Hepsin regulates TGF? signaling via fibronectin proteolysis

ABSTRACT: Transforming growth factor beta (TGF?) 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 TGF? activity by acting as a storage compartment of latent TGF?, but how TGF? 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 TGF? signaling through the release of latent TGF? from the ECM-storage compartment. Mammary glands in hepsin CRISPR knock-out mice showed reduced TGF? signaling and increased epithelial branching, accompanied by increased levels of fibronectin and latent TGF?1, while overexpression of hepsin in mammary tumors increased TGF? signaling. Cell-free and cell-based experiments showed that hepsin is capable of direct proteolytic cleavage of fibronectin but not latent TGF? and, importantly, that the ability of hepsin to activate TGF? signaling is dependent on fibronectin. Altogether, this study demonstrates a role for hepsin as a regulator of the TGF? pathway in the mammary gland via a novel mechanism involving proteolytic downmodulation of fibronectin.

SUBMITTER: Denis Belitskin 

PROVIDER: S-SCDT-EMBOR-2021-52532V1 | biostudies-other |

REPOSITORIES: biostudies-other