Proteolytic regulation and functional repertoire of soluble ADAM17

ADAM17 is a membrane-bound zinc metalloprotease. It is one of the major sheddases that plays a key role in cellular events like tumorigenesis, inflammation, and cell homeostasis by cleaving ectodomains of membrane-bound proteins such as Tumor necrosis factor-α, Interleukin-6 receptor, and Epidermal growth factor receptor ligands. The inactivated rhomboid proteins (iRhoms) 1 and 2 are indispensable for the trafficking and maturation of ADAM17. Additionally, iRhom1 and 2 are involved in substrate recruitment and specificity on the cell surface for membrane-bound ADAM17. Intriguingly, the proteolytic release of the ADAM17 ectodomain (sADAM17) has recently been addressed, with ADAM8 identified as its sheddase. In this thesis, the proteolytic release of sADAM17 was analyzed via in vitro experiments for endogenous and overexpressed, human and murine ADAM17. Further, the role of iRhom1/2 was explored in ADAM17 shedding and its subsequent maturation and activation. In contrast to membrane-bound ADAM17, sADAM17 matures and activates independently of iRhoms, attaining necessary PTMs. The second part of the thesis addressed functional aspects of sADAM17. A persisting shedding capacity of sADAM17 was detected in vitro against EGFR ligands in a substrate-dependent manner, compared to its membrane-bound counterpart. The shedding of AREG and HB-EGF by sADAM17 appeared to be independent of iRhom1/2, unlike that by membrane-bound ADAM17. Finally, the application of N-terminomics in TNBC cells revealed further substrates and potential roles of sADAM17 in extracellular matrix remodeling and subsequent invasion and metastasis. These findings indicate a novel regulatory mechanism of sADAM17, demonstrating its ability to process substrates near the plasma membrane and beyond. These insights enhance understanding of the molecular mechanisms underlying sADAM17-mediated cellular functions and disease pathways, while highlighting its part-time sheddase properties.

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