Latent transforming growth factor binding protein 4 regulates transforming growth factor beta receptor stability
| Autor: | Chi-Ting Su, Christine Jung, Branka Dabovic, Chih-Kang Chiang, Elaine C. Davis, Zsolt Urban, Jenq-Wen Huang, Suneeta Madan-Khetarpal, Elizabeth C. Lawrence, Kara L. Levine |
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| Rok vydání: | 2015 |
| Předmět: |
Male
Receptor Transforming Growth Factor-beta Type I Down-Regulation Smad2 Protein Protein Serine-Threonine Kinases Biology Cutis Laxa Mice Growth factor receptor TGF beta signaling pathway Genetics Animals Humans Immunoprecipitation Phosphorylation Molecular Biology Cells Cultured Genetics (clinical) Mice Knockout Receptor Transforming Growth Factor-beta Type II Articles General Medicine Transforming growth factor beta Fibroblasts Molecular biology Endocytosis Disease Models Animal Latent TGF-beta binding protein Transforming growth factor beta binding Latent TGF-beta Binding Proteins Case-Control Studies Mutation biology.protein Female Signal transduction Receptors Transforming Growth Factor beta Signal Transduction Transforming growth factor |
| Zdroj: | Human Molecular Genetics. 24:4024-4036 |
| ISSN: | 1460-2083 0964-6906 |
| DOI: | 10.1093/hmg/ddv139 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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