Hepsin regulates TGFβ signaling via fibronectin proteolysis
| العنوان: | Hepsin regulates TGFβ signaling via fibronectin proteolysis |
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| المؤلفون: | Kati Belitškina, Hanna-Ala Hongisto, Jeroen Pouwels, Olga Klezovitch, Outi Monni, Shishir M. Pant, Pirjo Laakkonen, Topi A. Tervonen, Ilida Suleymanova, Valeri Vasioukhin, Johanna Englund, Tiina Raatikainen, Satu Kuure, Shuo Li, Juha Klefström, Denis Belitskin, Qingyu Wu, Pauliina Munne |
| المساهمون: | CAN-PRO - Translational Cancer Medicine Program, Research Programs Unit, HUSLAB, Helsinki Institute of Life Science HiLIFE, Joint Activities, Centre of Excellence in Stem Cell Metabolism, Juha Klefström / Principal Investigator, Department of Oncology, University Management, ATG - Applied Tumor Genomics, STEMM - Stem Cells and Metabolism Research Program, Helsinki Institute of Life Science HiLIFE, Infra, Biosciences, Kidney development, Pirjo Maarit Laakkonen / Principal Investigator |
| المصدر: | EMBO Reports |
| بيانات النشر: | Wiley, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | medicine.medical_treatment, Cell, INVASION, Biochemistry, Extracellular matrix, Mice, 0302 clinical medicine, Transforming Growth Factor beta, Cancer, GENE-EXPRESSION, 0303 health sciences, medicine.diagnostic_test, biology, MICE DEFICIENT, Chemistry, Serine Endopeptidases, Articles, Transmembrane protein, PROSTATE-CANCER, 3. Good health, Cell biology, medicine.anatomical_structure, Cytokine, 030220 oncology & carcinogenesis, hepsin, Biotechnology, Proteolysis, Hepsin, Article, OVARIAN-CANCER, TGFβ, 03 medical and health sciences, breast cancer, fibronectin, TGF beta, MAMMARY-GLAND, TGF beta signaling pathway, Genetics, medicine, Animals, tumor microenvironment, TRANSMEMBRANE SERINE-PROTEASE, CELL, PLASMINOGEN-ACTIVATOR, Molecular Biology, 030304 developmental biology, Tumor microenvironment, GROWTH-FACTOR-BETA, Fibronectins, Fibronectin, biology.protein, 3111 Biomedicine, Cell Adhesion, Polarity & Cytoskeleton |
| الوصف: | Transforming growth factor‐beta (TGFβ) is a multifunctional cytokine with a well‐established role in mammary gland development and both oncogenic and tumor‐suppressive functions. The extracellular matrix (ECM) indirectly regulates TGFβ activity by acting as a storage compartment of latent‐TGFβ, but how TGFβ is released from the ECM via proteolytic mechanisms remains largely unknown. In this study, we demonstrate that hepsin, a type II transmembrane protease overexpressed in 70% of breast tumors, promotes canonical TGFβ signaling through the release of latent‐TGFβ from the ECM storage compartment. Mammary glands in hepsin CRISPR knockout mice showed reduced TGFβ signaling and increased epithelial branching, accompanied by increased levels of fibronectin and latent‐TGFβ1, while overexpression of hepsin in mammary tumors increased TGFβ signaling. Cell‐free and cell‐based experiments showed that hepsin is capable of direct proteolytic cleavage of fibronectin but not latent‐TGFβ and, importantly, that the ability of hepsin to activate TGFβ signaling is dependent on fibronectin. Altogether, this study demonstrates a role for hepsin as a regulator of the TGFβ pathway in the mammary gland via a novel mechanism involving proteolytic downmodulation of fibronectin. TGFβ is released from the ECM compartments of the mammary glands by hepsin mediated proteolytic cleavage of the ECM component fibronectin. |
| تدمد: | 1530-6860 0892-6638 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8f63cdd7f8b5ddc2c5f2d559f76bb69a https://doi.org/10.1096/fasebj.2021.35.s1.02255 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....8f63cdd7f8b5ddc2c5f2d559f76bb69a |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15306860 08926638 |
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