Role of ADAM10 in intestinal crypt homeostasis and tumorigenesis

Abstract

A disintegrin and metalloproteinases (ADAMs) are a family of multidomain, membrane-anchored proteases that regulate diverse cellular functions, including cell adhesion, migration, proteolysis and other cell signaling events. Catalytically-active ADAMs act as ectodomain sheddases that proteolytically cleave type I and type II transmembrane proteins and some GPI-anchored proteins from the cellular surface. ADAMs can also modulate other cellular signaling events through a process known as regulated intramembrane proteolysis (RIP). Through their proteolytic activity, ADAMs can 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. Dysregulation of these processes through aberrant expression, or sustained ADAM activity, is linked to chronic inflammation, inflammation-associated cancer and tumorigenesis. ADAM10 was the first disintegrin-metalloproteinase demonstrated to have proteolytic activity and is the prototypic ADAM associated with RIP activity (e.g. sequential Notch receptor processing). ADAM10 is abundantly expressed throughout the gastrointestinal tract and during normal intestinal homeostasis ADAM10 regulates many cellular processes associated with intestinal development, cell fate specification and maintenance of intestinal stem cell/progenitor populations. In addition, several signaling pathways that undergo ectodomain shedding by ADAM10 (e.g. Notch, EGFR/ErbB, IL-6/sIL-6R) help control intestinal injury/regenerative responses and may drive intestinal inflammation and colon cancer initiation and progression. Here, I review some of the proposed functions of ADAM10 associated with intestinal crypt homeostasis and tumorigenesis within the gastrointestinal tract in vivo.

NoxO1 Controls Proliferation of Colon Epithelial Cells

“…Notch also plays an extraordinary important role in the renewal of the colon epithelium, and ADAM10 is abundantly expressed throughout the gastrointestinal tract. During intestinal renewal homeostasis, ADAM10 regulates cellular processes such as cell fate specification and maintenance of intestinal stem cell/progenitor populations, controlling intestinal injury/regenerative responses and may drive intestinal inflammation and colon cancer initiation and progression ( 29 ). Therefore, a role of NoxO1 in all these processes is possible.…”

Colorectal Cancer: Genetic Abnormalities, Tumor Progression, Tumor Heterogeneity, Clonal Evolution and Tumor-Initiating Cells

“…NOTCH signaling is the dominant pathway activated by ADAM10 and ADM17. ADAM10-dependent NOTCH signaling controls the maintenance and survival of LGR5 + intestinal stem cells and regulates the cell fate specification of transit-amplifying progenitors; ADAM10 inhibition is associated with reduced stem cell proliferation and activity; furthermore, ADAM10 and NOTCH signaling plays an important role in maintaining quiescent Bmi1 + intestinal stem cells (reviewed in [ 408 ]). Studies carried out in experimental animal models have shown that NOTCH activation is able to promote, but not induce colon carcinogenesis.…”

The Many Facets of Metzincins and Their Endogenous Inhibitors: Perspectives on Ovarian Cancer Progression

“…In humans, the ADAMs are a family of 22 known genes, encoding at least 12 proteolytically active functional proteins. These functional proteins are involved in tumor metastasis, angiogenesis, membrane fusion, cytokine and growth factor shedding and cell migration as well as processes such as fertilization, neurogenesis, myogenesis, embryonic TGF-α and epidermal growth factor receptor (EGFR) release and signaling [ 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 ]. ADAMs are membrane-anchored metalloproteinase that process and shed the ectodomains of membrane-anchored growth factors, cytokines and growth factor receptors [ 79 , 82 , 83 , 84 , 85 ].…”