The ADAMs family of proteases: new biomarkers and therapeutic targets for cancer?

The ADAMs are a family of multidomain proteins shown to be involved in both proteolysis and cell adhesion [for review, see refs [1-3]]. Although primarily located on the cell membrane, soluble forms have been described for some ADAMs. 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. ADAMs thus play a role in remodelling or processing of cell membrane proteins. Several of the substrates processed by ADAMs, especially by ADAM10 and ADAM17, have been implicated in the pathogenesis or progression of cancer [for reviews, see refs [4,5]], though some proteolytically inactive ADAMs may also play important roles in carcinogenesis (summarised in Table 1). The aim of this article is to review the role of ADAMs in malignancy, focusing especially on their potential use as cancer biomarkers and therapeutic targets. Firstly however, we briefly review the protein structure and biological activities of ADAMs.The generalised structure of an ADAM protein contains 8 distinct domains or regions. In the typical ADAM protein, these domains are a signal domain, a prodomain, a metalloproteinase domain, a disintegrin or integrin-binding domain, a cysteine rich region, an EGF (epidermal growth factor)-like domain, a transmembrane sequence and an intracellular C-terminal end [1]. Like most proteases, the ADAMs are initially synthesised as enzymatically-inactive precursor 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 cysteine switch mechanism however, does not appear to play a role in maintaining the zymogen state of ADAM17 [6].Next to the prodomain is the MMP-like domai