Immunomodulatory role of metalloproteinase ADAM17 in tumor development

Abstract

ADAM17 is a member of the a disintegrin and metalloproteinase (ADAM) family of transmembrane proteases involved in the shedding of some cell membrane proteins and regulating various signaling pathways. More than 90 substrates are regulated by ADAM17, some of which are closely relevant to tumor formation and development. Besides, ADAM17 is also responsible for immune regulation and its substrate-mediated signal transduction. Recently, ADAM17 has been considered as a major target for the treatment of tumors and yet its immunomodulatory roles and mechanisms remain unclear. In this paper, we summarized the recent understanding of structure and several regulatory roles of ADAM17. Importantly, we highlighted the immunomodulatory roles of ADAM17 in tumor development, as well as small molecule inhibitors and monoclonal antibodies targeting ADAM17.

Keywords: ADAM17; immune response; inflammation; shedding activity; tumor microenvironment.

Figure 1

Molecular structure of the ADAM17 protein. (A) Sequence and structure of ADAM17. ADAM17 protein mainly comprises five extracellular domains, a transmembrane domain, and a cytoplasmic domain. (B) The classic cysteine-switch mechanism. The conserved cysteine switch is located in the prodomain. It coordinates with Zn²⁺ at the catalytic site of the metalloproteinase domain to produce an inactivated enzyme (ADAM17 precursor). Once its prodomain is cleaved, the adjacent furin site (RVKR sequence) is responsible for catalyzing the separation of zinc from cysteine, ultimately leading to ADAM17 activation. (C) The 3D catalytic structure of ADAM17 (PDB CODE: 1BKC) (31) with a hydroxamic acid-based inhibitor INN and Zn²⁺ shows N-terminal domains, α-helix (blue), β-sheet (green), and C-terminal domains. INN stands for N-{(2R)-2-[2-(hydroxyamino)-2-oxoethyl]-4-methylpentanoyl}-3-methyl-L-valyl-N-(2-aminoethyl)-L-alaninamide with the chemical structure of C19H37N5O5. INN, also known as TAPI-2, is an analogue of TAPI-1. This 3D image was made with the SWISS-MODEL Expasy.

Figure 2

Multiple regulatory roles of ADAM17. ADAM17 activity is affected by transcriptional regulation, and post-transcriptional and post-translational modification. ADAM17 activity is also associated with substrate shedding. iRhoms affect the shedding of ADAM17 and regulation of its downstream signaling pathways.

Figure 3

Immunomodulatory role of ADAM17 in tumor development.

Figure 4

Chemical structures of representative small molecule ADAM17 inhibitors.