Affinage

LTBP4

Latent-transforming growth factor beta-binding protein 4 · UniProt Q8N2S1

Length
1624 aa
Mass
173.4 kDa
Annotated
2026-04-28
46 papers in source corpus 23 papers cited in narrative 23 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LTBP4 is an extracellular matrix glycoprotein that serves dual functions as a structural scaffold for elastic fiber assembly and as a critical regulator of TGF-beta bioavailability. It sequesters latent TGF-beta in the ECM via its 3rd 8-cysteine repeat domain and is required for TGF-beta activation rather than secretion; loss of LTBP4 paradoxically increases latent TGF-beta secretion while reducing active TGF-beta, leading to compensatory BMP-4 upregulation in the lung (PMID:15466481, PMID:9660815). Two isoforms (LTBP-4L and LTBP-4S), driven by independent promoters with distinct tissue expression and TGF-beta binding properties, undergo conformational extension upon interaction with fibulin-4 (LTBP-4L) or fibulin-5 (LTBP-4S), an N-glycan-dependent process that enhances fibronectin binding and tropoelastin deposition for elastic fiber formation (PMID:31548410, PMID:40608550, PMID:20175115). Recessive loss-of-function mutations in LTBP4 cause a human connective tissue disorder with defective elastic fiber assembly and increased TGF-beta activity across multiple organ systems (PMID:19836010).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1997 Medium

    Establishing LTBP4 as a new member of the LTBP/fibrillin superfamily resolved its modular domain architecture (20 EG modules, 4 TB/8-Cys modules) and predicted it to be a TGF-beta-binding microfibrillar protein.

    Evidence cDNA sequencing and Northern blot showing high cardiac expression

    PMID:9271198

    Open questions at the time
    • No direct demonstration of TGF-beta binding at this stage
    • Protein-level validation not performed
  2. 1998 High

    Demonstrating that LTBP-4 forms disulfide-linked complexes with TGF-beta LAP via its 3rd 8-Cys repeat and is deposited in the ECM established it as a bona fide TGF-beta-sequestering matrix protein.

    Evidence cDNA cloning, immunoblotting, ECM fractionation, and plasmin release assay in human lung fibroblasts

    PMID:9660815

    Open questions at the time
    • Whether LTBP-4 is required for TGF-beta activation versus secretion was unknown
    • In vivo relevance not yet tested
  3. 2001 Medium

    Identification of a splice variant lacking the 3rd 8-Cys repeat revealed a mechanism for uncoupling LTBP4's structural ECM role from TGF-beta sequestration.

    Evidence RT-PCR and expression analysis across cell lines and tissues

    PMID:11683420

    Open questions at the time
    • Functional significance of this variant in vivo was not tested
    • Relative abundance across tissues not quantified at protein level
  4. 2002 High

    Knockout of LTBP-4 in mice produced emphysema, cardiomyopathy, and colorectal cancer with reduced ECM TGF-beta deposition and phospho-Smad2, establishing LTBP4 as essential for both elastic fiber integrity and local TGF-beta signaling in vivo.

    Evidence Gene trap knockout mouse with histology, immunohistochemistry, and phospho-Smad2 immunoblot

    PMID:12208849

    Open questions at the time
    • Mechanism of TGF-beta activation versus secretion not dissected
    • Contribution of individual isoforms unclear
  5. 2004 High

    Using LTBP-4-null fibroblasts resolved that LTBP4 is required for TGF-beta activation (not secretion), and showed that loss of this activation leads to compensatory BMP-4 upregulation — a phenotype rescued by LTBP-4 but not LTBP-1 transfection.

    Evidence TGF-beta bioassay, microarray, and rescue experiments in Ltbp4−/− fibroblasts

    PMID:15466481

    Open questions at the time
    • Molecular mechanism by which LTBP4 promotes TGF-beta activation not defined
    • Whether LTBP-4L or LTBP-4S mediates this effect was not resolved
  6. 2008 High

    Mapping LTBP-4's N-terminal fibronectin-binding and heparin-binding sites, and showing that fibronectin is indispensable for LTBP-4 ECM assembly, established the upstream requirement for fibronectin in LTBP4-mediated TGF-beta regulation.

    Evidence Binding assays, cell adhesion assays, and ECM fractionation in FN−/− fibroblasts

    PMID:18585707

    Open questions at the time
    • Structural basis of the FN–LTBP4 interaction not resolved
    • Whether fibronectin binding differs between LTBP-4L and LTBP-4S not tested
  7. 2009 High

    Isoform-specific (Ltbp4S−/−) knockout and TGF-beta2 neutralization dissected two independent functions of LTBP4 — elastic fiber assembly and TGF-beta regulation — since normalizing TGF-beta signaling rescued septation but not elastogenesis.

    Evidence Ltbp4S−/− mice with TGF-beta2 neutralization and developmental histology

    PMID:19016471

    Open questions at the time
    • Molecular mechanism of the elastogenesis-specific function not identified
    • Whether LTBP-4L compensates partially in LTBP-4S-null lung unclear
  8. 2009 High

    Human recessive LTBP4 mutations causing impaired LTBP4 ECM deposition, increased TGF-beta activity, and defective elastic fibers in multiple organs established LTBP4 as a Mendelian connective tissue disease gene.

    Evidence Patient genetics with functional validation in patient fibroblasts and tissue histology

    PMID:19836010

    Open questions at the time
    • Genotype–phenotype correlation across different mutations not fully mapped
    • Whether residual LTBP-4 function modifies severity unknown
  9. 2010 High

    Characterizing two independent promoters driving LTBP-4L and LTBP-4S with distinct tissue expression, TGF-beta1 complex formation, and ECM incorporation properties explained why different tissues are differentially affected by LTBP4 loss.

    Evidence Northern blot, immunoblotting, ECM fractionation, and promoter analysis

    PMID:20175115

    Open questions at the time
    • Transcriptional regulators of each promoter not identified
    • Post-translational regulation of isoform-specific functions not explored
  10. 2015 High

    Identification of fibulin-4 as a direct LTBP-4 binding partner, with LTBP-4L specifically required for fibulin-4 ECM incorporation, linked the two proteins in a shared elastogenic pathway.

    Evidence Co-immunoprecipitation and comparative ECM analysis in Ltbp4S−/− versus Ltbp4−/− mice

    PMID:25713297

    Open questions at the time
    • Binding domain on LTBP-4 not mapped
    • Whether fibulin-4 reciprocally affects LTBP-4 conformation was unknown
  11. 2016 High

    Compound Ltbp4S−/−;Fibulin-4R/R mutant mice displayed synergistic lethality and elastogenic defects not seen in either single mutant, confirming functional interdependence of LTBP-4 and fibulin-4 in vivo.

    Evidence Compound mutant mouse genetics with survival analysis and histology

    PMID:27585882

    Open questions at the time
    • Whether therapeutic supplementation of either protein can rescue the compound phenotype not tested
  12. 2018 High

    Demonstrating that pro-inflammatory macrophages produce LTBP4-bound latent TGF-beta1 under AMPK regulation, which is then activated by fibro-adipogenic progenitor-derived enzymes to drive collagen deposition, placed LTBP4 at the center of an inflammatory–fibrotic axis in DMD muscle.

    Evidence Macrophage isolation from DMD muscle, AMPK activation with AICAR, ltbp4 knockdown, fibroblast collagen assays, and in vivo pharmacology

    PMID:30463013

    Open questions at the time
    • Identity of the FAP-derived TGF-beta-activating enzymes acting on LTBP4-sequestered complexes not determined
    • Whether this axis operates in non-muscular fibrotic diseases unknown
  13. 2019 High

    Reconstitution experiments revealed that fibulin-4 multimers (not monomers) act as an extracellular chaperone switching LTBP-4L from a compact to an elongated conformation, thereby enhancing its binding to fibronectin and fibrillin-1 and promoting tropoelastin deposition.

    Evidence Recombinant protein reconstitution with biophysical conformational assays, binding assays, and monomer versus multimer comparison

    PMID:31548410

    Open questions at the time
    • Structural details of the compact versus extended states not resolved at atomic level
    • Whether the conformational switch is reversible in vivo not known
  14. 2022 Medium

    Placing LTBP4 downstream of YAP in vascular smooth muscle cells, and showing that LTBP4 silencing abolishes YAP's protective effect against aortic aneurysm, identified a transcriptional regulatory input into LTBP4 expression relevant to vascular disease.

    Evidence VSMC-specific YAP overexpression mouse model with LTBP4 silencing and AAA phenotyping

    PMID:35708897

    Open questions at the time
    • Direct transcriptional regulation of the LTBP4 promoter by YAP not demonstrated
    • Reciprocal LTBP4-to-YAP signaling via TGF-beta creates potential confounding
  15. 2023 Medium

    Linking LTBP4 deficiency to DRP1-dependent mitochondrial fragmentation, reduced bioenergetics, and increased oxidative stress — phenotypes rescued by DRP1 inhibition — revealed an unexpected intracellular consequence of LTBP4 loss beyond canonical ECM functions.

    Evidence LTBP4 knockdown in HK-2 cells and mice with IRI, mitochondrial bioenergetic profiling, and DRP1 inhibitor rescue

    PMID:37232163

    Open questions at the time
    • Whether the mitochondrial phenotype is a direct effect or secondary to altered TGF-beta signaling not resolved
    • Mechanism linking an ECM protein to DRP1 regulation not defined
  16. 2025 High

    Demonstrating that N-linked glycans on LTBP-4L are required for fibulin-4-induced extension, while fibulin-5 glycans drive LTBP-4S extension, defined two parallel glycan-dependent molecular axes (LTBP-4L/fibulin-4 and LTBP-4S/fibulin-5) that synergistically promote elastogenesis.

    Evidence Glycoproteomic analysis, enzymatic glycan removal, biophysical binding assays, recombinant reconstitution, and elastic fiber formation assay

    PMID:40608550

    Open questions at the time
    • Specific glycan sites critical for each interaction not mapped
    • In vivo validation of the dual-axis model not yet performed

Open questions

Synthesis pass · forward-looking unresolved questions
  • The molecular mechanism by which LTBP4 promotes TGF-beta activation (as opposed to mere sequestration) remains undefined, as does the structural basis for the compact-to-extended conformational transition at atomic resolution.
  • No reconstituted TGF-beta activation assay using purified LTBP4
  • Atomic-resolution structure of LTBP-4 in compact versus extended states unavailable
  • How the two isoform-specific elastogenic axes are coordinated in vivo during development is unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 5 GO:0098772 molecular function regulator activity 4
Localization
GO:0031012 extracellular matrix 8 GO:0005576 extracellular region 3
Pathway
R-HSA-162582 Signal Transduction 8 R-HSA-1474244 Extracellular matrix organization 7 R-HSA-1266738 Developmental Biology 3
Partners
ADAMTSL2ELNFBLN4FBLN5FBN1FN1TGFB1
Complex memberships
Latent TGF-beta complex (large latent complex)

Evidence

Reading pass · 23 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 LTBP-4 was identified as a novel member of the LTBP family, secreted from cultured human lung fibroblasts both in a free form and in a disulfide-bound complex with a TGF-beta LAP-like protein; both forms were deposited in the extracellular matrix, and matrix-associated LTBP-4 was susceptible to proteolytic release with plasmin. The 3rd 8-Cys repeat mediates association with TGF-beta.LAP. cDNA cloning, immunoblotting, ECM fractionation, plasmin treatment assay The Journal of biological chemistry High 9660815
1997 LTBP-4 protein structure was determined to consist of 20 EG modules (17 with calcium-binding consensus), 4 TB (8-cysteine) modules, and several proline-rich regions, predicting it to be a microfibrillar protein that binds TGF-beta; it is encoded by a single ~5 kb mRNA highly expressed in heart. cDNA sequencing, Northern blot FEBS letters Medium 9271198
2001 A novel alternatively spliced form of LTBP-4 lacking the 3rd 8-Cys repeat (LTBP-4delta8-Cys3rd) was identified; this isoform does not bind TGF-beta, providing a mechanism to decrease TGF-beta deposition without altering structural ECM functions. RT-PCR, expression analysis in cell lines and tissues Journal of cell science Medium 11683420
2002 Disruption of LTBP-4 in mice results in severe pulmonary emphysema, cardiomyopathy, and colorectal cancer associated with defects in elastic fiber structure, reduced TGF-beta deposition in the extracellular space, reduced phospho-Smad2, overexpression of c-myc, and uncontrolled epithelial cell proliferation, establishing LTBP-4 as both a structural ECM component and a local regulator of TGF-beta tissue deposition and signaling. Gene trap knockout mouse model, histology, immunohistochemistry, phospho-Smad2 immunoblot, ECM analysis Genes & development High 12208849
2004 LTBP-4-deficient lung fibroblasts produce decreased active TGF-beta but increased secretion of latent TGF-beta, demonstrating LTBP-4 is required for TGF-beta activation (not secretion); loss of LTBP-4-mediated TGF-beta1 activation leads to enhanced BMP-4 signaling and decreased gremlin expression in the lung, a phenotype rescued by LTBP-4 transfection but not LTBP-1 transfection, and restored to wild-type by active TGF-beta1 treatment. Fibroblast cultures from LTBP-4-/- mice, TGF-beta bioassay, microarray, transfection rescue, cytokine treatment The Journal of cell biology High 15466481
2008 LTBP-4 possesses heparin-binding activity particularly in its N-terminal region; LTBP-4 binds directly to fibronectin (FN) through N-terminal sites, and FN is indispensable for ECM assembly of LTBP-4. In FN-/- fibroblasts, LTBP-mediated ECM targeting was disturbed and TGF-beta activity was increased. LTBP-4 C-terminal domain supports fibroblast adhesion, and heparin reduces both FN binding and cell adhesion. Heparin-affinity assay, pulldown/binding assay, cell adhesion assay, FN-/- fibroblasts, ECM fractionation, TGF-beta activity assay Experimental cell research High 18585707
2009 LTBP-4S null mice show defects in elastogenesis visible as early as E14.5 in alveolar walls, blood vessel media, and airway epithelium; the air-sac septation defect is associated with excessive TGF-beta2 signaling and is reversed by lowering TGF-beta2 levels, while normalization of TGF-beta signaling does not rescue elastogenesis, demonstrating two independent functions of LTBP-4: regulation of elastic fiber assembly and regulation of TGF-beta levels in lungs. Ltbp4S-/- mouse model, histology, TGF-beta2 neutralization, developmental stage analysis Journal of cellular physiology High 19016471
2009 Recessive loss-of-function mutations in LTBP4 cause impaired synthesis and lack of deposition of LTBP4 into the ECM, resulting in increased TGF-beta activity in cultured fibroblasts and defective elastic fiber assembly in multiple human organ systems, demonstrating that LTBP4 couples TGF-beta signaling and ECM assembly. Human genetics (patient mutations), cell culture from patient fibroblasts, TGF-beta activity assay, ECM analysis, histology American journal of human genetics High 19836010
2010 LTBP-4L and LTBP-4S isoforms are regulated by two independent promoters with tissue-specific expression (liver expresses mainly LTBP-4L, lung and small intestine mainly LTBP-4S). During secretion, LTBP-4L complexes with TGF-beta1 while most LTBP-4S is secreted free. LTBP-4S is incorporated into the ECM while full-length LTBP-4L is not readily detectable in ECM. Northern blot, immunoblotting, ECM fractionation, promoter analysis, cell culture Journal of cellular physiology High 20175115
2013 IAAM haplotype fibroblasts exposed to TGF-beta display reduced phospho-SMAD signaling compared to VTTT haplotype fibroblasts, consistent with LTBP4's role as a regulator of TGF-beta; LTBP4 nonsynonymous coding variants (V194I, T787A, T820A, T1140M) influence age at loss of ambulation in DMD patients. Patient fibroblast TGF-beta stimulation assay, phospho-SMAD immunoblot, clinical cohort genotyping Annals of neurology Medium 23440719
2015 Inactivation of both LTBP-4 isoforms (Ltbp4-/-) in mice revealed that LTBP-4L is specifically required for incorporation of fibulin-4 into the ECM. Fibulin-4 was identified as a novel interaction partner of both LTBP-4 isoforms by co-immunoprecipitation. In Ltbp4S-/- mice (expressing only LTBP-4L), fibulin-4 ECM incorporation was normal, but was defective in Ltbp4-/- mice. Ltbp4-/- mouse model, co-immunoprecipitation, ECM fractionation, comparative analysis of isoform-specific knockout mice Disease models & mechanisms High 25713297
2016 Genetic epistasis in Ltbp4S-/-;Fibulin-4R/R compound mice showed severely impaired elastogenesis, defective alveolar septation, fragmented elastic lamellae, and aortic aneurysm formation not seen in single mutants alone, establishing a functional interaction between Ltbp-4L and fibulin-4 as a crucial requirement for survival and elastogenesis in vivo. Compound mutant mouse genetics, histology, survival analysis Disease models & mechanisms High 27585882
2016 LTBP4 induces Pdgfrβ signaling by inhibiting the antioxidant Nrf2/Keap1 pathway in a TGF-beta-dependent manner; Ltbp4S-/- mice have defective Pdgfrβ signaling contributing to pulmonary emphysema. Ltbp4S-/- mouse model, gene expression analysis, pathway inhibition/activation experiments Matrix biology Medium 27645114
2017 Three interacting mechanisms contribute to alveolar septation defects in Ltbp4-/- lungs: absence of intact elastic fiber network, reduced angiogenesis, and upregulation of TGF-beta activity resulting in profibrotic processes. Ltbp4-/- mouse lung analysis, histology, angiogenesis assays, TGF-beta signaling readouts American journal of physiology. Lung cellular and molecular physiology Medium 28684544
2018 Pro-inflammatory Ly6Cpos macrophages in DMD muscle exhibit high LTBP4 expression, producing elevated latent-TGF-beta1; AMPK activation decreases ltbp4 expression in these macrophages, reducing latent-TGF-beta1 production and fibrosis. Fibro-adipogenic progenitors provide TGF-beta-activating enzymes that act on LTBP4-sequestered TGF-beta1 to produce collagen from fibroblasts, establishing an AMPK-LTBP4 axis controlling TGF-beta1 production and fibrosis in DMD. Mouse and human DMD muscle analysis, macrophage isolation, AMPK activation (AICAR treatment), ltbp4 knockdown, fibroblast collagen assays, in vivo pharmacological inhibition Cell reports High 30463013
2018 Long-range regulatory variants at the LTBP4 locus (tagged by rs710160 on chr19) are associated with prolonged ambulation in DMD, with chromatin interaction data indicating these SNPs regulate LTBP4 expression; THBS1 (thrombospondin-1) was identified as an activator of TGF-beta signaling by direct binding to LTBP4. GWAS, gene expression databases, chromatin interaction analysis Annals of neurology Low 30014611
2019 Fibulin-4 induces a conformational switch in LTBP-4L from a compact to an elongated structure; this conformational change is induced only by fibulin-4 multimers (not monomers) through increased avidity, and results in enhanced LTBP-4L binding to fibronectin and fibrillin-1, increased LTBP-4L assembly, and promotion of tropoelastin deposition onto elongated LTBP-4L. Fibulin-4 acts as a molecular extracellular chaperone for LTBP-4L. Biophysical conformational assays, binding assays (fibronectin, fibrillin-1, tropoelastin), recombinant protein reconstitution, fibulin-4 monomer vs multimer comparison Proceedings of the National Academy of Sciences of the United States of America High 31548410
2021 LTBP4 deficiency (Ltbp4S-/- mice) leads to aggravated tubular interstitial fibrosis after unilateral ureteral obstruction; LTBP4 overexpression in proximal tubule cells stimulates angiogenesis via VEGFA upregulation and VEGFR activation in endothelial cells. LTBP4-deficient mice show aberrant angiogenesis, abnormal mitochondrial morphology, and enhanced oxidative stress. Ltbp4S-/- mouse UUO model, LTBP4 overexpression in HK-2 cells, transcriptomic analysis, tube formation assay, mitochondrial morphology analysis Cell death & disease Medium 34645813
2021 Aberrant interaction between mutated ADAMTSL2 and LTBP4 upregulates TGF-beta signaling in human fibroblasts; variant pairs in ADAMTSL2-LTBP4 affect the protein-protein interaction between these two molecules. Exome sequencing, Co-IP/interaction assay in human fibroblasts, TGF-beta signaling readout Gene Medium 34958866
2022 YAP overexpression in vascular smooth muscle cells promotes LTBP4 expression; silencing LTBP4 abolishes the protective role of YAP against abdominal aortic aneurysm formation, placing LTBP4 downstream of YAP in elastic fiber assembly in VSMCs. VSMC-specific YAP overexpression mouse model, LTBP4 silencing in vivo, AAA experimental model, histology Journal of cardiovascular translational research Medium 35708897
2022 LTBP4 knockdown in melanoma cells increases the percentage of active TGF-beta1 secreted; active TGF-beta1 inhibits YAP1 phosphorylation and induces YAP1 nuclear translocation, reducing Hippo signaling targets CTGF, Cyr61, and Birc5. LTBP4 overexpression activates the Hippo pathway via increased YAP1 phosphorylation and nuclear-cytoplasmic translocation, suppressing proliferation and metastasis. LTBP4 KD/OE in melanoma cells, ELISA for active TGF-beta1, immunofluorescence, Western blot, luciferase reporter, nude mouse tumor formation Frontiers in cell and developmental biology Medium 35252214
2023 LTBP4 deficiency in mice and HK-2 cells increases mitochondrial fragmentation (DRP1-dependent), decreases ATP production, reduces mitochondrial respiration and glycolysis, increases oxidative stress, and reduces angiogenesis after ischemia-reperfusion injury. Inhibition of DRP1-dependent mitochondrial fission ameliorated inflammation, oxidative stress, and fibrosis in LTBP4-deficient mice. Ltbp4 KD mice, IRI model, LTBP4 KD HK-2 cells, mitochondrial function assays (bioenergetics), DRP1 inhibitor treatment, angiogenesis assays with conditioned media Circulation research Medium 37232163
2025 N-linked glycans of LTBP-4L (but not fibulin-4) are critical for fibulin-4-mediated conformational extension of LTBP-4L; fibulin-5 strongly interacts with and induces conformational extension of LTBP-4S, requiring N-linked glycans of fibulin-5, leading to enhanced fibronectin binding, increased LTBP-4S deposition, and doubled elastic fiber formation. Two distinct molecular axes were defined: LTBP-4L/fibulin-4 and LTBP-4S/fibulin-5, with synergistic effects on elastogenesis. Glycoproteomic analysis, enzymatic glycan removal, biophysical binding assays, recombinant protein reconstitution, elastic fiber formation assay The FEBS journal High 40608550

Source papers

Stage 0 corpus · 46 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Disruption of the gene encoding the latent transforming growth factor-beta binding protein 4 (LTBP-4) causes abnormal lung development, cardiomyopathy, and colorectal cancer. Genes & development 205 12208849
2013 LTBP4 genotype predicts age of ambulatory loss in Duchenne muscular dystrophy. Annals of neurology 202 23440719
2018 AMPK Activation Regulates LTBP4-Dependent TGF-β1 Secretion by Pro-inflammatory Macrophages and Controls Fibrosis in Duchenne Muscular Dystrophy. Cell reports 178 30463013
2009 Mutations in LTBP4 cause a syndrome of impaired pulmonary, gastrointestinal, genitourinary, musculoskeletal, and dermal development. American journal of human genetics 122 19836010
1998 Identification and characterization of a new latent transforming growth factor-beta-binding protein, LTBP-4. The Journal of biological chemistry 113 9660815
2014 Validation of genetic modifiers for Duchenne muscular dystrophy: a multicentre study assessing SPP1 and LTBP4 variants. Journal of neurology, neurosurgery, and psychiatry 78 25476005
1997 Sequence and expression of a novel member (LTBP-4) of the family of latent transforming growth factor-beta binding proteins. FEBS letters 65 9271198
2004 Disruption of LTBP-4 function reduces TGF-beta activation and enhances BMP-4 signaling in the lung. The Journal of cell biology 63 15466481
2008 Fibronectin and heparin binding domains of latent TGF-beta binding protein (LTBP)-4 mediate matrix targeting and cell adhesion. Experimental cell research 55 18585707
2009 Dual functions for LTBP in lung development: LTBP-4 independently modulates elastogenesis and TGF-beta activity. Journal of cellular physiology 54 19016471
2018 Long-range genomic regulators of THBS1 and LTBP4 modify disease severity in duchenne muscular dystrophy. Annals of neurology 42 30014611
2015 Modeling autosomal recessive cutis laxa type 1C in mice reveals distinct functions for Ltbp-4 isoforms. Disease models & mechanisms 39 25713297
2021 The pan HDAC inhibitor Givinostat improves muscle function and histological parameters in two Duchenne muscular dystrophy murine models expressing different haplotypes of the LTBP4 gene. Skeletal muscle 38 34294164
2010 The combined expression pattern of BMP2, LTBP4, and DERL1 discriminates malignant from benign canine mammary tumors. Veterinary pathology 38 20375427
2021 LTBP4 in Health and Disease. Genes 34 34071145
2018 Non-Glycanated Biglycan and LTBP4: Leveraging the extracellular matrix for Duchenne Muscular Dystrophy therapeutics. Matrix biology : journal of the International Society for Matrix Biology 32 29481844
2010 Independent regulation of short and long forms of latent TGF-beta binding protein (LTBP)-4 in cultured fibroblasts and human tissues. Journal of cellular physiology 32 20175115
2019 Fibulin-4 exerts a dual role in LTBP-4L-mediated matrix assembly and function. Proceedings of the National Academy of Sciences of the United States of America 28 31548410
2001 Novel non-TGF-beta-binding splice variant of LTBP-4 in human cells and tissues provides means to decrease TGF-beta deposition. Journal of cell science 24 11683420
2023 LTBP4 Protects Against Renal Fibrosis via Mitochondrial and Vascular Impacts. Circulation research 22 37232163
2021 LTBP4 affects renal fibrosis by influencing angiogenesis and altering mitochondrial structure. Cell death & disease 22 34645813
2016 Function of Ltbp-4L and fibulin-4 in survival and elastogenesis in mice. Disease models & mechanisms 22 27585882
2011 Latent transforming growth factor binding protein 4 (LTBP4) is downregulated in mouse and human DCIS and mammary carcinomas. Cellular oncology (Dordrecht, Netherlands) 21 21468687
2017 Role of LTBP4 in alveolarization, angiogenesis, and fibrosis in lungs. American journal of physiology. Lung cellular and molecular physiology 18 28684544
2007 Latent transforming growth factor binding protein 4 (LTBP-4) is downregulated in human mammary adenocarcinomas in vitro and in vivo. APMIS : acta pathologica, microbiologica, et immunologica Scandinavica 18 17550376
2009 Downregulation of transforming growth factor β (TGFβ) and latent TGFβ binding protein (LTBP)-4 expression in late stage canine mammary tumours. Veterinary journal (London, England : 1997) 16 19836277
2022 Disruption of LTBP4 Inhibition-Induced TGFβ1 Activation Promoted Cell Proliferation and Metastasis in Skin Melanoma by Inhibiting the Activation of the Hippo-YAP1 Signaling Pathway. Frontiers in cell and developmental biology 14 35252214
2019 Clinical and molecular characterization of an 18-month-old infant with autosomal recessive cutis laxa type 1C due to a novel LTBP4 pathogenic variant, and literature review. Molecular genetics & genomic medicine 11 31115174
2016 Ltbp4 regulates Pdgfrβ expression via TGFβ-dependent modulation of Nrf2 transcription factor function. Matrix biology : journal of the International Society for Matrix Biology 11 27645114
2018 DMD mutation and LTBP4 haplotype do not predict onset of left ventricular dysfunction in Duchenne muscular dystrophy. Cardiology in the young 9 29766838
2022 LTBP4, SPP1, and CD40 Variants: Genetic Modifiers of Duchenne Muscular Dystrophy Analyzed in Serbian Patients. Genes 8 36011296
2021 Aberrant interaction between mutated ADAMTSL2 and LTBP4 is associated with adolescent idiopathic scoliosis. Gene 8 34958866
2020 Disruption of LTBP4 Induced Activated TGFβ1, Immunosuppression Signal and Promoted Pulmonary Metastasis in Hepatocellular Carcinoma. OncoTargets and therapy 8 32764991
2022 Specific Overexpression of YAP in Vascular Smooth Muscle Attenuated Abdominal Aortic Aneurysm Formation by Activating Elastic Fiber Assembly via LTBP4. Journal of cardiovascular translational research 4 35708897
2020 Two novel compound heterozygous variants of LTBP4 in a Chinese infant with cutis laxa type IC and a review of the related literature. BMC medical genomics 4 33302946
2022 Autosomal recessive cutis laxa type 1C with a homozygous LTBP4 splicing variant: a case report and update of literature. Molecular biology reports 3 35445908
2022 First report of a short in-frame biallelic deletion removing part of the EGF-like domain calcium-binding motif in LTBP4 and causing autosomal recessive cutis laxa type 1C. American journal of medical genetics. Part A 3 35972031
2019 Identification of a Novel 19-bp Deletion Mutation in LTBP4 Using Exome Sequencing in Two Siblings with Autosomal Recessive Cutis Laxa Type 1C. Journal of pediatric genetics 3 32341818
2024 The IAAM LTBP4 Haplotype is Protective Against Dystrophin-Deficient Cardiomyopathy. Journal of neuromuscular diseases 2 38363615
2025 Constitutional epimutations in LTBP4, a component of the TGF-β signaling, and in BRCA1, as potential drivers of early-onset colorectal cancer. Clinical epigenetics 1 41194282
2024 Novel indel variation of LTBP4 gene associates with risk of sudden cardiac death in Chinese populations with coronary artery disease. Legal medicine (Tokyo, Japan) 1 38547642
2024 Epigenetic identification of LTBP4 as a putative tumor suppressor in breast cancer. Epigenomics 1 39193795
2025 Impact of N-linked glycans on the dual short fibulin/LTBP-4 axes regulating elastogenesis. The FEBS journal 0 40608550
2025 Deleterious variants in LTBP4 are associated with severe pediatric sepsis. Pediatric research 0 41076474
2025 Fibulin-5 promotes fibroblast activation through LTBP-4 to improve the pathogenesis of hemorrhoids. BMC gastroenterology 0 41388516
2022 Association of polymorphisms rs2303729, rs10880, and rs1131620 of LTBP4 with sarcopenia in elderly patients with type 2 diabetes mellitus. Annals of human biology 0 36524797