Abstract
The ADAMs are transmembrane proteins implicated in proteolysis and cell adhesion. Forty gene members of the family have been identified, of which 21 are believed to be functional in humans. As proteases, their main substrates are the ectodomains of other transmembrane proteins. These substrates include precursor forms of growth factors, cytokines, growth factor receptors, cytokine receptors and several different types of adhesion molecules. Although altered expression of specific ADAMs has been implicated in different diseases, their best-documented role is in cancer formation and progression. ADAMs shown to play a role in cancer include ADAM9, ADAM10, ADAM12, ADAM15 and ADAM17. Two of the ADAMs, i.e., ADAM10 and 17 appear to promote cancer progression by releasing HER/EGFR ligands. The released ligands activate HER/EGFR signalling that culminates in increased cell proliferation, migration and survival. Consistent with a causative role in cancer, several ADAMs are emerging as potential cancer biomarkers for aiding cancer diagnosis and predicting patient outcome. Furthermore, a number of selective ADAM inhibitors, especially against ADAM10 and ADAM17, have been shown to have anti-cancer effects. At least one of these inhibitors is now undergoing clinical trials in patients with breast cancer.
Highlights
The ADAMs are transmembrane proteins implicated in proteolysis and cell adhesion
Review The ADAMs are a family of multidomain proteins shown to be involved in both proteolysis and cell adhesion [for review, see refs [1,2,3]]
The best established role for ADAMs is the activation of the proforms of certain growth factors and cytokines as well as the shedding of the extracellular domains of growth factor receptors and adhesion proteins
Summary
Forty gene members of the family have been identified, of which 21 are believed to be functional in humans As proteases, their main substrates are the ectodomains of other transmembrane proteins. As with MMPs, this inactive state in most of the ADAMs is due to the interaction of a cysteine residue in the prodomain with the zinc ion at the catalytic site For protease activation, this prodomain is removed by a furin-like convertase or by autocatalysis, depending on the specific ADAM [1,2]. This prodomain is removed by a furin-like convertase or by autocatalysis, depending on the specific ADAM [1,2] This cysteine switch mechanism does not appear to play a role in maintaining the zymogen state of ADAM17 [6]. Protease activity is the bestdefined function of ADAMs, with most of the putative substrates currently identified being transmembrane proteins
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