ArticleHuman molecular genetics2015
Latent transforming growth factor binding protein 4 regulates transforming growth factor beta receptor stability.
Article in Human molecular genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers, 1 of them a synthesis that pooled it.
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Who cites it
23 citing papers in PubMed, 1 synthesis or guideline pooled it, 37 citations in OpenAlex.
- Genomic and transcriptomic analyses of aortic stenosis enhance therapeutic target discovery and disease prediction.Nature genetics · 2026Pooled it
- Latent transforming growth factor beta binding protein 4: A regulator of mitochondrial function in acute kidney injury.Aging cell · 2023Review
- Crosstalk with lung fibroblasts shapes the growth and therapeutic response of mesothelioma cells.Cell death & disease · 2023Article
- 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 · 2022Review
- Autosomal recessive cutis laxa type 1C with a homozygous LTBP4 splicing variant: a case report and update of literature.Molecular biology reports · 2022Review
- Elastic Fibre Proteins in Elastogenesis and Wound Healing.International journal of molecular sciences · 2022Review
- Fetal Immunomodulatory Environment Following Cartilage Injury-The Key to CARTILAGE Regeneration?International journal of molecular sciences · 2021Article
- LTBP4 affects renal fibrosis by influencing angiogenesis and altering mitochondrial structure.Cell death & disease · 2021Article
- Bi-allelic premature truncating variants in LTBP1 cause cutis laxa syndrome.American journal of human genetics · 2021Article
- LTBP4 in Health and Disease.Genes · 2021Review
- Autosomal Recessive Cutis Laxa 1C Mutations Disrupt the Structure and Interactions of Latent TGFβ Binding Protein-4.Frontiers in genetics · 2021Article
- 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 · 2021Article
- Clinical and Molecular Delineation of Cutis Laxa Syndromes: Paradigms for Homeostasis.Advances in experimental medicine and biology · 2021Review
- 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 · 2020Review
- Genetic modifiers and phenotypic variability in neuromuscular disorders.Journal of applied genetics · 2020Review
- Overview of the Pulmonary Manifestations in Patients with Autosomal Recessive Cutis Laxa Type IC.Pediatric allergy, immunology, and pulmonology · 2020Article
- Transcriptomic Analysis of Human Mesenchymal Stem Cell Therapy in Incontinent Rat Injured Urethra.Tissue engineering. Part A · 2020Article
- Identification of a Novel 19-bp Deletion Mutation inJournal of pediatric genetics · 2020Article
- 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 · 2019Review
- HBx-related long non-coding RNA MALAT1 promotes cell metastasis via up-regulating LTBP3 in hepatocellular carcinoma.American journal of cancer research · 2017Article
Corrections and comments
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Authors and funding
10 authors at 6 institutions in 4 countries.
Funding
Abstract
Mutations in the gene for the latent transforming growth factor beta binding protein 4 (LTBP4) cause autosomal recessive cutis laxa type 1C. To understand the molecular disease mechanisms of this disease, we investigated the impact of LTBP4 loss on transforming growth factor beta (TGFβ) signaling. Despite elevated extracellular TGFβ activity, downstream signaling molecules of the TGFβ pathway, including pSMAD2 and pERK, were down-regulated in LTBP4 mutant human dermal fibroblasts. In addition, TGFβ receptors 1 and 2 (TGFBR1 and TGFBR2) were reduced at the protein but not at the ribonucleic acid level. Treatment with exogenous TGFβ1 led to an initially rapid increase in SMAD2 phosphorylation followed by a sustained depression of phosphorylation and receptor abundance. In mutant cells TGFBR1 was co-localized with lysosomes. Treatment with a TGFBR1 kinase inhibitor, endocytosis inhibitors or a lysosome inhibitor, normalized the levels of TGFBR1 and TGFBR2. Co-immunoprecipitation demonstrated a molecular interaction between LTBP4 and TGFBR2. Knockdown of LTBP4 reduced TGFβ receptor abundance and signaling in normal cells and supplementation of recombinant LTBP4 enhanced these measures in mutant cells. In a mouse model of Ltbp4 deficiency, reduced TGFβ signaling and receptor levels were normalized upon TGFBR1 kinase inhibitor treatment. Our results show that LTBP4 interacts with TGFBR2 and stabilizes TGFβ receptors by preventing their endocytosis and lysosomal degradation in a ligand-dependent and receptor kinase activity-dependent manner. These findings identify LTBP4 as a key molecule required for the stability of the TGFβ receptor complex, and a new mechanism by which the extracellular matrix regulates cytokine receptor signaling.
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