A disintegrin and metalloproteinase-12 (ADAM12): Function, roles in disease progression, and clinical implications

Abstract

Background A disintegrin and metalloproteinase-12 (ADAM12) is a member of the greater ADAM family of enzymes: these are multifunctional, generally membrane-bound, zinc proteases for which there are forty genes known (21 of these appearing in humans). ADAM12 has been implicated in the pathogenesis of various cancers, liver fibrogenesis, hypertension, and asthma, and its elevation or decrease in human serum has been linked to these and other physiological/pathological conditions. Scope In this review, we begin with a brief overview of the ADAM family of enzymes and protein structure. We then discuss the role of ADAM12 in the progression and/or diagnosis of various disease conditions, and we will conclude with an exploration of currently known natural and synthetic inhibitors. Major Conclusions ADAM12 has potential to emerge as a successful drug target, although targeting the metalloproteinase domain with any specificity will be difficult to achieve due to structural similarity between the members of the ADAM and MMP family of enzymes. Overall, more research is required to establish ADAM12 being as a highly desirable biomarker and drug target of different diseases, and their selective inhibitors as potential therapeutic agents. General Significance Given the appearance of elevated levels of ADAM12 in various diseases, particularly breast cancer, our understanding of this enzyme both as a biomarker and a potential drug target could help make significant inroads into both early diagnosis and treatment of disease.

Metalloproteinases ADAM12 and MMP‐14 are associated with cavernous sinus invasion in pituitary adenomas

“…ADAM12 exists in two alternatively spliced forms, a membrane-bound form (ADAM12L), with all ADAM typical structural domains; and a secreted form (ADAM12S) lacking the transmembrane and the cytoplasmic domain. 31 Discrete functions can be attributed to the individual ADAM12 domains. Both isoforms of ADAM12 are active proteases containing the catalytic domain of ADAM12 with the consensus HEXGHXXGXXHD zinc-binding motif,.…”

Urinary ADAM12 and MMP-9/NGAL Complex Detect the Presence of Gastric Cancer

“…The ADAMs, a family of MMPrelated metalloproteinases, are associated with cell adhesion, cell signaling, and proteolytic processing of a number of transmembrane proteins and play crucial roles in cancer progression and metastasis (28). ADAM12 is a member of this family and contributes to cancer progression and invasion through cleavage of various membrane-bound proteins (28,29) and high expression of ADAM12 has been reported in several cancer tissues such as brain (30), lung (31) and others. We have previously reported that ADAM12 promotes growth and metastasis of breast cancer (32) as well as of breast cancer risk (26) and that urinary levels of ADAM12 are predictive of disease status and stage in patients with breast cancer (33).…”

Derivation of a fifteen gene prognostic panel for six cancers

“…Conserved biological pathways between breast and ovarian cancer are known 44 , while some of the identified prognostic markers are also previously reported as cancer prognostic factors. CTSK expression is reported to govern breast tumor progression and prognosis by promoting extracellular matrix degradation and angiogenesis 45 ; CD53 expression was significantly associated with distant metastasis-free survival in ER − breast cancer patients 46 ; ADAM12 is proposed as a biomarker and drug target in breast cancer 47 . Significantly, although we identified two master regulators viz.…”