{"gene":"TLN1","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2023,"finding":"TLN1 contains a cancer-enriched alternative exon (exon 17b, 51 nucleotides) between exons 17 and 18 that inserts 17 amino acids after Gln665 in the R1-R2 linker region, lowering the force required to open R1-R2 mechanosensitive switch domains, enhancing vinculin binding, and altering cell adhesion dynamics and motility. The TGF-β/SMAD3 signaling pathway regulates this isoform switch.","method":"Differential pre-mRNA splicing analysis, biochemical force-extension assays, vinculin binding assays, live cell adhesion/motility imaging, TGF-β/SMAD3 pathway perturbation","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods (splicing analysis, in vitro biochemical assays, mutagenesis-equivalent isoform comparison, cell imaging, pathway perturbation) in a single focused study","pmids":["36880935"],"is_preprint":false},{"year":2022,"finding":"TLN1 interacts with integrin β1 at focal adhesions in TNBC cells; silencing TLN1 attenuates tumor cell migration by interfering with dynamic focal adhesion formation with integrin β1, thereby regulating the FAK-AKT signaling pathway and epithelial-mesenchymal transition. A small-molecule (C67399) that blocks the TLN1–integrin β1 protein-protein interface suppresses TNBC metastasis in xenograft models.","method":"Western blot, RT-PCR, siRNA knockdown, computational small-molecule screening targeting the TLN1–integrin β1 binding interface, xenograft assay, focal adhesion dynamics imaging","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — reciprocal functional validation with KD and chemical inhibitor, multiple readouts, single lab","pmids":["35285795"],"is_preprint":false},{"year":2021,"finding":"TLN1 and FAK form a Cdk5/Tln1/FAK axis that drives cancer cell trans-endothelial migration (extravasation); the structural (scaffold) function of FAK and Tln1, rather than their phosphorylation status, is required for invadopodia formation and actin polymerization-dependent vascular breaching. Inhibition of FAK-S732 phosphorylation delocalizes ERK from the nucleus, decreasing phospho-ERK.","method":"3D microfluidic vascularized models, siRNA knockdown of Tln1 and FAK, chemical FAK inhibition, in vivo lung colonization assay, biochemical and imaging tools","journal":"Biomaterials","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — orthogonal in vitro 3D models plus in vivo validation, single lab, genetic and chemical perturbation","pmids":["34333365"],"is_preprint":false},{"year":2025,"finding":"EMP1 upregulation inhibits SMURF1-mediated ubiquitination and degradation of TLN1 by competing with SMURF1 for the TLN1 binding site, leading to TLN1 accumulation, increased FAK phosphorylation, and amplified hepatic stellate cell activation and inflammatory liver injury. Silencing EMP1 suppresses the TLN1/FAK post-translational modification cascade.","method":"Rodent MASLD-IRI models, siRNA/EMP1 silencing, co-immunoprecipitation to map EMP1–SMURF1–TLN1 interactions, Western blot for ubiquitination and FAK phosphorylation, human sample validation","journal":"Molecular biomedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishing competitive binding, multiple readouts in rodent and cell models, single lab","pmids":["41284206"],"is_preprint":false},{"year":2025,"finding":"FLI1 and GATA1 co-operatively regulate TLN1 transcription through a functional intronic FLI1-binding region in the TLN1 gene. FLI1 variants with defective nuclear localization, transcriptional activity, or protein stability show reduced cooperative transcriptional activity with GATA1, resulting in an ~88% reduction of talin-1 protein in patient platelets and consequent platelet dysfunction.","method":"Single-cell RNA sequencing of patient megakaryocytes, chromatin immunoprecipitation sequencing (ChIP-seq), luciferase reporter assays, Western blot of patient platelets, in vitro transcriptional activity assays for FLI1 variants","journal":"Haematologica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq plus luciferase reporter plus patient platelet protein quantification, single lab with multiple orthogonal methods","pmids":["39744817"],"is_preprint":false},{"year":2024,"finding":"LAYN (layilin) interacts with TLN1 (confirmed by co-immunoprecipitation), and the CREB1–LAYN–TLN1–β1 integrin axis promotes cholangiocarcinoma metastasis; TLN1 knockdown suppresses β1 integrin expression and phosphorylation of c-Jun, p38 MAPK, and ERK, reversing the pro-metastatic effects of LAYN overexpression.","method":"Co-immunoprecipitation (LAYN–TLN1 interaction), chromatin immunoprecipitation (CREB1 binding to LAYN promoter), siRNA knockdown, Western blot, Transwell migration/invasion assays, nude mouse metastasis model","journal":"Heliyon","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP for interaction, ChIP for transcriptional regulation, functional rescue, single lab","pmids":["39286102"],"is_preprint":false},{"year":2026,"finding":"TLN1 directly interacts with NGFR (nerve growth factor receptor) in castration-resistant prostate cancer cells (confirmed by molecular docking and Co-IP); TLN1 knockdown upregulates NGFR and suppresses CRPC cell proliferation, migration, invasion, and EMT through modulation of the MAPK and PI3K-AKT signaling pathways. NGFR knockdown reverses the tumor-suppressive effects of TLN1 silencing.","method":"Mass spectrometry (serum peptides), Co-immunoprecipitation, molecular docking, transcriptome sequencing, siRNA knockdown, xenograft mouse model, CCK-8/colony formation/wound healing/Transwell assays, Western blot","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP and molecular docking for direct interaction, functional epistasis via rescue experiment, single lab","pmids":["42112334"],"is_preprint":false},{"year":2023,"finding":"TLN1 overexpression in cardiac microvascular endothelial cells increases ITGA5 (integrin alpha 5) expression, and ITGA5 knockdown reverses the protective effects of TLN1 overexpression against ox-LDL-induced apoptosis, reduced proliferation, angiogenesis, inflammatory response, and oxidative stress, indicating TLN1 acts upstream of ITGA5 in this pathway.","method":"Overexpression and siRNA knockdown in CMVECs, ox-LDL injury model, CCK-8 proliferation assay, apoptosis assay, angiogenesis assay, Western blot","journal":"Folia morphologica","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, overexpression/knockdown with functional readouts but no direct binding or interaction assay between TLN1 and ITGA5","pmids":["37144848"],"is_preprint":false},{"year":2013,"finding":"TLN1 loss-of-function (shRNA) enhances docetaxel chemosensitivity selectively in triple-negative breast cancer cell lines and reduces tumor mass in mammary fat pad xenograft models after chemotherapy, establishing TLN1 as a modulator of chemotherapy response in TNBC.","method":"RNAi screen (328 shRNA cell lines), validation in 8 breast cancer cell lines, mouse xenograft model","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide RNAi screen with in vitro and in vivo validation across multiple cell lines, single lab","pmids":["23479679"],"is_preprint":false},{"year":2013,"finding":"TLN1 is a direct target of miR-9 in ovarian serous carcinoma; miR-9 overexpression inhibits TLN1-dependent FAK/AKT pathway activation, and TLN1 knockdown phenocopies miR-9 overexpression in suppressing cell proliferation, migration, and invasion.","method":"Exogenous miR-9 transfection, TLN1 siRNA knockdown, Western blot for FAK/AKT pathway, functional proliferation/migration/invasion assays (implied direct target validation)","journal":"International journal of molecular medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, phenotypic rescue and pathway Western blots but direct miR-9/TLN1 targeting experiment details are incomplete in abstract","pmids":["23722670"],"is_preprint":false},{"year":2023,"finding":"TLN1 is subject to lysine malonylation (Kmal) post-translational modification, identified by affinity enrichment and LC-MS/MS in peripheral blood mononuclear cells from ESRD patients, implicating this modification in TLN1 function in the Rap1 and platelet activation signaling pathways.","method":"Affinity enrichment, LC-MS/MS proteomics (malonylome profiling)","journal":"Proteome science","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single proteomic study identifying the modification site, no functional validation of the malonylation on TLN1 activity","pmids":["37833721"],"is_preprint":false}],"current_model":"TLN1 (talin-1) is a mechanosensitive focal adhesion scaffold that links integrins (particularly β1 integrin) to the actin cytoskeleton; it contains force-dependent R1-R13 switch domains whose opening threshold is modulated by a cancer-enriched alternative exon (exon 17b) regulated by TGF-β/SMAD3 signaling, enhancing vinculin binding and altering adhesion dynamics; TLN1 protein stability is controlled by SMURF1-mediated ubiquitination (antagonized by EMP1), its transcription is co-operatively regulated by FLI1 and GATA1 in megakaryocytes, and it signals downstream through FAK-AKT, MAPK, and ERK pathways to drive integrin activation, invadopodia formation, trans-endothelial migration, and EMT in cancer and vascular contexts."},"narrative":{"mechanistic_narrative":"TLN1 (talin-1) is a mechanosensitive focal adhesion scaffold that physically links integrins to the actin cytoskeleton and converts adhesion engagement into intracellular signaling that drives cell migration, invasion, and epithelial-mesenchymal transition [PMID:35285795, PMID:36880935]. Its force-responsive architecture is tunable: a cancer-enriched alternative exon (exon 17b) inserts 17 residues into the R1-R2 linker, lowering the force threshold for opening the R1-R2 mechanosensitive switch domains, enhancing vinculin binding and altering adhesion dynamics, with this isoform switch under TGF-β/SMAD3 control [PMID:36880935]. At focal adhesions TLN1 engages β1 integrin to nucleate dynamic adhesions and activate FAK-AKT signaling and EMT, and disrupting the TLN1–β1 integrin interface suppresses tumor migration and metastasis [PMID:35285795]. Beyond β1 integrin, TLN1 partners with FAK in a Cdk5/TLN1/FAK axis whose scaffold (rather than catalytic) function supports invadopodia formation and trans-endothelial migration [PMID:34333365], and it associates with additional membrane partners including LAYN and NGFR to feed FAK-AKT, MAPK/ERK, and PI3K-AKT signaling in cancer contexts [PMID:39286102, PMID:42112334]. TLN1 abundance is set both transcriptionally—cooperative FLI1/GATA1 regulation through an intronic FLI1-binding region is required for normal talin-1 levels in megakaryocytes, with FLI1 variants causing ~88% loss of platelet talin-1 and platelet dysfunction [PMID:39744817]—and post-translationally, via SMURF1-mediated ubiquitination and degradation that EMP1 antagonizes by competing for the TLN1 binding site [PMID:41284206].","teleology":[{"year":2013,"claim":"Established TLN1 as a functionally important, druggable dependency in cancer rather than a passive structural protein, by showing its loss alters therapeutic response.","evidence":"shRNA RNAi screen across breast cancer cell lines with xenograft validation showing TLN1 loss enhances docetaxel chemosensitivity in TNBC","pmids":["23479679"],"confidence":"Medium","gaps":["Does not define the molecular mechanism linking TLN1 to chemoresponse","Restricted to TNBC; generalizability unaddressed"]},{"year":2013,"claim":"Connected TLN1 to upstream regulatory control and downstream effector signaling by placing it in a miR-9/TLN1/FAK-AKT axis controlling proliferation and invasion.","evidence":"miR-9 transfection and TLN1 siRNA with FAK/AKT Western blots and migration/invasion assays in ovarian serous carcinoma","pmids":["23722670"],"confidence":"Low","gaps":["Direct miR-9 targeting of the TLN1 transcript not rigorously demonstrated in the abstract","Single cancer type, single lab"]},{"year":2021,"claim":"Separated TLN1's scaffold function from phosphorylation-dependent signaling, showing the structural role in a Cdk5/TLN1/FAK axis is what enables invadopodia and vascular breaching.","evidence":"3D microfluidic vascularized models with siRNA knockdown of TLN1 and FAK, chemical FAK inhibition, and in vivo lung colonization","pmids":["34333365"],"confidence":"Medium","gaps":["Molecular detail of how Cdk5 couples to the TLN1/FAK complex unresolved","Direct TLN1–FAK binding interface not mapped"]},{"year":2022,"claim":"Defined the TLN1–β1 integrin interface as a targetable node driving adhesion dynamics and metastasis, moving from correlation to a chemically tractable mechanism.","evidence":"siRNA knockdown, computational small-molecule screen against the TLN1–β1 binding interface (C67399), focal adhesion imaging, and TNBC xenograft metastasis","pmids":["35285795"],"confidence":"Medium","gaps":["Specificity of C67399 for the TLN1–integrin interface in vivo not fully characterized","Single lab"]},{"year":2023,"claim":"Revealed how TLN1 mechanosensitivity is tuned in disease via a cancer-enriched alternative exon that lowers the force threshold for switch-domain opening, linking splicing to adhesion mechanics.","evidence":"Splicing analysis, in vitro force-extension and vinculin binding assays, live adhesion/motility imaging, and TGF-β/SMAD3 pathway perturbation","pmids":["36880935"],"confidence":"High","gaps":["In vivo prevalence and functional consequence of exon 17b across tumor types not established","Mechanism by which SMAD3 directs the splice choice not detailed"]},{"year":2023,"claim":"Extended TLN1 function into vascular endothelial protection by placing it upstream of ITGA5, broadening its role beyond migration.","evidence":"Overexpression/knockdown of TLN1 and ITGA5 in cardiac microvascular endothelial cells under ox-LDL injury with functional rescue","pmids":["37144848"],"confidence":"Low","gaps":["No direct TLN1–ITGA5 binding assay","Mechanism by which TLN1 raises ITGA5 expression unknown"]},{"year":2023,"claim":"Catalogued a novel post-translational modification (lysine malonylation) on TLN1, raising a regulatory layer relevant to platelet activation signaling.","evidence":"Affinity enrichment and LC-MS/MS malonylome profiling of PBMCs from ESRD patients","pmids":["37833721"],"confidence":"Low","gaps":["No functional validation that malonylation alters TLN1 activity","Single proteomic descriptive study"]},{"year":2024,"claim":"Identified LAYN as a direct TLN1 partner within a transcription-to-adhesion axis (CREB1-LAYN-TLN1-β1 integrin) driving cholangiocarcinoma metastasis via MAPK/ERK signaling.","evidence":"Co-IP for LAYN–TLN1, ChIP for CREB1, siRNA, Western blot, Transwell assays, and nude mouse metastasis model","pmids":["39286102"],"confidence":"Medium","gaps":["Reciprocal/structural mapping of the LAYN–TLN1 interface absent","Single lab and cancer type"]},{"year":2025,"claim":"Defined transcriptional control of TLN1 abundance, showing cooperative FLI1/GATA1 regulation is required for talin-1 expression in megakaryocytes and links FLI1 variants to platelet disease.","evidence":"scRNA-seq of patient megakaryocytes, ChIP-seq, luciferase reporters, FLI1 variant transcription assays, and Western blot of patient platelets","pmids":["39744817"],"confidence":"Medium","gaps":["Whether reduced talin-1 alone accounts for the platelet phenotype not isolated","GATA1 contribution to the intronic element not separately dissected"]},{"year":2025,"claim":"Established post-translational control of TLN1 stability through SMURF1-mediated ubiquitination and its antagonism by EMP1, linking TLN1 turnover to hepatic stellate cell activation.","evidence":"Rodent MASLD-IRI models, EMP1 silencing, Co-IP mapping EMP1–SMURF1–TLN1 competition, and Western blot for ubiquitination and FAK phosphorylation","pmids":["41284206"],"confidence":"Medium","gaps":["SMURF1 ubiquitination site(s) on TLN1 not mapped","Single lab; competitive binding inferred from Co-IP"]},{"year":2026,"claim":"Added NGFR as a direct TLN1 partner in castration-resistant prostate cancer, with epistasis showing TLN1 acts through NGFR to drive proliferation, invasion, and EMT via MAPK and PI3K-AKT.","evidence":"Mass spectrometry, Co-IP, molecular docking, transcriptome sequencing, siRNA, xenograft, and functional assays with NGFR rescue","pmids":["42112334"],"confidence":"Medium","gaps":["Structural basis of the TLN1–NGFR interaction not resolved beyond docking","Single lab and tumor context"]},{"year":null,"claim":"How the distinct regulatory layers on TLN1 — splice-isoform mechanotuning, transcriptional control, ubiquitin-dependent turnover, and malonylation — are integrated to set adhesion behavior in a given cell type remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unified model coupling TLN1 abundance, modification state, and isoform identity to adhesion output","Cross-talk among SMURF1/EMP1, FLI1/GATA1, and SMAD3 inputs not tested together"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,1]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,2]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[0]}],"localization":[],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,5,6]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,5,6]},{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[4,10]}],"complexes":["focal adhesion"],"partners":["ITGB1","FAK","VINCULIN","LAYN","NGFR","SMURF1","EMP1","ITGA5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y490","full_name":"Talin-1","aliases":[],"length_aa":2541,"mass_kda":269.8,"function":"High molecular weight cytoskeletal protein concentrated at regions of cell-matrix and cell-cell contacts. Involved in connections of major cytoskeletal structures to the plasma membrane. With KANK1 co-organize the assembly of cortical microtubule stabilizing complexes (CMSCs) positioned to control microtubule-actin crosstalk at focal adhesions (FAs) rims","subcellular_location":"Cell projection, ruffle membrane; Cytoplasm, cytoskeleton; Cell surface; Cell junction, focal adhesion","url":"https://www.uniprot.org/uniprotkb/Q9Y490/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TLN1","classification":"Not Classified","n_dependent_lines":711,"n_total_lines":1208,"dependency_fraction":0.5885761589403974},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"SAR1B","stoichiometry":0.2},{"gene":"VCL","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TLN1","total_profiled":1310},"omim":[{"mim_id":"618843","title":"LAYILIN; LAYN","url":"https://www.omim.org/entry/618843"},{"mim_id":"617801","title":"CYCLASE-ASSOCIATED ACTIN CYTOSKELETON REGULATORY PROTEIN 1; CAP1","url":"https://www.omim.org/entry/617801"},{"mim_id":"613504","title":"ZINC FINGER FYVE DOMAIN-CONTAINING PROTEIN 21; ZFYVE21","url":"https://www.omim.org/entry/613504"},{"mim_id":"610094","title":"DEF6 GUANINE NUCLEOTIDE EXCHANGE FACTOR; DEF6","url":"https://www.omim.org/entry/610094"},{"mim_id":"609507","title":"TOPOISOMERASE I-BINDING ARGININE/SERINE-RICH PROTEIN; TOPORS","url":"https://www.omim.org/entry/609507"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Focal adhesion sites","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"},{"location":"Plasma membrane","reliability":"Additional"},{"location":"Centriolar satellite","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"blood vessel","ntpm":345.2}],"url":"https://www.proteinatlas.org/search/TLN1"},"hgnc":{"alias_symbol":["ILWEQ"],"prev_symbol":["TLN"]},"alphafold":{"accession":"Q9Y490","domains":[{"cath_id":"3.10.20.90","chopping":"5-84","consensus_level":"high","plddt":79.5273,"start":5,"end":84},{"cath_id":"2.30.29.30","chopping":"311-383","consensus_level":"medium","plddt":76.1937,"start":311,"end":383},{"cath_id":"1.20.1420.10","chopping":"491-518_537-657","consensus_level":"medium","plddt":83.0589,"start":491,"end":657},{"cath_id":"1.20.120.230","chopping":"798-911","consensus_level":"medium","plddt":79.5028,"start":798,"end":911},{"cath_id":"1.20.1420.10","chopping":"1076-1148_1155-1204","consensus_level":"high","plddt":79.6029,"start":1076,"end":1204},{"cath_id":"1.20.1420.10","chopping":"1205-1356","consensus_level":"medium","plddt":73.1206,"start":1205,"end":1356},{"cath_id":"1.20.120.230","chopping":"1479-1582","consensus_level":"medium","plddt":77.2763,"start":1479,"end":1582},{"cath_id":"1.20.1420.10","chopping":"1660-1822","consensus_level":"medium","plddt":83.6338,"start":1660,"end":1822},{"cath_id":"1.20.1420.10","chopping":"1824-1972","consensus_level":"medium","plddt":80.7286,"start":1824,"end":1972},{"cath_id":"1.20.1420.10","chopping":"1973-2138","consensus_level":"high","plddt":82.401,"start":1973,"end":2138},{"cath_id":"1.20.1420.10","chopping":"2163-2294","consensus_level":"medium","plddt":79.6735,"start":2163,"end":2294},{"cath_id":"1.20.1410.10","chopping":"2302-2325_2342-2478","consensus_level":"high","plddt":70.1067,"start":2302,"end":2478}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y490","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y490-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y490-F1-predicted_aligned_error_v6.png","plddt_mean":75.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TLN1","jax_strain_url":"https://www.jax.org/strain/search?query=TLN1"},"sequence":{"accession":"Q9Y490","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y490.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y490/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y490"}},"corpus_meta":[{"pmid":"23479679","id":"PMC_23479679","title":"A targeted RNAi screen of the breast cancer genome identifies KIF14 and TLN1 as genes that modulate docetaxel chemosensitivity in triple-negative breast cancer.","date":"2013","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/23479679","citation_count":62,"is_preprint":false},{"pmid":"23722670","id":"PMC_23722670","title":"miR-9 functions as a tumor suppressor in ovarian serous carcinoma by targeting TLN1.","date":"2013","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/23722670","citation_count":60,"is_preprint":false},{"pmid":"30888838","id":"PMC_30888838","title":"Rare Missense Variants in TLN1 Are Associated With Familial and Sporadic Spontaneous Coronary Artery Dissection.","date":"2019","source":"Circulation. 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immunology","url":"https://pubmed.ncbi.nlm.nih.gov/42112334","citation_count":0,"is_preprint":false},{"pmid":"42258031","id":"PMC_42258031","title":"The alternative splicing events and the function of TLN1 in clear cell renal cell carcinoma.","date":"2026","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/42258031","citation_count":0,"is_preprint":false},{"pmid":"40159367","id":"PMC_40159367","title":"Tandem Mass Tag-Labeling Proteomics Reveals TLN1 as a Potential Factor in Cardiogenic Pulmonary Edema.","date":"2025","source":"International heart journal","url":"https://pubmed.ncbi.nlm.nih.gov/40159367","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.30.685158","title":"Integrated metabolomic and genomic insights into amino acid incorporation within the hybrid polyketide-alkaloid antibiotic TLN-05220","date":"2025-10-31","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.30.685158","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.03.09.25323497","title":"Pan-Omics Fusion and Machine Learning Unveil Congenital Tooth Agenesis-Ecto-mesodermal Diseases Link and Biomarker Discovery","date":"2025-03-11","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.09.25323497","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15381,"output_tokens":3149,"usd":0.046689,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10581,"output_tokens":3909,"usd":0.075315,"stage2_stop_reason":"end_turn"},"total_usd":0.122004,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2023,\n      \"finding\": \"TLN1 contains a cancer-enriched alternative exon (exon 17b, 51 nucleotides) between exons 17 and 18 that inserts 17 amino acids after Gln665 in the R1-R2 linker region, lowering the force required to open R1-R2 mechanosensitive switch domains, enhancing vinculin binding, and altering cell adhesion dynamics and motility. The TGF-β/SMAD3 signaling pathway regulates this isoform switch.\",\n      \"method\": \"Differential pre-mRNA splicing analysis, biochemical force-extension assays, vinculin binding assays, live cell adhesion/motility imaging, TGF-β/SMAD3 pathway perturbation\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods (splicing analysis, in vitro biochemical assays, mutagenesis-equivalent isoform comparison, cell imaging, pathway perturbation) in a single focused study\",\n      \"pmids\": [\"36880935\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TLN1 interacts with integrin β1 at focal adhesions in TNBC cells; silencing TLN1 attenuates tumor cell migration by interfering with dynamic focal adhesion formation with integrin β1, thereby regulating the FAK-AKT signaling pathway and epithelial-mesenchymal transition. A small-molecule (C67399) that blocks the TLN1–integrin β1 protein-protein interface suppresses TNBC metastasis in xenograft models.\",\n      \"method\": \"Western blot, RT-PCR, siRNA knockdown, computational small-molecule screening targeting the TLN1–integrin β1 binding interface, xenograft assay, focal adhesion dynamics imaging\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — reciprocal functional validation with KD and chemical inhibitor, multiple readouts, single lab\",\n      \"pmids\": [\"35285795\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TLN1 and FAK form a Cdk5/Tln1/FAK axis that drives cancer cell trans-endothelial migration (extravasation); the structural (scaffold) function of FAK and Tln1, rather than their phosphorylation status, is required for invadopodia formation and actin polymerization-dependent vascular breaching. Inhibition of FAK-S732 phosphorylation delocalizes ERK from the nucleus, decreasing phospho-ERK.\",\n      \"method\": \"3D microfluidic vascularized models, siRNA knockdown of Tln1 and FAK, chemical FAK inhibition, in vivo lung colonization assay, biochemical and imaging tools\",\n      \"journal\": \"Biomaterials\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — orthogonal in vitro 3D models plus in vivo validation, single lab, genetic and chemical perturbation\",\n      \"pmids\": [\"34333365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"EMP1 upregulation inhibits SMURF1-mediated ubiquitination and degradation of TLN1 by competing with SMURF1 for the TLN1 binding site, leading to TLN1 accumulation, increased FAK phosphorylation, and amplified hepatic stellate cell activation and inflammatory liver injury. Silencing EMP1 suppresses the TLN1/FAK post-translational modification cascade.\",\n      \"method\": \"Rodent MASLD-IRI models, siRNA/EMP1 silencing, co-immunoprecipitation to map EMP1–SMURF1–TLN1 interactions, Western blot for ubiquitination and FAK phosphorylation, human sample validation\",\n      \"journal\": \"Molecular biomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishing competitive binding, multiple readouts in rodent and cell models, single lab\",\n      \"pmids\": [\"41284206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FLI1 and GATA1 co-operatively regulate TLN1 transcription through a functional intronic FLI1-binding region in the TLN1 gene. FLI1 variants with defective nuclear localization, transcriptional activity, or protein stability show reduced cooperative transcriptional activity with GATA1, resulting in an ~88% reduction of talin-1 protein in patient platelets and consequent platelet dysfunction.\",\n      \"method\": \"Single-cell RNA sequencing of patient megakaryocytes, chromatin immunoprecipitation sequencing (ChIP-seq), luciferase reporter assays, Western blot of patient platelets, in vitro transcriptional activity assays for FLI1 variants\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq plus luciferase reporter plus patient platelet protein quantification, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"39744817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LAYN (layilin) interacts with TLN1 (confirmed by co-immunoprecipitation), and the CREB1–LAYN–TLN1–β1 integrin axis promotes cholangiocarcinoma metastasis; TLN1 knockdown suppresses β1 integrin expression and phosphorylation of c-Jun, p38 MAPK, and ERK, reversing the pro-metastatic effects of LAYN overexpression.\",\n      \"method\": \"Co-immunoprecipitation (LAYN–TLN1 interaction), chromatin immunoprecipitation (CREB1 binding to LAYN promoter), siRNA knockdown, Western blot, Transwell migration/invasion assays, nude mouse metastasis model\",\n      \"journal\": \"Heliyon\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP for interaction, ChIP for transcriptional regulation, functional rescue, single lab\",\n      \"pmids\": [\"39286102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"TLN1 directly interacts with NGFR (nerve growth factor receptor) in castration-resistant prostate cancer cells (confirmed by molecular docking and Co-IP); TLN1 knockdown upregulates NGFR and suppresses CRPC cell proliferation, migration, invasion, and EMT through modulation of the MAPK and PI3K-AKT signaling pathways. NGFR knockdown reverses the tumor-suppressive effects of TLN1 silencing.\",\n      \"method\": \"Mass spectrometry (serum peptides), Co-immunoprecipitation, molecular docking, transcriptome sequencing, siRNA knockdown, xenograft mouse model, CCK-8/colony formation/wound healing/Transwell assays, Western blot\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP and molecular docking for direct interaction, functional epistasis via rescue experiment, single lab\",\n      \"pmids\": [\"42112334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TLN1 overexpression in cardiac microvascular endothelial cells increases ITGA5 (integrin alpha 5) expression, and ITGA5 knockdown reverses the protective effects of TLN1 overexpression against ox-LDL-induced apoptosis, reduced proliferation, angiogenesis, inflammatory response, and oxidative stress, indicating TLN1 acts upstream of ITGA5 in this pathway.\",\n      \"method\": \"Overexpression and siRNA knockdown in CMVECs, ox-LDL injury model, CCK-8 proliferation assay, apoptosis assay, angiogenesis assay, Western blot\",\n      \"journal\": \"Folia morphologica\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, overexpression/knockdown with functional readouts but no direct binding or interaction assay between TLN1 and ITGA5\",\n      \"pmids\": [\"37144848\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TLN1 loss-of-function (shRNA) enhances docetaxel chemosensitivity selectively in triple-negative breast cancer cell lines and reduces tumor mass in mammary fat pad xenograft models after chemotherapy, establishing TLN1 as a modulator of chemotherapy response in TNBC.\",\n      \"method\": \"RNAi screen (328 shRNA cell lines), validation in 8 breast cancer cell lines, mouse xenograft model\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide RNAi screen with in vitro and in vivo validation across multiple cell lines, single lab\",\n      \"pmids\": [\"23479679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TLN1 is a direct target of miR-9 in ovarian serous carcinoma; miR-9 overexpression inhibits TLN1-dependent FAK/AKT pathway activation, and TLN1 knockdown phenocopies miR-9 overexpression in suppressing cell proliferation, migration, and invasion.\",\n      \"method\": \"Exogenous miR-9 transfection, TLN1 siRNA knockdown, Western blot for FAK/AKT pathway, functional proliferation/migration/invasion assays (implied direct target validation)\",\n      \"journal\": \"International journal of molecular medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, phenotypic rescue and pathway Western blots but direct miR-9/TLN1 targeting experiment details are incomplete in abstract\",\n      \"pmids\": [\"23722670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TLN1 is subject to lysine malonylation (Kmal) post-translational modification, identified by affinity enrichment and LC-MS/MS in peripheral blood mononuclear cells from ESRD patients, implicating this modification in TLN1 function in the Rap1 and platelet activation signaling pathways.\",\n      \"method\": \"Affinity enrichment, LC-MS/MS proteomics (malonylome profiling)\",\n      \"journal\": \"Proteome science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single proteomic study identifying the modification site, no functional validation of the malonylation on TLN1 activity\",\n      \"pmids\": [\"37833721\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TLN1 (talin-1) is a mechanosensitive focal adhesion scaffold that links integrins (particularly β1 integrin) to the actin cytoskeleton; it contains force-dependent R1-R13 switch domains whose opening threshold is modulated by a cancer-enriched alternative exon (exon 17b) regulated by TGF-β/SMAD3 signaling, enhancing vinculin binding and altering adhesion dynamics; TLN1 protein stability is controlled by SMURF1-mediated ubiquitination (antagonized by EMP1), its transcription is co-operatively regulated by FLI1 and GATA1 in megakaryocytes, and it signals downstream through FAK-AKT, MAPK, and ERK pathways to drive integrin activation, invadopodia formation, trans-endothelial migration, and EMT in cancer and vascular contexts.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TLN1 (talin-1) is a mechanosensitive focal adhesion scaffold that physically links integrins to the actin cytoskeleton and converts adhesion engagement into intracellular signaling that drives cell migration, invasion, and epithelial-mesenchymal transition [#1, #0]. Its force-responsive architecture is tunable: a cancer-enriched alternative exon (exon 17b) inserts 17 residues into the R1-R2 linker, lowering the force threshold for opening the R1-R2 mechanosensitive switch domains, enhancing vinculin binding and altering adhesion dynamics, with this isoform switch under TGF-\\u03b2/SMAD3 control [#0]. At focal adhesions TLN1 engages \\u03b21 integrin to nucleate dynamic adhesions and activate FAK-AKT signaling and EMT, and disrupting the TLN1\\u2013\\u03b21 integrin interface suppresses tumor migration and metastasis [#1]. Beyond \\u03b21 integrin, TLN1 partners with FAK in a Cdk5/TLN1/FAK axis whose scaffold (rather than catalytic) function supports invadopodia formation and trans-endothelial migration [#2], and it associates with additional membrane partners including LAYN and NGFR to feed FAK-AKT, MAPK/ERK, and PI3K-AKT signaling in cancer contexts [#5, #6]. TLN1 abundance is set both transcriptionally\\u2014cooperative FLI1/GATA1 regulation through an intronic FLI1-binding region is required for normal talin-1 levels in megakaryocytes, with FLI1 variants causing ~88% loss of platelet talin-1 and platelet dysfunction [#4]\\u2014and post-translationally, via SMURF1-mediated ubiquitination and degradation that EMP1 antagonizes by competing for the TLN1 binding site [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Established TLN1 as a functionally important, druggable dependency in cancer rather than a passive structural protein, by showing its loss alters therapeutic response.\",\n      \"evidence\": \"shRNA RNAi screen across breast cancer cell lines with xenograft validation showing TLN1 loss enhances docetaxel chemosensitivity in TNBC\",\n      \"pmids\": [\"23479679\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not define the molecular mechanism linking TLN1 to chemoresponse\", \"Restricted to TNBC; generalizability unaddressed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connected TLN1 to upstream regulatory control and downstream effector signaling by placing it in a miR-9/TLN1/FAK-AKT axis controlling proliferation and invasion.\",\n      \"evidence\": \"miR-9 transfection and TLN1 siRNA with FAK/AKT Western blots and migration/invasion assays in ovarian serous carcinoma\",\n      \"pmids\": [\"23722670\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Direct miR-9 targeting of the TLN1 transcript not rigorously demonstrated in the abstract\", \"Single cancer type, single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Separated TLN1's scaffold function from phosphorylation-dependent signaling, showing the structural role in a Cdk5/TLN1/FAK axis is what enables invadopodia and vascular breaching.\",\n      \"evidence\": \"3D microfluidic vascularized models with siRNA knockdown of TLN1 and FAK, chemical FAK inhibition, and in vivo lung colonization\",\n      \"pmids\": [\"34333365\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular detail of how Cdk5 couples to the TLN1/FAK complex unresolved\", \"Direct TLN1\\u2013FAK binding interface not mapped\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined the TLN1\\u2013\\u03b21 integrin interface as a targetable node driving adhesion dynamics and metastasis, moving from correlation to a chemically tractable mechanism.\",\n      \"evidence\": \"siRNA knockdown, computational small-molecule screen against the TLN1\\u2013\\u03b21 binding interface (C67399), focal adhesion imaging, and TNBC xenograft metastasis\",\n      \"pmids\": [\"35285795\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specificity of C67399 for the TLN1\\u2013integrin interface in vivo not fully characterized\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed how TLN1 mechanosensitivity is tuned in disease via a cancer-enriched alternative exon that lowers the force threshold for switch-domain opening, linking splicing to adhesion mechanics.\",\n      \"evidence\": \"Splicing analysis, in vitro force-extension and vinculin binding assays, live adhesion/motility imaging, and TGF-\\u03b2/SMAD3 pathway perturbation\",\n      \"pmids\": [\"36880935\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo prevalence and functional consequence of exon 17b across tumor types not established\", \"Mechanism by which SMAD3 directs the splice choice not detailed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended TLN1 function into vascular endothelial protection by placing it upstream of ITGA5, broadening its role beyond migration.\",\n      \"evidence\": \"Overexpression/knockdown of TLN1 and ITGA5 in cardiac microvascular endothelial cells under ox-LDL injury with functional rescue\",\n      \"pmids\": [\"37144848\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct TLN1\\u2013ITGA5 binding assay\", \"Mechanism by which TLN1 raises ITGA5 expression unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Catalogued a novel post-translational modification (lysine malonylation) on TLN1, raising a regulatory layer relevant to platelet activation signaling.\",\n      \"evidence\": \"Affinity enrichment and LC-MS/MS malonylome profiling of PBMCs from ESRD patients\",\n      \"pmids\": [\"37833721\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No functional validation that malonylation alters TLN1 activity\", \"Single proteomic descriptive study\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified LAYN as a direct TLN1 partner within a transcription-to-adhesion axis (CREB1-LAYN-TLN1-\\u03b21 integrin) driving cholangiocarcinoma metastasis via MAPK/ERK signaling.\",\n      \"evidence\": \"Co-IP for LAYN\\u2013TLN1, ChIP for CREB1, siRNA, Western blot, Transwell assays, and nude mouse metastasis model\",\n      \"pmids\": [\"39286102\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reciprocal/structural mapping of the LAYN\\u2013TLN1 interface absent\", \"Single lab and cancer type\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined transcriptional control of TLN1 abundance, showing cooperative FLI1/GATA1 regulation is required for talin-1 expression in megakaryocytes and links FLI1 variants to platelet disease.\",\n      \"evidence\": \"scRNA-seq of patient megakaryocytes, ChIP-seq, luciferase reporters, FLI1 variant transcription assays, and Western blot of patient platelets\",\n      \"pmids\": [\"39744817\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether reduced talin-1 alone accounts for the platelet phenotype not isolated\", \"GATA1 contribution to the intronic element not separately dissected\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established post-translational control of TLN1 stability through SMURF1-mediated ubiquitination and its antagonism by EMP1, linking TLN1 turnover to hepatic stellate cell activation.\",\n      \"evidence\": \"Rodent MASLD-IRI models, EMP1 silencing, Co-IP mapping EMP1\\u2013SMURF1\\u2013TLN1 competition, and Western blot for ubiquitination and FAK phosphorylation\",\n      \"pmids\": [\"41284206\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SMURF1 ubiquitination site(s) on TLN1 not mapped\", \"Single lab; competitive binding inferred from Co-IP\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Added NGFR as a direct TLN1 partner in castration-resistant prostate cancer, with epistasis showing TLN1 acts through NGFR to drive proliferation, invasion, and EMT via MAPK and PI3K-AKT.\",\n      \"evidence\": \"Mass spectrometry, Co-IP, molecular docking, transcriptome sequencing, siRNA, xenograft, and functional assays with NGFR rescue\",\n      \"pmids\": [\"42112334\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of the TLN1\\u2013NGFR interaction not resolved beyond docking\", \"Single lab and tumor context\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the distinct regulatory layers on TLN1 \\u2014 splice-isoform mechanotuning, transcriptional control, ubiquitin-dependent turnover, and malonylation \\u2014 are integrated to set adhesion behavior in a given cell type remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified model coupling TLN1 abundance, modification state, and isoform identity to adhesion output\", \"Cross-talk among SMURF1/EMP1, FLI1/GATA1, and SMAD3 inputs not tested together\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005925\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 5, 6]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 5, 6]},\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [4, 10]}\n    ],\n    \"complexes\": [\"focal adhesion\"],\n    \"partners\": [\"ITGB1\", \"FAK\", \"vinculin\", \"LAYN\", \"NGFR\", \"SMURF1\", \"EMP1\", \"ITGA5\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}