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Review
. 2019 Dec 28:467:50-57.
doi: 10.1016/j.canlet.2019.10.003. Epub 2019 Oct 5.

ADAM proteases: Emerging role and targeting of the non-catalytic domains

Nayanendu Saha  1 , Dorothea Robev  2 , Juha P Himanen  2 , Dimitar B Nikolov  2
Affiliations
Review

ADAM proteases: Emerging role and targeting of the non-catalytic domains

Nayanendu Saha et al. Cancer Lett. .

Abstract

ADAM proteases are multi domain transmembrane metalloproteases that cleave a range of cell surface proteins and activate signaling pathways implicated in tumor progression, including those mediated by Notch, EFGR, and the Eph receptors. Consequently, they have emerged as key therapeutic targets in the efforts to inhibit tumor initiation and progression. To that end, two main approaches have been taken to develop ADAM antagonists: (i) small molecule inhibitors, and (ii) monoclonal antibodies. In this mini-review we describe the distinct features of ADAM proteases, particularly of ADAM10 and ADAM17, their domain organization, conformational rearrangements, regulation, as well as their emerging importance as therapeutic targets in cancer. Further, we highlight an anti-ADAM10 monoclonal antibody that we have recently developed, which has shown significant promise in inhibiting Notch signaling and deterring growth of solid tumors in pre-clinical settings.

Keywords: ADAM10; ADAM17; Integrins; Notch signaling; Therapeutic antibody.

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Conflict of interest statement

Conflicts of interest

The authors declare that they have no competing interest.

Figures

Fig. 1.
Fig. 1.
ADAM domains and proposed conformations. The ‘closed’ and ‘open’ ectodomain conformations of ADAM10 and ADAM17 are proposed to reflect alternate disulfide bonding arrangements of the D + C region. Both ADAM10 and ADAM17 contain a CxxCC motif, a consensus site for PDI-mediated disulphide exchange. Thus, their ectodomain conformations are influenced by redox effects.
Fig. 2.
Fig. 2.
A close up-view of the disulfide-bonding pattern in the mAb (8C7)-bound ADAM10. The disulfide forming cysteines are shown as blue and yellow spheres. The ADAM10 D and C domains are represented in red. The heavy chain of the 8C7 mAb is in green and the light chain in wheat [114].
Fig. 3.
Fig. 3.
Comparison of the mAb 8C7-bound ADAM10 D + C structure with the structures of the related snake venom metalloproteinases Atragin and VAP1 (3A), as well as the structure of the complete ADAM10 ectodomain (3B) [115].
See this image and copyright information in PMC

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