{"gene":"LTBP1","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":1996,"finding":"The third 8-Cys repeat (TB3) of LTBP-1 binds covalently to the LAP region of TGF-β1 via disulfide bond exchange, with Cys33 of β1-LAP identified as the required cysteine; the N-terminal region of LTBP-1 (first ~400 amino acids) associates covalently with the ECM.","method":"Co-expression of TGF-β1 and LTBP-1 fragments in mammalian cells followed by immunoblotting of secreted fusion protein complexes; site-directed mutagenesis of LAP cysteine","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with domain mapping and mutagenesis in a single rigorous study","pmids":["8617200"],"is_preprint":false},{"year":2003,"finding":"The NMR solution structure of TB3 from LTBP1 revealed that a two-residue insertion relative to fibrillin-1 TB domains increases solvent accessibility of the Cys2–Cys6 disulfide bond, identifying it as the disulfide exchanged with LAP; a ring of negatively charged residues surrounds this bond and likely facilitates complex formation.","method":"Solution NMR structure determination; site-directed mutagenesis; NMR perturbation studies","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 — NMR structure combined with mutagenesis and functional validation","pmids":["14607119"],"is_preprint":false},{"year":2001,"finding":"LTBP-1 contains three distinct ECM-binding domains corresponding to the first (hybrid), second, and fourth 8-Cys domains of LTBP-1S; each binds independently and covalently to fibroblast ECM and can competitively inhibit incorporation of native LTBP-1.","method":"Recombinant fragment production in mammalian expression system; binding assays to fibroblast ECM; competitive inhibition; sodium deoxycholate resistance assays","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1–2 — multiple overlapping recombinant fragments tested with competition assays and two cell types","pmids":["11112702"],"is_preprint":false},{"year":2005,"finding":"A 24-amino-acid sequence in the hinge domain of LTBP-1 is required for integrin αvβ6-mediated activation of latent TGF-β; this activation also requires fibronectin and its receptor α5β1 for proper matrix incorporation of the hinge-containing LTBP-1 polypeptide.","method":"Binding assays of LTBP-1 polypeptides to fibronectin; fibronectin-null and α5β1-null cell lines; latent TGF-β activation assays","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 — reciprocal binding assays with null-cell genetic validation and multiple orthogonal methods","pmids":["16260650"],"is_preprint":false},{"year":2008,"finding":"MT1-MMP (MMP14) releases latent TGF-β1 from endothelial cell ECM by proteolytically processing ECM-bound LTBP-1; this process requires PKC and ERK1/2 signaling and is not replicated by secreted MMPs or the uPA/plasmin system.","method":"Lentiviral shRNA gene silencing of MT1-MMP; metalloproteinase inhibitors TIMP-2 and TIMP-3; phorbol ester activation of endothelial cells; immunoblotting of released LTBP-1 fragments","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 2 — genetic silencing plus pharmacological inhibition with specificity controls","pmids":["18602101"],"is_preprint":false},{"year":2007,"finding":"The C-terminal region of LTBP-1 binds to the amino-terminal region of fibrillin-1 at the same or overlapping site as LTBP-2; competitive binding studies with C-terminal fragments of LTBP-1 and LTBP-2 demonstrated mutual competition for fibrillin-1 binding.","method":"Solid-phase binding assays; overlay blotting; competitive binding experiments with recombinant C-terminal fragments; EDTA/Ca2+ chelation to probe Ca2+-dependence","journal":"Matrix biology","confidence":"Medium","confidence_rationale":"Tier 2 — solid-phase and competitive binding with recombinant proteins, single lab","pmids":["17293099"],"is_preprint":false},{"year":2019,"finding":"PTPS binds LTBP1 following AMPK-mediated phosphorylation of PTPS at Thr58 under hypoxia; within the resulting PTPS/iNOS/LTBP1 complex, iNOS-catalyzed S-nitrosylation of LTBP1 targets it for proteasome-dependent degradation, thereby reducing TGF-β secretion and maintaining tumor cell proliferation.","method":"Co-immunoprecipitation; mass spectrometry identification of S-nitrosylation site; proteasome inhibitor experiments; iNOS inhibition; AMPK pathway analysis; cell growth assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 — Co-IP with multiple pathway perturbations and modification-site identification in a single rigorous study","pmids":["31628042"],"is_preprint":false},{"year":2021,"finding":"POGLUT2 and POGLUT3 O-glucosylate multiple EGF repeats on LTBP1; loss of POGLUT2 and/or POGLUT3 reduces secretion of fibrillin-1, suggesting these modifications promote proper folding and secretion of LTBP1-associated proteins.","method":"Mass spectrometry analysis of O-glucosylation sites; POGLUT2 and POGLUT3 knockout HEK293T cells; in vitro secretion assays with recombinant N-terminal fibrillin-1 fragment","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — MS site identification combined with KO cell secretion assays","pmids":["34411563"],"is_preprint":false},{"year":2022,"finding":"LTBP1 promotes incorporation of fibrillin-1 and fibrillin-2 into the ECM in a TGF-β-independent manner; this function is differentially exerted by the LTBP1S and LTBP1L isoforms.","method":"In vitro ECM incorporation assays; comparison of LTBP1S and LTBP1L isoform effects; loss-of-function experiments in cell culture","journal":"Matrix biology","confidence":"Medium","confidence_rationale":"Tier 2 — defined cellular phenotype with isoform-specific comparison, single lab","pmids":["35452817"],"is_preprint":false},{"year":2000,"finding":"The conserved N-glycosylation site within the third 8-Cys (TB3) domain of LTBP-1 is modified with complex and hybrid glycans in insect cells; glycosylation is proposed to influence 8-Cys domain protein-protein interactions based on structural modeling.","method":"MALDI-TOF mass spectrometry; enzymatic glycan analysis; recombinant CR3 expression in Sf9 and High-Five insect cells","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 — mass spectrometry characterization of modification, but functional consequence inferred by modeling","pmids":["10677208"],"is_preprint":false},{"year":2002,"finding":"Xenopus LTBP-1, expressed in the organizer and dorsal mesoderm, potentiates activin and nodal signaling in animal cap assays without requiring covalent association with activin, indicating LTBP-1 can enhance TGF-β superfamily member activity through non-covalent extracellular interactions.","method":"Xenopus animal cap assays; conditioned medium addition experiments; whole-mount in situ hybridization for spatial expression","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 — functional gain-of-function assay in Xenopus with conditioned medium controls","pmids":["12142025"],"is_preprint":false},{"year":2008,"finding":"AhR represses Ltbp-1 transcription by recruiting HDAC2 to the Ltbp-1 promoter, maintaining histone hypoacetylation and preventing pCREB1(Ser133) binding; in AhR-null cells, loss of HDAC2 recruitment allows pCREB1 binding and Ltbp-1 overexpression.","method":"Chromatin immunoprecipitation (ChIP); siRNA knockdown of HDAC2; reporter gene assays; AhR overexpression; site-directed mutagenesis of promoter elements","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 2 — ChIP combined with RNAi and reporter assays providing multiple orthogonal lines of evidence","pmids":["18508077"],"is_preprint":false},{"year":2006,"finding":"LTBP-1 contributes to TGF-β1 activation by promoting activities of plasminogen activators/plasmin and elastase; siRNA knockdown of LTBP-1 reduced active TGF-β1 levels and these protease activities, while restoring MMP-2 activity.","method":"siRNA knockdown of LTBP-1 in AhR-null MEF; TGF-β1 ELISA; protease activity assays; TGF-β neutralizing antibody; specific protease inhibitors","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — siRNA with multiple protease activity readouts and pharmacological controls","pmids":["16187295"],"is_preprint":false},{"year":2014,"finding":"NMR spectroscopic analysis of the LTBP1 C-terminus revealed that the four structured domains (cbEGF14, TB3, EGF3, cbEGF15) adopt canonical folds with flexible interdomain linkers, except for the EGF3-cbEGF15 pair which has a well-defined interface; this flexible 'knotted rope' structure may facilitate matrix interactions and protease accessibility for TGF-β activation.","method":"NMR spectroscopy of overlapping C-terminal LTBP1 fragments; 15N relaxation studies; bioinformatics structural analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 1 — NMR structure determination, but functional consequences inferred rather than directly tested","pmids":["24489852"],"is_preprint":false},{"year":2024,"finding":"Lactate released from PLLA is taken up by fibroblasts via MCT1 and promotes LTBP1 lactylation at lysine 752 through a KAT8-dependent mechanism, which increases collagen I and collagen III protein levels.","method":"Pan-lysine lactylation measurement; KAT8 inhibition/knockdown; MCT1 transport inhibition; western blotting of LTBP1 lactylation and collagen expression in fibroblasts","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2 — PTM site identified with writer enzyme (KAT8) and transporter implicated, single lab","pmids":["39102921"],"is_preprint":false},{"year":2025,"finding":"LTA4H induces HNRNPA1 phosphorylation, enhancing LTA4H-HNRNPA1 interaction and functionally inhibiting HNRNPA1-mediated Ltbp1 mRNA maturation and processing in the nucleus, thereby reducing LTBP1 expression and downstream TGF-β secretion.","method":"Co-immunoprecipitation of LTA4H and HNRNPA1; phosphorylation analysis; nuclear fractionation; mRNA processing assays; LTBP1 knockdown and overexpression in HCC cells","journal":"Cell reports. Medicine","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP with phosphorylation analysis and functional mRNA processing readout, single lab","pmids":["40056904"],"is_preprint":false},{"year":2024,"finding":"OPG, fibulin-1, and LTBP1 colocalize in the interstitial ECM of lung tissue; proximity ligation assays confirmed fibulin-1 bridges OPG and LTBP1 in close proximity, suggesting a trimeric complex in the extracellular environment.","method":"Immunofluorescence colocalization; proximity ligation assay (PLA); fibulin-1 knockout mice showing reduced OPG deposition","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 — proximity ligation and colocalization, preprint, single lab","pmids":[],"is_preprint":true}],"current_model":"LTBP1 is a multi-domain extracellular matrix glycoprotein that covalently links latent TGF-β1 (via disulfide exchange at its third 8-Cys/TB3 domain) to the ECM, where it sequesters the growth factor; it promotes TGF-β activation through fibronectin- and integrin αvβ6-dependent mechanisms and MT1-MMP-mediated proteolysis of its hinge region, facilitates fibrillin-1/2 incorporation into microfibrils independently of TGF-β, undergoes post-translational modifications including S-nitrosylation (driving proteasomal degradation via the PTPS/iNOS complex), O-glucosylation on EGF repeats by POGLUT2/3, and lactylation at K752 by KAT8 (promoting collagen synthesis), and its transcription is epigenetically repressed by AhR-recruited HDAC2 at its promoter."},"narrative":{"teleology":[{"year":1996,"claim":"Established how LTBP1 physically links latent TGF-β1 to the ECM: the TB3 domain forms a disulfide bond with Cys33 of β1-LAP, while the N-terminal ~400 residues anchor independently and covalently to the matrix.","evidence":"Co-expression of TGF-β1 and LTBP1 domain fragments in mammalian cells with site-directed mutagenesis of LAP cysteines","pmids":["8617200"],"confidence":"High","gaps":["Identity of the LTBP1 cysteine participating in exchange was not pinpointed","ECM-anchoring receptor/ligand on the N-terminal side not identified"]},{"year":2001,"claim":"Resolved a long-standing question of how many ECM-attachment sites exist: three independent 8-Cys domains each bind covalently to fibroblast ECM and compete with native LTBP1 for incorporation, explaining multivalent matrix anchoring.","evidence":"Recombinant fragment binding and competition assays against fibroblast ECM with deoxycholate resistance controls","pmids":["11112702"],"confidence":"High","gaps":["Specific ECM receptors for each binding domain not identified","Relative contribution of each domain in vivo unknown"]},{"year":2003,"claim":"Identified the structural basis for LAP recognition: NMR of TB3 showed a two-residue insertion exposes the Cys2–Cys6 disulfide for exchange, surrounded by a negatively charged surface facilitating complex formation.","evidence":"Solution NMR structure of TB3 domain combined with mutagenesis and NMR perturbation studies","pmids":["14607119"],"confidence":"High","gaps":["No co-structure of TB3 bound to LAP obtained","Role of the charged ring in binding kinetics not quantified"]},{"year":2005,"claim":"Defined the integrin-dependent TGF-β activation mechanism: a 24-amino-acid hinge sequence in LTBP1 is required for αvβ6-mediated activation, which additionally depends on fibronectin/α5β1 for proper matrix incorporation.","evidence":"Binding assays with LTBP1 polypeptides plus fibronectin-null and α5β1-null cell lines and latent TGF-β activation assays","pmids":["16260650"],"confidence":"High","gaps":["Whether mechanical force through integrin directly opens the complex or requires cofactors was not resolved","Hinge–integrin direct interaction not demonstrated"]},{"year":2007,"claim":"Showed that LTBP1 connects the latent TGF-β complex to fibrillin-1 microfibrils through its C-terminal region, competing with LTBP2 for the same N-terminal fibrillin-1 binding site.","evidence":"Solid-phase and competitive binding assays with recombinant C-terminal fragments of LTBP1 and LTBP2","pmids":["17293099"],"confidence":"Medium","gaps":["In vivo validation of competitive binding with LTBP2 lacking","Stoichiometry and affinity constants not precisely determined"]},{"year":2008,"claim":"Identified two parallel regulatory axes: MT1-MMP proteolytically releases latent TGF-β1 from ECM-bound LTBP1 via PKC/ERK signaling in endothelial cells, while AhR represses Ltbp1 transcription by recruiting HDAC2 to maintain promoter hypoacetylation.","evidence":"shRNA silencing of MT1-MMP with TIMP controls in endothelial cells; ChIP, siRNA, and reporter assays for AhR/HDAC2 at Ltbp1 promoter in MEFs","pmids":["18602101","18508077"],"confidence":"High","gaps":["MT1-MMP cleavage site on LTBP1 not mapped","Whether AhR/HDAC2 regulation is conserved in human tissues not shown"]},{"year":2019,"claim":"Uncovered a post-translational degradation pathway: under hypoxia, AMPK-phosphorylated PTPS recruits iNOS to S-nitrosylate LTBP1, directing it to proteasomal degradation and thereby limiting TGF-β secretion in tumor cells.","evidence":"Co-immunoprecipitation, mass spectrometry of S-nitrosylation site, proteasome and iNOS inhibitor experiments in tumor cells","pmids":["31628042"],"confidence":"High","gaps":["Exact S-nitrosylation site(s) on LTBP1 and whether modification is reversible not fully mapped","In vivo tumor relevance demonstrated in limited models"]},{"year":2021,"claim":"Showed that EGF repeats on LTBP1 are O-glucosylated by POGLUT2/3, modifications that promote fibrillin-1 secretion, connecting LTBP1 post-translational processing to microfibril assembly.","evidence":"Mass spectrometry site identification; POGLUT2/3 knockout HEK293T cells with fibrillin-1 secretion assays","pmids":["34411563"],"confidence":"High","gaps":["Effect of O-glucosylation on LTBP1 folding versus secretion not separated","Whether LTBP1 itself requires O-glucosylation for its own secretion not tested"]},{"year":2022,"claim":"Established a TGF-β-independent function: LTBP1 promotes fibrillin-1 and fibrillin-2 ECM incorporation with isoform-specific differences between LTBP1S and LTBP1L.","evidence":"In vitro ECM incorporation assays comparing LTBP1 isoforms with loss-of-function experiments","pmids":["35452817"],"confidence":"Medium","gaps":["Molecular basis for isoform-specific activity not determined","In vivo microfibril phenotype of LTBP1 isoform-selective loss not characterized"]},{"year":2024,"claim":"Identified lactylation as a new regulatory modification: lactate-driven, KAT8-dependent lactylation of LTBP1 at K752 enhances collagen I/III expression in fibroblasts, linking metabolic signaling to ECM remodeling through LTBP1.","evidence":"KAT8 inhibition/knockdown, MCT1 transport inhibition, western blotting of lactylation and collagen levels in fibroblasts","pmids":["39102921"],"confidence":"Medium","gaps":["Whether lactylation alters TGF-β binding or activation is unknown","Mechanism by which lactylated LTBP1 upregulates collagen not defined"]},{"year":2025,"claim":"Revealed an mRNA-level regulatory circuit: LTA4H induces HNRNPA1 phosphorylation, disrupting HNRNPA1-mediated Ltbp1 mRNA maturation and reducing LTBP1 protein and downstream TGF-β secretion in hepatocellular carcinoma.","evidence":"Co-immunoprecipitation, phosphorylation analysis, nuclear fractionation, and mRNA processing assays in HCC cells","pmids":["40056904"],"confidence":"Medium","gaps":["Specific mRNA processing step affected (splicing, export, or stability) not fully delineated","Whether this pathway operates outside HCC is unknown"]},{"year":null,"claim":"Key open questions include: the precise structural mechanism by which integrin-mediated mechanical force on the LTBP1 hinge releases TGF-β from LAP; the in vivo consequences of individual post-translational modifications (S-nitrosylation, O-glucosylation, lactylation) on ECM homeostasis; and whether LTBP1's TGF-β-independent role in microfibril assembly is essential for connective tissue integrity.","evidence":"","pmids":[],"confidence":"High","gaps":["No co-structure of LTBP1–LAP complex exists","In vivo genetic dissection of individual LTBP1 ECM-binding domains not performed","Relative physiological importance of proteolytic versus integrin-mediated TGF-β activation through LTBP1 is unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,2,5,8]}],"localization":[{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[0,2,3,5,8,16]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,2,3,10]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,3,4,6,12]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[2,5,7,8,14]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[6,7,9,14]}],"complexes":["Large latent TGF-β1 complex (LLC)","PTPS/iNOS/LTBP1 complex"],"partners":["TGFB1","FBN1","FBN2","MMP14","ITGAV","PTPS","NOS2","KAT8"],"other_free_text":[]},"mechanistic_narrative":"LTBP1 is a multi-domain extracellular matrix glycoprotein that functions as the principal scaffold for sequestering, localizing, and regulating the activation of latent TGF-β1 in the ECM. Its third 8-Cys/TB3 domain covalently binds the latency-associated peptide (LAP) of TGF-β1 through disulfide exchange at an exposed Cys2–Cys6 bond, while three independent ECM-binding domains and a C-terminal fibrillin-1-interacting region anchor the complex to microfibrils [PMID:8617200, PMID:14607119, PMID:11112702, PMID:17293099]. Activation of sequestered TGF-β1 proceeds through integrin αvβ6- and fibronectin-dependent mechanical mechanisms requiring a 24-amino-acid hinge sequence, and through MT1-MMP-mediated proteolytic cleavage of the hinge region [PMID:16260650, PMID:18602101]. Beyond TGF-β regulation, LTBP1 promotes TGF-β-independent incorporation of fibrillin-1 and fibrillin-2 into the ECM, undergoes regulatory post-translational modifications including S-nitrosylation (targeting it for proteasomal degradation via a PTPS/iNOS complex), O-glucosylation by POGLUT2/3, and KAT8-dependent lactylation at K752 that promotes collagen synthesis, and its transcription is repressed by AhR-recruited HDAC2 [PMID:35452817, PMID:31628042, PMID:34411563, PMID:39102921, PMID:18508077]."},"prefetch_data":{"uniprot":{"accession":"Q14766","full_name":"Latent-transforming growth factor beta-binding protein 1","aliases":["Transforming growth factor beta-1-binding protein 1","TGF-beta1-BP-1"],"length_aa":1721,"mass_kda":186.8,"function":"Key regulator of transforming growth factor beta (TGFB1, TGFB2 and TGFB3) that controls TGF-beta activation by maintaining it in a latent state during storage in extracellular space (PubMed:2022183, PubMed:8617200, PubMed:8939931). Associates specifically via disulfide bonds with the Latency-associated peptide (LAP), which is the regulatory chain of TGF-beta, and regulates integrin-dependent activation of TGF-beta (PubMed:15184403, PubMed:8617200, PubMed:8939931). Outcompeted by LRRC32/GARP for binding to LAP regulatory chain of TGF-beta (PubMed:22278742)","subcellular_location":"Secreted; Secreted, extracellular space, extracellular matrix","url":"https://www.uniprot.org/uniprotkb/Q14766/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LTBP1","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/LTBP1","total_profiled":1310},"omim":[{"mim_id":"619451","title":"CUTIS LAXA, AUTOSOMAL RECESSIVE, TYPE IIE; ARCL2E","url":"https://www.omim.org/entry/619451"},{"mim_id":"617135","title":"L3MBTL HISTONE METHYL-LYSINE-BINDING PROTEIN 4; L3MBTL4","url":"https://www.omim.org/entry/617135"},{"mim_id":"612277","title":"ADAMTS-LIKE PROTEIN 2; ADAMTSL2","url":"https://www.omim.org/entry/612277"},{"mim_id":"604710","title":"LATENT TRANSFORMING GROWTH FACTOR-BETA-BINDING PROTEIN 4; LTBP4","url":"https://www.omim.org/entry/604710"},{"mim_id":"602091","title":"LATENT TRANSFORMING GROWTH FACTOR-BETA-BINDING PROTEIN 2; LTBP2","url":"https://www.omim.org/entry/602091"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"blood vessel","ntpm":382.8}],"url":"https://www.proteinatlas.org/search/LTBP1"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q14766","domains":[{"cath_id":"-","chopping":"351-386_401-435_485-501","consensus_level":"medium","plddt":61.2778,"start":351,"end":501},{"cath_id":"3.90.290.10","chopping":"673-738","consensus_level":"medium","plddt":80.5455,"start":673,"end":738},{"cath_id":"3.90.290.10","chopping":"1348-1410_1424-1469","consensus_level":"high","plddt":82.6774,"start":1348,"end":1469},{"cath_id":"3.90.290.10","chopping":"1523-1583","consensus_level":"medium","plddt":79.5797,"start":1523,"end":1583}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14766","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q14766-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q14766-F1-predicted_aligned_error_v6.png","plddt_mean":58.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LTBP1","jax_strain_url":"https://www.jax.org/strain/search?query=LTBP1"},"sequence":{"accession":"Q14766","fasta_url":"https://rest.uniprot.org/uniprotkb/Q14766.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q14766/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14766"}},"corpus_meta":[{"pmid":"8617200","id":"PMC_8617200","title":"Association of the small latent transforming growth factor-beta with an eight cysteine repeat of its binding protein LTBP-1.","date":"1996","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/8617200","citation_count":187,"is_preprint":false},{"pmid":"16260650","id":"PMC_16260650","title":"Fibronectin is required for integrin alphavbeta6-mediated activation of latent TGF-beta complexes containing LTBP-1.","date":"2005","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/16260650","citation_count":144,"is_preprint":false},{"pmid":"18602101","id":"PMC_18602101","title":"MT1-MMP releases latent TGF-beta1 from endothelial cell extracellular matrix via proteolytic processing of LTBP-1.","date":"2008","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/18602101","citation_count":126,"is_preprint":false},{"pmid":"17293099","id":"PMC_17293099","title":"LTBP-2 specifically interacts with the amino-terminal region of fibrillin-1 and competes with LTBP-1 for binding to this microfibrillar protein.","date":"2007","source":"Matrix biology : journal of the International Society for Matrix Biology","url":"https://pubmed.ncbi.nlm.nih.gov/17293099","citation_count":113,"is_preprint":false},{"pmid":"11112702","id":"PMC_11112702","title":"Latent TGF-beta binding protein LTBP-1 contains three potential extracellular matrix interacting domains.","date":"2001","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/11112702","citation_count":87,"is_preprint":false},{"pmid":"9764833","id":"PMC_9764833","title":"The cutaneous microfibrillar apparatus contains latent transforming growth factor-beta binding protein-1 (LTBP-1) and is a repository for latent TGF-beta1.","date":"1998","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/9764833","citation_count":68,"is_preprint":false},{"pmid":"10551816","id":"PMC_10551816","title":"Independent promoters regulate the expression of two amino terminally distinct forms of latent transforming growth factor-beta binding protein-1 (LTBP-1) in a cell type-specific manner.","date":"1999","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10551816","citation_count":46,"is_preprint":false},{"pmid":"14607119","id":"PMC_14607119","title":"Solution structure of the third TB domain from LTBP1 provides insight into assembly of the large latent complex that sequesters latent TGF-beta.","date":"2003","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/14607119","citation_count":45,"is_preprint":false},{"pmid":"31628042","id":"PMC_31628042","title":"PTPS Facilitates Compartmentalized LTBP1 S-Nitrosylation and Promotes Tumor Growth under Hypoxia.","date":"2019","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/31628042","citation_count":44,"is_preprint":false},{"pmid":"25528440","id":"PMC_25528440","title":"Marek's disease virus-encoded analog of microRNA-155 activates the oncogene c-Myc by targeting LTBP1 and suppressing the TGF-β signaling pathway.","date":"2014","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/25528440","citation_count":44,"is_preprint":false},{"pmid":"14762110","id":"PMC_14762110","title":"Overexpression of latent transforming growth factor-beta binding protein 1 (LTBP-1) in dioxin receptor-null mouse embryo fibroblasts.","date":"2004","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/14762110","citation_count":44,"is_preprint":false},{"pmid":"10025676","id":"PMC_10025676","title":"Vitamin D3 metabolites regulate LTBP1 and latent TGF-beta1 expression and latent TGF-beta1 incorporation in the extracellular matrix of chondrocytes.","date":"1999","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10025676","citation_count":43,"is_preprint":false},{"pmid":"32216815","id":"PMC_32216815","title":"LTBP1 promotes esophageal squamous cell carcinoma progression through epithelial-mesenchymal transition and cancer-associated fibroblasts transformation.","date":"2020","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32216815","citation_count":35,"is_preprint":false},{"pmid":"18508077","id":"PMC_18508077","title":"Recruitment of CREB1 and histone deacetylase 2 (HDAC2) to the mouse Ltbp-1 promoter regulates its constitutive expression in a dioxin receptor-dependent manner.","date":"2008","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/18508077","citation_count":33,"is_preprint":false},{"pmid":"39102921","id":"PMC_39102921","title":"Lactate triggers KAT8-mediated LTBP1 lactylation at lysine 752 to promote skin rejuvenation by inducing collagen synthesis in fibroblasts.","date":"2024","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/39102921","citation_count":32,"is_preprint":false},{"pmid":"16187295","id":"PMC_16187295","title":"LTBP-1 blockade in dioxin receptor-null mouse embryo fibroblasts decreases TGF-beta activity: Role of extracellular proteases plasmin and elastase.","date":"2006","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16187295","citation_count":31,"is_preprint":false},{"pmid":"10677208","id":"PMC_10677208","title":"Hybrid and complex glycans are linked to the conserved N-glycosylation site of the third eight-cysteine domain of LTBP-1 in insect cells.","date":"2000","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10677208","citation_count":30,"is_preprint":false},{"pmid":"11376559","id":"PMC_11376559","title":"Overexpression of latent transforming growth factor-beta 1 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fusion protein complexes; site-directed mutagenesis of LAP cysteine\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with domain mapping and mutagenesis in a single rigorous study\",\n      \"pmids\": [\"8617200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The NMR solution structure of TB3 from LTBP1 revealed that a two-residue insertion relative to fibrillin-1 TB domains increases solvent accessibility of the Cys2–Cys6 disulfide bond, identifying it as the disulfide exchanged with LAP; a ring of negatively charged residues surrounds this bond and likely facilitates complex formation.\",\n      \"method\": \"Solution NMR structure determination; site-directed mutagenesis; NMR perturbation studies\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR structure combined with mutagenesis and functional validation\",\n      \"pmids\": [\"14607119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"LTBP-1 contains three distinct ECM-binding domains corresponding to the first (hybrid), second, and fourth 8-Cys domains of LTBP-1S; each binds independently and covalently to fibroblast ECM and can competitively inhibit incorporation of native LTBP-1.\",\n      \"method\": \"Recombinant fragment production in mammalian expression system; binding assays to fibroblast ECM; competitive inhibition; sodium deoxycholate resistance assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple overlapping recombinant fragments tested with competition assays and two cell types\",\n      \"pmids\": [\"11112702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"A 24-amino-acid sequence in the hinge domain of LTBP-1 is required for integrin αvβ6-mediated activation of latent TGF-β; this activation also requires fibronectin and its receptor α5β1 for proper matrix incorporation of the hinge-containing LTBP-1 polypeptide.\",\n      \"method\": \"Binding assays of LTBP-1 polypeptides to fibronectin; fibronectin-null and α5β1-null cell lines; latent TGF-β activation assays\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal binding assays with null-cell genetic validation and multiple orthogonal methods\",\n      \"pmids\": [\"16260650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"MT1-MMP (MMP14) releases latent TGF-β1 from endothelial cell ECM by proteolytically processing ECM-bound LTBP-1; this process requires PKC and ERK1/2 signaling and is not replicated by secreted MMPs or the uPA/plasmin system.\",\n      \"method\": \"Lentiviral shRNA gene silencing of MT1-MMP; metalloproteinase inhibitors TIMP-2 and TIMP-3; phorbol ester activation of endothelial cells; immunoblotting of released LTBP-1 fragments\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic silencing plus pharmacological inhibition with specificity controls\",\n      \"pmids\": [\"18602101\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The C-terminal region of LTBP-1 binds to the amino-terminal region of fibrillin-1 at the same or overlapping site as LTBP-2; competitive binding studies with C-terminal fragments of LTBP-1 and LTBP-2 demonstrated mutual competition for fibrillin-1 binding.\",\n      \"method\": \"Solid-phase binding assays; overlay blotting; competitive binding experiments with recombinant C-terminal fragments; EDTA/Ca2+ chelation to probe Ca2+-dependence\",\n      \"journal\": \"Matrix biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — solid-phase and competitive binding with recombinant proteins, single lab\",\n      \"pmids\": [\"17293099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PTPS binds LTBP1 following AMPK-mediated phosphorylation of PTPS at Thr58 under hypoxia; within the resulting PTPS/iNOS/LTBP1 complex, iNOS-catalyzed S-nitrosylation of LTBP1 targets it for proteasome-dependent degradation, thereby reducing TGF-β secretion and maintaining tumor cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation; mass spectrometry identification of S-nitrosylation site; proteasome inhibitor experiments; iNOS inhibition; AMPK pathway analysis; cell growth assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with multiple pathway perturbations and modification-site identification in a single rigorous study\",\n      \"pmids\": [\"31628042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"POGLUT2 and POGLUT3 O-glucosylate multiple EGF repeats on LTBP1; loss of POGLUT2 and/or POGLUT3 reduces secretion of fibrillin-1, suggesting these modifications promote proper folding and secretion of LTBP1-associated proteins.\",\n      \"method\": \"Mass spectrometry analysis of O-glucosylation sites; POGLUT2 and POGLUT3 knockout HEK293T cells; in vitro secretion assays with recombinant N-terminal fibrillin-1 fragment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — MS site identification combined with KO cell secretion assays\",\n      \"pmids\": [\"34411563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LTBP1 promotes incorporation of fibrillin-1 and fibrillin-2 into the ECM in a TGF-β-independent manner; this function is differentially exerted by the LTBP1S and LTBP1L isoforms.\",\n      \"method\": \"In vitro ECM incorporation assays; comparison of LTBP1S and LTBP1L isoform effects; loss-of-function experiments in cell culture\",\n      \"journal\": \"Matrix biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — defined cellular phenotype with isoform-specific comparison, single lab\",\n      \"pmids\": [\"35452817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The conserved N-glycosylation site within the third 8-Cys (TB3) domain of LTBP-1 is modified with complex and hybrid glycans in insect cells; glycosylation is proposed to influence 8-Cys domain protein-protein interactions based on structural modeling.\",\n      \"method\": \"MALDI-TOF mass spectrometry; enzymatic glycan analysis; recombinant CR3 expression in Sf9 and High-Five insect cells\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — mass spectrometry characterization of modification, but functional consequence inferred by modeling\",\n      \"pmids\": [\"10677208\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Xenopus LTBP-1, expressed in the organizer and dorsal mesoderm, potentiates activin and nodal signaling in animal cap assays without requiring covalent association with activin, indicating LTBP-1 can enhance TGF-β superfamily member activity through non-covalent extracellular interactions.\",\n      \"method\": \"Xenopus animal cap assays; conditioned medium addition experiments; whole-mount in situ hybridization for spatial expression\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional gain-of-function assay in Xenopus with conditioned medium controls\",\n      \"pmids\": [\"12142025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"AhR represses Ltbp-1 transcription by recruiting HDAC2 to the Ltbp-1 promoter, maintaining histone hypoacetylation and preventing pCREB1(Ser133) binding; in AhR-null cells, loss of HDAC2 recruitment allows pCREB1 binding and Ltbp-1 overexpression.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP); siRNA knockdown of HDAC2; reporter gene assays; AhR overexpression; site-directed mutagenesis of promoter elements\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP combined with RNAi and reporter assays providing multiple orthogonal lines of evidence\",\n      \"pmids\": [\"18508077\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"LTBP-1 contributes to TGF-β1 activation by promoting activities of plasminogen activators/plasmin and elastase; siRNA knockdown of LTBP-1 reduced active TGF-β1 levels and these protease activities, while restoring MMP-2 activity.\",\n      \"method\": \"siRNA knockdown of LTBP-1 in AhR-null MEF; TGF-β1 ELISA; protease activity assays; TGF-β neutralizing antibody; specific protease inhibitors\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — siRNA with multiple protease activity readouts and pharmacological controls\",\n      \"pmids\": [\"16187295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"NMR spectroscopic analysis of the LTBP1 C-terminus revealed that the four structured domains (cbEGF14, TB3, EGF3, cbEGF15) adopt canonical folds with flexible interdomain linkers, except for the EGF3-cbEGF15 pair which has a well-defined interface; this flexible 'knotted rope' structure may facilitate matrix interactions and protease accessibility for TGF-β activation.\",\n      \"method\": \"NMR spectroscopy of overlapping C-terminal LTBP1 fragments; 15N relaxation studies; bioinformatics structural analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — NMR structure determination, but functional consequences inferred rather than directly tested\",\n      \"pmids\": [\"24489852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Lactate released from PLLA is taken up by fibroblasts via MCT1 and promotes LTBP1 lactylation at lysine 752 through a KAT8-dependent mechanism, which increases collagen I and collagen III protein levels.\",\n      \"method\": \"Pan-lysine lactylation measurement; KAT8 inhibition/knockdown; MCT1 transport inhibition; western blotting of LTBP1 lactylation and collagen expression in fibroblasts\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — PTM site identified with writer enzyme (KAT8) and transporter implicated, single lab\",\n      \"pmids\": [\"39102921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LTA4H induces HNRNPA1 phosphorylation, enhancing LTA4H-HNRNPA1 interaction and functionally inhibiting HNRNPA1-mediated Ltbp1 mRNA maturation and processing in the nucleus, thereby reducing LTBP1 expression and downstream TGF-β secretion.\",\n      \"method\": \"Co-immunoprecipitation of LTA4H and HNRNPA1; phosphorylation analysis; nuclear fractionation; mRNA processing assays; LTBP1 knockdown and overexpression in HCC cells\",\n      \"journal\": \"Cell reports. Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with phosphorylation analysis and functional mRNA processing readout, single lab\",\n      \"pmids\": [\"40056904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"OPG, fibulin-1, and LTBP1 colocalize in the interstitial ECM of lung tissue; proximity ligation assays confirmed fibulin-1 bridges OPG and LTBP1 in close proximity, suggesting a trimeric complex in the extracellular environment.\",\n      \"method\": \"Immunofluorescence colocalization; proximity ligation assay (PLA); fibulin-1 knockout mice showing reduced OPG deposition\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — proximity ligation and colocalization, preprint, single lab\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"LTBP1 is a multi-domain extracellular matrix glycoprotein that covalently links latent TGF-β1 (via disulfide exchange at its third 8-Cys/TB3 domain) to the ECM, where it sequesters the growth factor; it promotes TGF-β activation through fibronectin- and integrin αvβ6-dependent mechanisms and MT1-MMP-mediated proteolysis of its hinge region, facilitates fibrillin-1/2 incorporation into microfibrils independently of TGF-β, undergoes post-translational modifications including S-nitrosylation (driving proteasomal degradation via the PTPS/iNOS complex), O-glucosylation on EGF repeats by POGLUT2/3, and lactylation at K752 by KAT8 (promoting collagen synthesis), and its transcription is epigenetically repressed by AhR-recruited HDAC2 at its promoter.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"LTBP1 is a multi-domain extracellular matrix glycoprotein that functions as the principal scaffold for sequestering, localizing, and regulating the activation of latent TGF-β1 in the ECM. Its third 8-Cys/TB3 domain covalently binds the latency-associated peptide (LAP) of TGF-β1 through disulfide exchange at an exposed Cys2–Cys6 bond, while three independent ECM-binding domains and a C-terminal fibrillin-1-interacting region anchor the complex to microfibrils [PMID:8617200, PMID:14607119, PMID:11112702, PMID:17293099]. Activation of sequestered TGF-β1 proceeds through integrin αvβ6- and fibronectin-dependent mechanical mechanisms requiring a 24-amino-acid hinge sequence, and through MT1-MMP-mediated proteolytic cleavage of the hinge region [PMID:16260650, PMID:18602101]. Beyond TGF-β regulation, LTBP1 promotes TGF-β-independent incorporation of fibrillin-1 and fibrillin-2 into the ECM, undergoes regulatory post-translational modifications including S-nitrosylation (targeting it for proteasomal degradation via a PTPS/iNOS complex), O-glucosylation by POGLUT2/3, and KAT8-dependent lactylation at K752 that promotes collagen synthesis, and its transcription is repressed by AhR-recruited HDAC2 [PMID:35452817, PMID:31628042, PMID:34411563, PMID:39102921, PMID:18508077].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established how LTBP1 physically links latent TGF-β1 to the ECM: the TB3 domain forms a disulfide bond with Cys33 of β1-LAP, while the N-terminal ~400 residues anchor independently and covalently to the matrix.\",\n      \"evidence\": \"Co-expression of TGF-β1 and LTBP1 domain fragments in mammalian cells with site-directed mutagenesis of LAP cysteines\",\n      \"pmids\": [\"8617200\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the LTBP1 cysteine participating in exchange was not pinpointed\", \"ECM-anchoring receptor/ligand on the N-terminal side not identified\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Resolved a long-standing question of how many ECM-attachment sites exist: three independent 8-Cys domains each bind covalently to fibroblast ECM and compete with native LTBP1 for incorporation, explaining multivalent matrix anchoring.\",\n      \"evidence\": \"Recombinant fragment binding and competition assays against fibroblast ECM with deoxycholate resistance controls\",\n      \"pmids\": [\"11112702\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific ECM receptors for each binding domain not identified\", \"Relative contribution of each domain in vivo unknown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identified the structural basis for LAP recognition: NMR of TB3 showed a two-residue insertion exposes the Cys2–Cys6 disulfide for exchange, surrounded by a negatively charged surface facilitating complex formation.\",\n      \"evidence\": \"Solution NMR structure of TB3 domain combined with mutagenesis and NMR perturbation studies\",\n      \"pmids\": [\"14607119\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No co-structure of TB3 bound to LAP obtained\", \"Role of the charged ring in binding kinetics not quantified\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined the integrin-dependent TGF-β activation mechanism: a 24-amino-acid hinge sequence in LTBP1 is required for αvβ6-mediated activation, which additionally depends on fibronectin/α5β1 for proper matrix incorporation.\",\n      \"evidence\": \"Binding assays with LTBP1 polypeptides plus fibronectin-null and α5β1-null cell lines and latent TGF-β activation assays\",\n      \"pmids\": [\"16260650\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether mechanical force through integrin directly opens the complex or requires cofactors was not resolved\", \"Hinge–integrin direct interaction not demonstrated\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed that LTBP1 connects the latent TGF-β complex to fibrillin-1 microfibrils through its C-terminal region, competing with LTBP2 for the same N-terminal fibrillin-1 binding site.\",\n      \"evidence\": \"Solid-phase and competitive binding assays with recombinant C-terminal fragments of LTBP1 and LTBP2\",\n      \"pmids\": [\"17293099\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo validation of competitive binding with LTBP2 lacking\", \"Stoichiometry and affinity constants not precisely determined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified two parallel regulatory axes: MT1-MMP proteolytically releases latent TGF-β1 from ECM-bound LTBP1 via PKC/ERK signaling in endothelial cells, while AhR represses Ltbp1 transcription by recruiting HDAC2 to maintain promoter hypoacetylation.\",\n      \"evidence\": \"shRNA silencing of MT1-MMP with TIMP controls in endothelial cells; ChIP, siRNA, and reporter assays for AhR/HDAC2 at Ltbp1 promoter in MEFs\",\n      \"pmids\": [\"18602101\", \"18508077\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"MT1-MMP cleavage site on LTBP1 not mapped\", \"Whether AhR/HDAC2 regulation is conserved in human tissues not shown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Uncovered a post-translational degradation pathway: under hypoxia, AMPK-phosphorylated PTPS recruits iNOS to S-nitrosylate LTBP1, directing it to proteasomal degradation and thereby limiting TGF-β secretion in tumor cells.\",\n      \"evidence\": \"Co-immunoprecipitation, mass spectrometry of S-nitrosylation site, proteasome and iNOS inhibitor experiments in tumor cells\",\n      \"pmids\": [\"31628042\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Exact S-nitrosylation site(s) on LTBP1 and whether modification is reversible not fully mapped\", \"In vivo tumor relevance demonstrated in limited models\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed that EGF repeats on LTBP1 are O-glucosylated by POGLUT2/3, modifications that promote fibrillin-1 secretion, connecting LTBP1 post-translational processing to microfibril assembly.\",\n      \"evidence\": \"Mass spectrometry site identification; POGLUT2/3 knockout HEK293T cells with fibrillin-1 secretion assays\",\n      \"pmids\": [\"34411563\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Effect of O-glucosylation on LTBP1 folding versus secretion not separated\", \"Whether LTBP1 itself requires O-glucosylation for its own secretion not tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established a TGF-β-independent function: LTBP1 promotes fibrillin-1 and fibrillin-2 ECM incorporation with isoform-specific differences between LTBP1S and LTBP1L.\",\n      \"evidence\": \"In vitro ECM incorporation assays comparing LTBP1 isoforms with loss-of-function experiments\",\n      \"pmids\": [\"35452817\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis for isoform-specific activity not determined\", \"In vivo microfibril phenotype of LTBP1 isoform-selective loss not characterized\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified lactylation as a new regulatory modification: lactate-driven, KAT8-dependent lactylation of LTBP1 at K752 enhances collagen I/III expression in fibroblasts, linking metabolic signaling to ECM remodeling through LTBP1.\",\n      \"evidence\": \"KAT8 inhibition/knockdown, MCT1 transport inhibition, western blotting of lactylation and collagen levels in fibroblasts\",\n      \"pmids\": [\"39102921\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether lactylation alters TGF-β binding or activation is unknown\", \"Mechanism by which lactylated LTBP1 upregulates collagen not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed an mRNA-level regulatory circuit: LTA4H induces HNRNPA1 phosphorylation, disrupting HNRNPA1-mediated Ltbp1 mRNA maturation and reducing LTBP1 protein and downstream TGF-β secretion in hepatocellular carcinoma.\",\n      \"evidence\": \"Co-immunoprecipitation, phosphorylation analysis, nuclear fractionation, and mRNA processing assays in HCC cells\",\n      \"pmids\": [\"40056904\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific mRNA processing step affected (splicing, export, or stability) not fully delineated\", \"Whether this pathway operates outside HCC is unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include: the precise structural mechanism by which integrin-mediated mechanical force on the LTBP1 hinge releases TGF-β from LAP; the in vivo consequences of individual post-translational modifications (S-nitrosylation, O-glucosylation, lactylation) on ECM homeostasis; and whether LTBP1's TGF-β-independent role in microfibril assembly is essential for connective tissue integrity.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No co-structure of LTBP1–LAP complex exists\", \"In vivo genetic dissection of individual LTBP1 ECM-binding domains not performed\", \"Relative physiological importance of proteolytic versus integrin-mediated TGF-β activation through LTBP1 is unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 2, 5, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [0, 2, 3, 5, 8, 16]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 2, 3, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 3, 4, 6, 12]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [2, 5, 7, 8, 14]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [6, 7, 9, 14]}\n    ],\n    \"complexes\": [\n      \"Large latent TGF-β1 complex (LLC)\",\n      \"PTPS/iNOS/LTBP1 complex\"\n    ],\n    \"partners\": [\n      \"TGFB1\",\n      \"FBN1\",\n      \"FBN2\",\n      \"MMP14\",\n      \"ITGAV\",\n      \"PTPS\",\n      \"NOS2\",\n      \"KAT8\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}