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Hepsin regulates TGFβ signaling via fibronectin proteolysis
Author(s) -
Belitskin Denis,
Pant Shishir,
Munne Pauliina,
Suleymanova Ilida,
Belitškina Kati,
Hongisto HannaAla,
Englund Johanna,
Raatikainen Tiina,
Vasioukhin Valeri,
Klezovitch Olga,
Li Shuo,
Wu Qingyu,
Monni Outi,
Kuure Satu,
Laakonen Pirjo,
Pouwels Jeroen,
Tervonen Topi,
Klefström Juha
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.02255
Subject(s) - fibronectin , extracellular matrix , microbiology and biotechnology , transforming growth factor , signal transduction , transforming growth factor beta , proteolysis , chemistry , biology , biochemistry , enzyme
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 knock‐out 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.