ADAMs in cancer cell proliferation and progression

Abstract

A disintegrin and metalloproteinases (ADAMs) are a new gene family of proteins with sequence similarity to the reprolysin family of snake venomases that share the metalloproteinase domain with matrix metalloproteinases (MMPs). They are structurally classified into two groups: the membrane-anchored ADAM and ADAM with thrombospondin motifs (ADAMTS). These molecules are involved in various biological events such as cell adhesion, cell fusion, cell migration, membrane protein shedding and proteolysis. Studies on the biochemical characteristics and biological functions of ADAMs are in progress, and accumulated lines of evidence have shown that some ADAMs are expressed in malignant tumors and participate in the pathology of cancers. The activities of ADAMs are regulated by gene expression, intracytoplasmic and pericellular regulation, activation of the zymogens and inhibition of activities by inhibitors. Many ADAM species, including ADAM8, ADAM9, ADAM10, ADAM12, ADAM15, ADAM17, ADAM19, ADAM28, ADAMTS1, ADAMTS4 and ADAMTS5, are expressed in human malignant tumors. Many of them are involved in the regulation of growth factor activities and integrin functions, leading to promotion of cell growth and invasion, although the precise mechanisms of these are not clear at the present time. In this article, we review recent information about ADAM family members and their implications for cancer cell proliferation and progression.

Figure 1

Domain structures of a disintegrin and metalloproteinase (ADAM) and ADAM with thrombospondin motifs (ADAMTS). Members of the ADAM gene family are classified as membrane‐anchored ADAM and secreted‐type ADAMTS subgroups. CR, cysteine‐rich domain; CT, cytosolic tail; Dis, disintegrin domain; E, epidermal growth factor‐like domain; MP, metalloproteinase domain; Pro, propeptide domain; SP, spacer domain; TM, transmembrane domain; TS, thrombospondin‐like domain.

Figure 2

Prospective role of a disintegrin and metalloproteinases (ADAMs) in breast carcinoma cell proliferation. ADAM28s and ADAM28m are overexpressed as active forms in breast carcinoma cells. ADAM28 cleaves insulin‐like growth factor binding protein‐3 (IGFBP‐3) and releases insulin‐like growth factor‐I (IGF‐I) through the IGF‐I–IGFBP‐3 complex. IGF‐I induces cell proliferation through phosphorylation of the IGF type I receptor (IGF‐IR) and extracellular signal‐regulated kinase 1/2 (ERK1/2). Note that IGFBP‐3 cleavage can be inhibited by treatment with anti‐ADAM28 antibody or an ADAM inhibitor, KB‐R7785, as well as ADAM28 small interfering RNA (siRNA).

Figure 3

An overview of a disintegrin and metalloproteinases (ADAM) in cancer biology. Five different pathways may be involved in ADAM‐mediated cancer cell proliferation and progression. (1) ProADAMs are activated by furin or matrix metalloproteinases (MMPs). (2) Sheddase activity of ADAMs is stimulated by external factors (e.g. 12‐O‐tetradecanoylphorbol‐13‐acetate [TPA]), leading to shedding of cell surface ligands such as heparin‐binding‐epidermal growth factor (HP‐EGF) and transforming growth factor (TGF)‐α. This process perhaps involves protein kinase C (PKC) and mitogen‐activated protein kinase (MAPK) pathways. Then, soluble growth factors such as HP‐EGF activate epidermal growth factor receptor on the cells in autocrine and paracrine manners. (3) The interaction of the disintegrin and cysteine‐rich domains of ADAM with integrins or syndecans on the cells may help them to cleave the substrates (e.g. extracellular matrix [ECM]). (4) ADAMs modulate extracellular matrix–integrin interactions, and thus they can indirectly promote proliferation signals through integrins. (5) ADAM may process other undetermined membrane‐anchored molecules such as chemokines, cytokines and their receptors, which are related to cancer cell proliferation and progression. CR, cysteine‐rich domain; CT, cytosolic tail; Dis, disintegrin domain; E, epidermal growth factor‐like domain; MP, metalloproteinase domain; Pro, propeptide domain; TM, transmembrane domain.