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Review
. 2017 Nov;1864(11 Pt B):2228-2239.
doi: 10.1016/j.bbamcr.2017.07.011. Epub 2017 Jul 22.

Role of ADAM10 in intestinal crypt homeostasis and tumorigenesis

Affiliations
Review

Role of ADAM10 in intestinal crypt homeostasis and tumorigenesis

Peter J Dempsey. Biochim Biophys Acta Mol Cell Res. 2017 Nov.

Abstract

A disintegrin and metalloproteinases (ADAMs) are a family of mSultidomain, 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. This article is part of a Special Issue entitled: Proteolysis as a Regulatory Event in Pathophysiology edited by Stefan Rose-John.

Keywords: ADAM10; Cell lineage specification; Intestinal stem cells; Notch.

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Figures

Figure 1
Figure 1. Stem and differentiated cells of the small intestine
Overview of the crypt-villus architecture and cellular composition of small intestine. A, Representative H&E staining of the mouse small intestine. The mouse small intestine is comprised of repeating crypt-villus units. B, Schematic diagram of the cellular composition of an individual crypt outlined in A. Lgr5+ CBCs are positioned at the crypt base, intercalated between Paneth cells. Lgr5+ CBCs are an essential component of the intestinal stem cell (ISC) niche and give rise to rapidly proliferating transit-amplifying (TA) progenitor cells. TA cells appear above the stem cell niche and rapidly migrate towards the crypt-villus junction. Before TA cells exit the crypts, they differentiate into distinct absorptive and secretory cell lineages. Differentiated absorptive lineage cell types include absorptive enterocytes and microfold “M” cells (not shown). Differentiated secretory lineage cell types include goblet, Paneth and enteroendocrine and tuft cells. All differentiated post-mitotic intestinal cells emerge from the crypts, migrate along the villus surface, and are eventually shed from the villus tips into the gut lumen. The one exception are the Paneth cells, which first appear above the stem cell niche but are then retained at crypt base. Paneth cells have a longer lifespan (~30 days), compared to other differentiated cell types (~5 days). Blue asterisk, location of representative +4 quiescent stem cells (e.g. Bmi1+ cells). Other potential stem cell markers are discussed in the text. C, Schematic diagram of the intestinal stem cell niche. Both Paneth cells and lamina propria cells (e.g. pericryptal myofibroblasts, immune cells, endothelial cells, enteric neurons, etc) provide crucial and often times redundant signals required for maintenance and survival of the Lgr5+ CBC stem cell compartment. Paneth cells present Notch ligands (e.g. Dll1 and Dll4), ErbB ligands (e.g. EGF) and Wnt ligands (e.g. Wnt3) to support Lgr5+ CBCs. Lamina propria cells present additional Wnt ligands, other ErbB ligands (e.g. amphiregulin and epiregulin), BMP antagonists (e.g. noggin and gremlin) and R-spondins.
Figure 2
Figure 2. ADAM10 acts iteratively to regulate Notch signaling in ISCs and transit-amplifying TA progenitors during intestinal crypt homeostasis
A, Schematic diagram of ADAM10-mediated Notch signaling events in the crypt compartment. First, ADAM10-mediated Notch signaling is required for the survival and maintenance of Lgr5+ CBCs. Second, ADAM10-mediated Notch is required for cell fate specification of TA cells. TA cells use classical Notch lateral inhibition to determine their cell fate specification into absorptive and secretory progenitors. Notch “active” progenitors are fated to absorptive progenitors and undergo several rounds of proliferation before differentiating into post-mitotic enterocytes and microfold M cells. In Dll1+ Notch “low” progenitors are fated to secretory progenitors, which rapidly exit the cell cycle and differentiate into distinct secretory cell types including goblet, Paneth, enteroendocrine and tuft cells. Note: ADAM10 is abundantly expressed on all differentiated intestinal epithelial cell types, implying that ADAM10 is involved in other shedding events in these post-mitotic intestinal cells. Potential ADAM10 substrates include E-cadherin, EGF, Ephrin B1 etc. The profound effects of ADAM10-deficiency in the ISC/progenitor compartment have hindered analysis of other ADAM10 substrates in vivo. B, Schematic diagram of ADAM10-mediated Notch signaling in Lgr5+ CBCs. Lgr5+ CBCs expressing Notch1/2 receptors are intercalated between Paneth cells expressing Dll-4 ligand (and a to a lesser extent Dll-1), in the small intestinal stem cell niche. High Notch activity in Lgr5+ CBCs is required for proliferation and survival of stem cells and maintenance of the stem cell pool. Notch signaling is activated in Lgr5+ CBCs when Dll4 ligand, found on the cell surface of Paneth cells, binds to Notch receptors expressed on the cell surface of Lgr5+ CBCs. Notch is sequentially cleaved by ADAM10 and γ-secretase to generate NICD that translocates to the nucleus, where its forms an active transcriptional complex. In Notch “active” Lgr5+ CBCs, Notch target genes include the Hes/Hey transcription factors which repress Dll-1/4 ligand transcription and concomitantly enhance expression of the stem cell marker Olfm4 in an Atoh1 independent manner. ADAM10 is not required in Paneth cells to maintain the Lgr5+ CBC stem cell pool, but it may be involved in other redundant signaling pathways (e.g. EGF) that contribute to the stem cell niche. C, Schematic diagram ADAM10-mediated Notch signaling involved in cell fate specification within the TA progenitor compartment. In Notch “active” TA progenitors, Notch target genes include the Hes/Hey transcription factors, which repress Atoh1 and Dll-1/4 ligand transcription. These cells are fated to absorptive progenitors, which undergo several rounds of proliferation before differentiating into post-mitotic enterocytes. In Dll-1+ TA cells, low Notch activity allows de-repression of Atoh1 and Dll-1/4 ligand expression. These cells are fated to secretory progenitors, which rapidly exit the cell cycle and differentiate into distinct secretory cell types.

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References

    1. Howard L, Glynn P. Membrane-associated metalloproteinase recognized by characteristic cleavage of myelin basic protein: assay and isolation. Methods Enzymol. 1995;248:388–395. - PubMed
    1. Weber S, Saftig P. Ectodomain shedding and ADAMs in development. Development. 2012;139:3693–3709. - PubMed
    1. Edwards DR, Handsley MM, Pennington CJ. The ADAM metalloproteinases. Mol Aspects Med. 2008;29:258–289. - PMC - PubMed
    1. Endres K, Fahrenholz F. Regulation of alpha-secretase ADAM10 expression and activity. Exp Brain Res. 2012;217:343–352. - PubMed
    1. Reiss K, Saftig P. The "a disintegrin and metalloprotease" (ADAM) family of sheddases: physiological and cellular functions. Seminars in cell & developmental biology. 2009;20:126–137. - PubMed

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