","id":"PMC_33197448","title":"The Balance of Stromal BMP Signaling Mediated by GREM1 and ISLR Drives Colorectal Carcinogenesis.","date":"2020","source":"Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/33197448","citation_count":131,"is_preprint":false},{"pmid":"32128839","id":"PMC_32128839","title":"Secreted stromal protein ISLR promotes intestinal regeneration by suppressing epithelial Hippo signaling.","date":"2020","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/32128839","citation_count":56,"is_preprint":false},{"pmid":"34676218","id":"PMC_34676218","title":"Roles of the Mesenchymal Stromal/Stem Cell Marker Meflin/Islr in Cancer Fibrosis.","date":"2021","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/34676218","citation_count":37,"is_preprint":false},{"pmid":"9325048","id":"PMC_9325048","title":"Cloning of the cDNA for a new member of the immunoglobulin superfamily (ISLR) containing leucine-rich repeat (LRR).","date":"1997","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/9325048","citation_count":36,"is_preprint":false},{"pmid":"32696215","id":"PMC_32696215","title":"ISLR regulates skeletal muscle atrophy via IGF1-PI3K/Akt-Foxo signaling pathway.","date":"2020","source":"Cell and tissue research","url":"https://pubmed.ncbi.nlm.nih.gov/32696215","citation_count":23,"is_preprint":false},{"pmid":"34713300","id":"PMC_34713300","title":"Silencing of ISLR inhibits tumour progression and glycolysis by inactivating the IL‑6/JAK/STAT3 pathway in non‑small cell lung cancer.","date":"2021","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34713300","citation_count":22,"is_preprint":false},{"pmid":"10512678","id":"PMC_10512678","title":"Human and mouse ISLR (immunoglobulin superfamily containing leucine-rich repeat) genes: genomic structure and tissue expression.","date":"1999","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/10512678","citation_count":15,"is_preprint":false},{"pmid":"32612640","id":"PMC_32612640","title":"An Analysis Regarding the Association Between the ISLR Gene and Gastric Carcinogenesis.","date":"2020","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/32612640","citation_count":14,"is_preprint":false},{"pmid":"34520435","id":"PMC_34520435","title":"ISLR affects colon cancer progression by regulating the epithelial-mesenchymal transition signaling pathway.","date":"2022","source":"Anti-cancer drugs","url":"https://pubmed.ncbi.nlm.nih.gov/34520435","citation_count":6,"is_preprint":false},{"pmid":"38597911","id":"PMC_38597911","title":"Islr regulates satellite cells asymmetric division through the SPARC/p-ERK1/2 signaling pathway.","date":"2024","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/38597911","citation_count":5,"is_preprint":false},{"pmid":"36077405","id":"PMC_36077405","title":"Immunoglobulin Superfamily Containing Leucine-Rich Repeat (Islr) Participates in IL-6-Mediated Crosstalk between Muscle and Brown Adipose Tissue to Regulate Energy Homeostasis.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36077405","citation_count":5,"is_preprint":false},{"pmid":"37116777","id":"PMC_37116777","title":"Islr regulates insulin sensitivity by interacting with Psma4 to control insulin receptor alpha levels in obese mice.","date":"2023","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/37116777","citation_count":4,"is_preprint":false},{"pmid":"40765807","id":"PMC_40765807","title":"Meflin/Islr is a marker of fibroblasts that arise in fibrotic regions after spinal cord injury.","date":"2025","source":"Nagoya journal of medical science","url":"https://pubmed.ncbi.nlm.nih.gov/40765807","citation_count":3,"is_preprint":false},{"pmid":"39136356","id":"PMC_39136356","title":"Meflin/ISLR is a marker of adipose stem and progenitor cells in mice and humans that suppresses white adipose tissue remodeling and fibrosis.","date":"2024","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/39136356","citation_count":3,"is_preprint":false},{"pmid":"40517736","id":"PMC_40517736","title":"ISLR knockdown enhances radiotherapy-induced anti-tumor immunity by disrupting the Treg-mregDC-lymphoid niche in triple-negative breast cancer.","date":"2025","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/40517736","citation_count":2,"is_preprint":false},{"pmid":"37427332","id":"PMC_37427332","title":"ISLR interacts with MGAT5 to promote the malignant progression of human gastric cancer AGS cells.","date":"2023","source":"Iranian journal of basic medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37427332","citation_count":2,"is_preprint":false},{"pmid":"41213602","id":"PMC_41213602","title":"Meflin/ISLR is a meningeal cell-specific marker involved in the development of meninges and meningioma progression.","date":"2025","source":"Brain pathology (Zurich, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/41213602","citation_count":1,"is_preprint":false},{"pmid":"40727465","id":"PMC_40727465","title":"ISLR as a Cuproptosis-Related Predictor and Therapeutic Target in Heart Failure: A Multi-Omics and Bioinformatics Approach.","date":"2025","source":"Journal of inflammation research","url":"https://pubmed.ncbi.nlm.nih.gov/40727465","citation_count":0,"is_preprint":false},{"pmid":"38786060","id":"PMC_38786060","title":"Immunoglobulin Superfamily Containing Leucine-Rich Repeat (ISLR) Serves as a Redox Sensor That Modulates Antioxidant Capacity by Suppressing Pyruvate Kinase Isozyme M2 Activity.","date":"2024","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/38786060","citation_count":0,"is_preprint":false},{"pmid":"41745847","id":"PMC_41745847","title":"Integrated Analysis of Transcriptome and sRNA Sequencing Reveals Mmu-miR-503-5p Regulates the Aluminum Chloride Stress Response of GC-1spg Cells by Targeting Islr.","date":"2026","source":"Toxics","url":"https://pubmed.ncbi.nlm.nih.gov/41745847","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11871,"output_tokens":3058,"usd":0.040741,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10558,"output_tokens":3363,"usd":0.068432,"stage2_stop_reason":"end_turn"},"total_usd":0.109173,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"ISLR was identified as a novel protein containing a leucine-rich repeat (LRR) with conserved flanking sequences and a C2-type immunoglobulin-like domain, mapped to human chromosome 15q23-q24, consistent with a role in protein-protein interaction or cell adhesion.\",\n      \"method\": \"cDNA cloning, domain analysis, Northern blot, fluorescence in situ hybridization\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, structural/domain characterization by cloning and mapping, no functional assay\",\n      \"pmids\": [\"9325048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The ISLR gene produces two transcript isoforms (ISLR-1 and ISLR-2) from different first exons but encoding an identical protein; the mouse ortholog Islr is expressed in retinal ganglion cells, inner nuclear layer, and photoreceptor inner segments.\",\n      \"method\": \"cDNA library screening, genomic sequencing, in situ hybridization, radiation hybrid mapping\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, direct sequencing and localization by ISH\",\n      \"pmids\": [\"10512678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ISLR (Meflin) in cancer-associated fibroblasts promotes BMP signaling (opposing the BMP inhibitor GREM1), and fibroblast Islr overexpression or AAV8-mediated Islr delivery to hepatocytes increased BMP signaling and improved survival in a mouse model of CRC hepatic metastasis; GREM1 and ISLR are regulated by TGF-β and FOXL1.\",\n      \"method\": \"Mouse CRC hepatic metastasis model, AAV8 gene delivery, CRC tumoroids, in situ hybridization, signaling assays\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (in vivo mouse model, organoids, gene delivery), functional BMP signaling readout, replicated across systems\",\n      \"pmids\": [\"33197448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Stromal ISLR, induced by ETS1, is secreted and inhibits epithelial Hippo signaling to activate YAP in epithelial cells, promoting intestinal regeneration and tumorigenesis; stromal-specific Islr deletion in mice markedly impaired intestinal regeneration and suppressed colon tumorigenesis.\",\n      \"method\": \"Conditional knockout mouse model, intestinal regeneration assays, colon tumorigenesis model, epistasis with Hippo-YAP pathway\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function in vivo with defined phenotypic and pathway readout (YAP activation), ETS1 upstream regulation confirmed, multiple orthogonal methods\",\n      \"pmids\": [\"32128839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ISLR regulates skeletal muscle atrophy via the IGF1-PI3K/Akt-FOXO signaling pathway; ISLR silencing increased expression of atrophy-related genes atrogin-1 and MuRF-1 and increased caspase-8 and caspase-9, while ISLR overexpression rescued dexamethasone-induced atrophy in myoblasts.\",\n      \"method\": \"siRNA knockdown, overexpression in myoblasts, Western blot, dexamethasone atrophy model\",\n      \"journal\": \"Cell and tissue research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, knockdown/overexpression in cell culture with signaling readouts, no in vivo validation or reconstitution\",\n      \"pmids\": [\"32696215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ISLR silencing in NSCLC cells inhibited proliferation, EMT, migration, invasion, and glycolysis by inactivating the IL-6/JAK/STAT3 pathway; ISLR knockdown inhibited IL-6-induced tumor progression.\",\n      \"method\": \"siRNA knockdown, overexpression, Western blot, GSEA, IL-6 pathway activator rescue experiment\",\n      \"journal\": \"International journal of molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, cell-based knockdown/OE with pathway validation by pathway activator rescue\",\n      \"pmids\": [\"34713300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Islr interacts with NADH:Ubiquinone Oxidoreductase Core Subunit S2 (Ndufs2) in brown adipose tissue and functions as a brake on IL-6 signaling, preventing IL-6 from promoting BAT mitochondrial activity and thermogenesis; Islr loss in BAT improved mitochondrial function and energy expenditure.\",\n      \"method\": \"Islr knockout mouse model, cardiotoxin injury model, protein interaction assay, metabolic/thermogenesis measurements\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, in vivo knockout with metabolic readouts and protein interaction, but single study\",\n      \"pmids\": [\"36077405\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ISLR activates the EMT signaling pathway to promote colon cancer cell proliferation, migration, and invasion; inhibition of EMT suppressed the growth-promoting effect of ISLR overexpression.\",\n      \"method\": \"siRNA knockdown, overexpression, KEGG pathway enrichment, Western blot, functional cell assays\",\n      \"journal\": \"Anti-cancer drugs\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, cell-based assays with pathway inferred from KEGG, limited mechanistic dissection\",\n      \"pmids\": [\"34520435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ISLR mediates ubiquitin-independent proteasomal degradation of insulin receptor alpha (Insrα) by specifically interacting with proteasome subunit alpha type 4 (Psma4); Islr knockout increased Insrα levels and enhanced insulin sensitivity in adipocytes and in vivo in obese mice.\",\n      \"method\": \"Co-immunoprecipitation, Islr knockout mouse model, siRNA knockdown in white adipose tissue, Western blot, metabolic assays\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP defining interaction with Psma4, in vivo knockout and siRNA knockdown with functional insulin sensitivity readout, multiple orthogonal methods in single lab\",\n      \"pmids\": [\"37116777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ISLR interacts with MGAT5 (N-acetylglucosaminyltransferase V) in gastric cancer cells, and MGAT5 overexpression reversed the effects of ISLR knockdown on tumor cell viability, proliferation, migration, invasion, and EMT.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, MGAT5 overexpression rescue, Western blot, functional cell assays\",\n      \"journal\": \"Iranian journal of basic medical sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, Co-IP for interaction plus functional rescue, limited mechanistic depth\",\n      \"pmids\": [\"37427332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Islr binds to and promotes degradation of SPARC (secreted protein acidic and rich in cysteine), which activates p-ERK1/2 signaling required for asymmetric division of satellite cells; Islr deletion reduced muscle regeneration by decreasing the satellite cell pool and promoting asymmetric division.\",\n      \"method\": \"Islr conditional knockout in mice, protein interaction assay (binding to SPARC), Western blot for p-ERK1/2, muscle regeneration assays\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vivo knockout with mechanistic pathway (SPARC/p-ERK1/2) and direct binding shown, single lab\",\n      \"pmids\": [\"38597911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ISLR functions as a redox sensor, perceiving reactive oxygen species (ROS) through its cysteine residue 19, and then undergoes rapid degradation via the autophagy-lysosome pathway; reduced ISLR promotes tetramerization of PKM2, enhancing pyruvate kinase activity and glycolysis to increase antioxidant capacity.\",\n      \"method\": \"ROS stimulation, cysteine mutagenesis (C19), autophagy-lysosome pathway inhibition, PKM2 activity assay, PKM2 tetramerization assay\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — active-site mutagenesis (C19), in vitro enzymatic activity assay for PKM2, and pathway mechanistic follow-up in single lab\",\n      \"pmids\": [\"38786060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ISLR directly interacts with CD74 and regulates its transcriptional activity in TNBC cells, modulating the MIF/CD74 signaling pathway; ISLR knockdown decreased IL-10 and TGF-β secretion and promoted CD8+ T cell infiltration, and radiotherapy reduced ISLR expression.\",\n      \"method\": \"Co-immunoprecipitation/interaction assay, siRNA knockdown, overexpression, cytokine assay, xenograft mouse model with RT and PD-1 blockade\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, direct interaction with CD74 established by binding assay, functional in vivo rescue, but limited mechanistic dissection of transcriptional activity\",\n      \"pmids\": [\"40517736\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ISLR (Meflin) is a secreted/cell-surface LRR-immunoglobulin superfamily protein expressed in fibroblasts and mesenchymal stromal cells that acts as a pleiotropic signaling regulator: it promotes BMP signaling in stromal cells to restrain colorectal cancer, inhibits epithelial Hippo/YAP signaling downstream of ETS1 to drive intestinal regeneration, mediates ubiquitin-independent proteasomal degradation of insulin receptor alpha via interaction with Psma4, promotes degradation of SPARC to activate ERK1/2-dependent satellite cell asymmetric division, acts as a redox sensor whose ROS-triggered autophagic degradation relieves suppression of PKM2 tetramerization, and interacts with CD74 to modulate MIF/CD74-mediated immune evasion.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ISLR (Meflin) is a secreted/cell-surface leucine-rich-repeat and immunoglobulin-domain protein, originally identified by cDNA cloning as a putative protein-interaction/adhesion molecule [#0], that functions as a pleiotropic regulator of stromal and mesenchymal signaling. In the intestinal and tumor stroma it controls two paracrine axes: it promotes BMP signaling in cancer-associated fibroblasts, opposing the BMP inhibitor GREM1 and restraining colorectal cancer hepatic metastasis [#2], while as an ETS1-induced secreted factor it inhibits epithelial Hippo signaling to activate YAP, driving intestinal regeneration and tumorigenesis [#3]. ISLR also acts through direct protein partners to control protein turnover and signaling: it mediates ubiquitin-independent proteasomal degradation of insulin receptor alpha via interaction with the proteasome subunit Psma4, thereby limiting insulin sensitivity [#8], and binds and promotes degradation of SPARC to license p-ERK1/2-dependent asymmetric division of muscle satellite cells [#10]. As a redox sensor, ISLR perceives ROS through cysteine 19 and undergoes autophagy-lysosomal degradation, relieving its suppression of PKM2 tetramerization and thereby enhancing glycolysis and antioxidant capacity [#11]. Additional interactions with CD74 modulate MIF/CD74 immune signaling and CD8+ T-cell infiltration [#12]. Across cancer cell models ISLR has been linked to proliferation, EMT, and migration through IL-6/JAK/STAT3 and EMT programs [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established ISLR as a distinct gene product with a defined domain architecture, framing it as a candidate protein-interaction or adhesion molecule.\",\n      \"evidence\": \"cDNA cloning, domain analysis, and chromosomal mapping to 15q23-q24\",\n      \"pmids\": [\"9325048\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional assay or binding partner identified\", \"Cellular localization of the protein not determined\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Defined the gene's transcript structure and tissue expression, showing two isoforms encoding an identical protein and ortholog expression in retinal neurons.\",\n      \"evidence\": \"cDNA library screening, genomic sequencing, and in situ hybridization in mouse\",\n      \"pmids\": [\"10512678\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role in retina not tested\", \"No mechanism linking expression to phenotype\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed that stromal ISLR shapes epithelial fate through two paracrine pathways — promoting BMP signaling against GREM1 to restrain CRC metastasis, and inhibiting Hippo to activate YAP for intestinal regeneration.\",\n      \"evidence\": \"Mouse CRC hepatic metastasis and intestinal regeneration models, conditional knockout, AAV8 delivery, tumoroids, and pathway epistasis\",\n      \"pmids\": [\"33197448\", \"32128839\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular receptor/binding mechanism by which secreted ISLR alters BMP or Hippo signaling not defined\", \"How a single protein produces opposing pro- and anti-tumor effects across contexts unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Implicated ISLR in skeletal muscle homeostasis via IGF1-PI3K/Akt-FOXO signaling controlling atrophy programs.\",\n      \"evidence\": \"siRNA knockdown and overexpression in myoblasts with dexamethasone atrophy model and Western blot\",\n      \"pmids\": [\"32696215\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vivo validation\", \"Direct molecular target in the pathway not identified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked ISLR to NSCLC tumor progression and glycolysis through the IL-6/JAK/STAT3 pathway.\",\n      \"evidence\": \"siRNA knockdown, overexpression, GSEA, and IL-6 pathway-activator rescue in NSCLC cells\",\n      \"pmids\": [\"34713300\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting ISLR to STAT3 activation not defined\", \"Cell-line only, no in vivo confirmation\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified an intracellular partner (Ndufs2) and a role as a brake on IL-6-driven thermogenesis in brown adipose tissue.\",\n      \"evidence\": \"Islr knockout mouse, protein interaction assay, and metabolic/thermogenesis measurements\",\n      \"pmids\": [\"36077405\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect nature of Ndufs2 interaction not resolved\", \"Single study\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined a direct mechanism for ISLR in metabolism: it interacts with the proteasome subunit Psma4 to drive ubiquitin-independent degradation of insulin receptor alpha, limiting insulin sensitivity.\",\n      \"evidence\": \"Co-immunoprecipitation, Islr knockout mouse, adipose siRNA knockdown, and metabolic assays\",\n      \"pmids\": [\"37116777\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of Psma4 recognition and substrate hand-off not defined\", \"Whether the same mechanism operates outside adipocytes unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified MGAT5 as an ISLR partner mediating its pro-tumor effects in gastric cancer.\",\n      \"evidence\": \"Co-immunoprecipitation, siRNA knockdown, and MGAT5 overexpression rescue in gastric cancer cells\",\n      \"pmids\": [\"37427332\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the interaction at the molecular level unclear\", \"No reciprocal validation or in vivo test\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed ISLR controls muscle satellite cell fate by binding and degrading SPARC to enable p-ERK1/2-dependent asymmetric division.\",\n      \"evidence\": \"Islr conditional knockout, SPARC binding assay, p-ERK1/2 Western blot, and muscle regeneration assays\",\n      \"pmids\": [\"38597911\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of SPARC degradation not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established ISLR as a ROS sensor whose cysteine-19-dependent autophagic degradation relieves suppression of PKM2 tetramerization, coupling redox state to glycolysis.\",\n      \"evidence\": \"ROS stimulation, C19 cysteine mutagenesis, autophagy-lysosome inhibition, and PKM2 activity/tetramerization assays\",\n      \"pmids\": [\"38786060\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect effect on PKM2 not fully resolved\", \"Single study\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected ISLR to tumor immune evasion via direct CD74 interaction modulating MIF/CD74 signaling and CD8+ T-cell infiltration.\",\n      \"evidence\": \"Co-immunoprecipitation, knockdown/overexpression, cytokine assays, and TNBC xenograft with radiotherapy and PD-1 blockade\",\n      \"pmids\": [\"40517736\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which ISLR regulates CD74 transcriptional activity undefined\", \"Limited mechanistic dissection\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single secreted LRR-Ig protein engages such diverse, often opposing partners (BMP/GREM1, YAP, Psma4, SPARC, PKM2, CD74) through a unified biochemical activity remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model linking domain architecture to its multiple interactions\", \"Whether secreted and intracellular pools represent distinct functional forms unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [8, 10]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 3, 12]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PSMA4\", \"SPARC\", \"CD74\", \"MGAT5\", \"NDUFS2\", \"PKM2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":6,"faith_total":6,"faith_pct":100.0}}