ADAM Proteases and Gastrointestinal Function

Abstract

A disintegrin and metalloproteinases (ADAMs) are a family of cell surface proteases that regulate diverse cellular functions, including cell adhesion, migration, cellular signaling, and proteolysis. Proteolytically active ADAMs are responsible for ectodomain shedding of membrane-associated proteins. ADAMs rapidly modulate key cell signaling pathways in response to changes in the extracellular environment (e.g., inflammation) and play a central role in coordinating intercellular communication within the local microenvironment. ADAM10 and ADAM17 are the most studied members of the ADAM family in the gastrointestinal tract. ADAMs regulate many cellular processes associated with intestinal development, cell fate specification, and the maintenance of intestinal stem cell/progenitor populations. Several signaling pathway molecules that undergo ectodomain shedding by ADAMs [e.g., ligands and receptors from epidermal growth factor receptor (EGFR)/ErbB and tumor necrosis factor α (TNFα) receptor (TNFR) families] help drive and control intestinal inflammation and injury/repair responses. Dysregulation of these processes through aberrant ADAM expression or sustained ADAM activity is linked to chronic inflammation, inflammation-associated cancer, and tumorigenesis.

The ADAMs family of proteases as targets for the treatment of cancer

“…[3][4][5] Structurally similar to the widely described matrix metalloproteinase (MMP) family, 6,7 the ADAMs are members of the metzincin subgroup of proteins within the zinc protease superfamily. Functionally, the ADAMs possess 2 main biological activities, proteolysis and adhesion.…”

“…Thus, differential mRNA splicing has been shown to give rise to both membrane and soluble forms of ADAM9, ADAM11, ADAM12, ADAM15 and ADAM28. 7 As well as differential splicing, different forms of specific ADAMs may be generated by proteolysis. For example, ADAM10 has been shown to be processed into several different forms by ADAM9, ADAM15 and gamma-secretase.…”

Structural Basis for Regulated Proteolysis by the α-Secretase ADAM10

“…ADAM (a disintegrin and metalloproteinase) endopeptidases are an abundant and diverse family of type-I transmembrane metalloproteinases that hydrolyze adhesion molecules, signaling receptors and growth factors. The human genome encodes 22 different ADAMs, essential for numerous developmental events (Weber and Saftig, 2012) including spermatogenesis, fertilization (Cho et al, 1998), immune and gastrointestinal system development (Jones et al, 2016), angiogenesis (Glomski et al, 2011), and development of the central nervous system (Jorissen et al, 2010; Kuhn et al, 2016). Moreover, dysregulated ADAM activity is implicated in a variety of pathophysiologic states, including asthma (Weskamp et al, 2006), infertility (Cho et al, 1998), Alzheimer’s disease (Suh et al, 2013), and cancer (Murphy, 2008).…”

Role of ADAM10 in intestinal crypt homeostasis and tumorigenesis

“…Notch, EGF, ErbB2/HER2, E-cadherin, IL-6/sIL-6R, Ephrin/Eph, etc. )[2–6]. For a number of ADAM substrates, ectodomain shedding is also an initiating and rate-limiting step for sequential cleavage events in a process termed “regulated intramembrane proteolysis” (RIP).…”