論文 - 詳細
| RRC ID | 65884 |
|---|---|
| 著者 | Seo T, Sakon T, Nakazawa S, Nishioka A, Watanabe K, Matsumoto K, Akasaka M, Shioi N, Sawada H, Araki S. |
| タイトル | Haemorrhagic snake venom metalloproteases and human ADAMs cleave LRP5/6, which disrupts cell-cell adhesions in vitro and induces haemorrhage in vivo. |
| ジャーナル | FEBS J |
| Abstract |
Snake venom metalloproteases (SVMPs) are members of the a disintegrin and metalloprotease (ADAM) family of proteins, as they possess similar domains. SVMPs are known to elicit snake venom-induced haemorrhage; however, the target proteins and cleavage sites are not known. In this work, we identified a target protein of vascular apoptosis-inducing protein 1 (VAP1), an SVMP, relevant to its ability to induce haemorrhage. VAP1 disrupted cell-cell adhesions by relocating VE-cadherin and γ-catenin from the cell-cell junction to the cytosol, without inducing proteolysis of VE-cadherin. The Wnt receptors low-density lipoprotein receptor-related proteins 5 and 6 (LRP5/6) are known to promote catenin relocation, and are rendered constitutively active in Wnt signalling by truncation. Thus, we examined whether VAP1 cleaves LRP5/6 to induce catenin relocation. Indeed, we found that VAP1 cleaved the extracellular region of LRP6 and LRP5. This cleavage removes four inhibitory β-propeller structures, resulting in activation of LRP5/6. Recombinant human ADAM8 and ADAM12 also cleaved LRP6 at the same site. An antibody against a peptide including the LRP6-cleavage site inhibited VAP1-induced VE-cadherin relocation and disruption of cell-cell adhesions in cultured cells, and blocked haemorrhage in mice in vivo. Intriguingly, animals resistant to the effects of haemorrhagic snake venom express variants of LRP5/6 that lack the VAP1-cleavage site, or low-density lipoprotein receptor domain class A domains involved in formation of the constitutively active form. The results validate LRP5/6 as physiological targets of ADAMs. Furthermore, they indicate that SVMP-induced cleavage of LRP5/6 causes disruption of cell-cell adhesion and haemorrhage, potentially opening new avenues for the treatment of snake bites. |
| 巻・号 | 284(11) |
| ページ | 1657-1671 |
| 公開日 | 2017-6-1 |
| DOI | 10.1111/febs.14066 |
| PMID | 28425175 |
| MeSH | ADAM Proteins / metabolism* ADAM Proteins / pharmacology ADAM12 Protein / metabolism ADAM12 Protein / pharmacology Amino Acid Sequence Animals Antibodies, Neutralizing / pharmacology Apoptosis Regulatory Proteins / metabolism* Cell Adhesion / drug effects Cell Adhesion / physiology Crotalid Venoms / metabolism* Drug Resistance Fibrinogen / metabolism Fibronectins / metabolism HeLa Cells Hemorrhage / chemically induced* Human Umbilical Vein Endothelial Cells Humans Hydrophobic and Hydrophilic Interactions Low Density Lipoprotein Receptor-Related Protein-5 / chemistry Low Density Lipoprotein Receptor-Related Protein-5 / physiology* Low Density Lipoprotein Receptor-Related Protein-6 / chemistry Low Density Lipoprotein Receptor-Related Protein-6 / physiology* Male Membrane Proteins / metabolism Membrane Proteins / pharmacology Metalloendopeptidases / metabolism* Mice Models, Molecular Molecular Docking Simulation Protein Domains Protein Structure, Secondary / drug effects Recombinant Proteins / metabolism Sequence Alignment Sequence Homology, Amino Acid Species Specificity Vertebrates / metabolism Wnt Signaling Pathway / drug effects Wnt Signaling Pathway / physiology |
| IF | 4.392 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | News |
| 各媒体での言及数の合計 | 7 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | HeLa |