The good, the bad and the ugly substrates for ADAM10 and ADAM17 in brain pathology, inflammation and cancer

Abstract

Various surface molecules undergo regulated cleavage by the disintegrin and metalloproteinases ADAM10 and ADAM17. The list of substrates includes molecules involved in brain pathology, inflammation and cancer. In the brain both proteases mediate neuroprotective cleavage events such as inactivation of amyloid precursor protein. In inflammatory settings signaling of cytokines including TNFα and IL-6 is triggered by proteolytic release of soluble agonists and leukocyte recruitment is controlled by the cleavage of adhesion molecules. Moreover, in tumors, ADAM10- and ADAM17-mediated shedding events trigger proliferative signaling via activation of growth factors including ErbB family members. Concepts of either increasing ADAM10- or ADAM17-activity to limit neurodegeneration or suppressing their activity to block inflammation or tumor growth have to be carefully scrutinized for their potential side effects in various tissues and pathologies.

Introduction

The surface-expressed metalloproteinases ADAM10 and ADAM17 (also known as tumor necrosis factor α-converting enzyme, TACE) play important roles in various physiological and pathophysiological processes. From early development until adulthood, ADAM10 and ADAM17 are found in most tissues and are constitutively expressed in neurons, vascular cells, leukocytes and tumor cells. From mice with targeted disruption of adam10 or adam17 genes it became evident that both proteases are crucial for developmental processes [1], [2]. Recent in vitro research strongly suggests that both proteases are also critically involved in various diseases and repair functions. Both proteases have been made responsible for the limited proteolysis of more than 40 type 1 surface molecules (for review see [3], [4], [5], [6], [7]). Cleavage of these substrates occurs at an extracellular sites proximal to the cell membrane thereby releasing the soluble ectodomain from the cell surface. In many cases shedding is regulated by proinflammatory or pathogenic mediators including ligands for G-protein-coupled receptors (GPCRs), cytokines or bacterial toxins [5], [8]. Interestingly, some surface molecules are shed by ADAM10 and ADAM17 while others are shed by either ADAM10 or ADAM17. Specific inhibitors have been generated that preferentially block ADAM10 but not ADAM17 [9], [10] and vice versa [11] and allow to discriminate the functions of both proteases under various conditions. Inhibition studies were further complemented by knock-out or knock-down approaches [1], [12]. This review will list the substrates that have been identified using these methods and discuss the multiple roles of ADAM10 and ADAM17 in central nervous system (CNS) pathology, inflammation and cancer (Table 1). In the CNS, “good” substrates can be found that participate in neuroprotection and regeneration, whereas in inflammatory processes rather “bad” substrates are involved in leukocyte recruitment and, finally, in tumors the “ugly” substrates contribute to the promotion of tumor growth and invasion.