TMEFF2 shedding is regulated by oxidative stress and mediated by ADAMs and transmembrane serine proteases implicated in prostate cancer

Gaweł-Bęben, Katarzyna; Ali, Nazim; Ellis, Vincent; Velasco, Gloria; Poghosyan, Zaruhi; Ager, Ann; Knäuper, Vera

Abstract

TMEFF2 is a type I transmembrane protein with two follistatin (FS) and one EGF-like domain over-expressed in prostate cancer; however its biological role in prostate cancer development and progression remains unclear, which may, at least in part, be explained by its proteolytic processing. The extracellular part of TMEFF2 (TMEFF2-ECD) is cleaved by ADAM17 and the membrane-retained fragment is further processed by the gamma-secretase complex. TMEFF2 shedding is increased with cell crowding, a condition associated with the tumour microenvironment, which was mediated by oxidative stress signalling, requiring jun-kinase (JNK) activation. Moreover, we have identified that TMEFF2 is also a novel substrate for other proteases implicated in prostate cancer, including two ADAMs (ADAM9 and ADAM12) and the type II transmembrane serine proteinases (TTSPs) matriptase-1 and hepsin. Whereas cleavage by ADAM9 and ADAM12 generates previously identified TMEFF2-ECD, proteolytic processing by matriptase-1 and hepsin produced TMEFF2 fragments, composed of TMEFF2-ECD or FS and/or EGF-like domains as well as novel membrane retained fragments. Differential TMEFF2 processing from a single transmembrane protein may be a general mechanism to modulate transmembrane protein levels and domains, dependent on the repertoire of ADAMs or TTSPs expressed by the target cell.

Citation

Gaweł-Bęben, K., Ali, N., Ellis, V., Velasco, G., Poghosyan, Z., Ager, A., & Knäuper, V. (2017). TMEFF2 shedding is regulated by oxidative stress and mediated by ADAMs and transmembrane serine proteases implicated in prostate cancer. Cell Biology International, 42(3), 273 - 280. https://doi.org/10.1002/cbin.10832

• Acceptance Date: Jul 26, 2017
• Publication Date: Aug 1, 2017
• Publicly Available Date: May 30, 2023
• Journal: Cell Biology International
• Print ISSN: 1065-6995
• Publisher: Wiley
• Volume: 42
• Issue: 3
• Pages: 273 - 280
• DOI: https://doi.org/10.1002/cbin.10832
• Publisher URL: https://onlinelibrary.wiley.com/doi/10.1002/cbin.10832