Reversion of DEFA4Cre-Expressing Paneth Cells to a Stem Cell State in Response to Notch Activation or Intestinal Injury

Jones, Jennifer; Brindley, Constance D.; Rajala, Michael W.; Myers, Martin G.; Dempsey, Peter J.

doi:10.1016/s0016-5085(17)34363-9

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“…Interestingly, a milder Paneth cell phenotype was observed in mice upon overexpression of ADAM10 mutant lacking the prodomain and metalloproteinase domain in mice [101], a finding consistent with in vitro studies showing that ADAM10 can cleave the Ephrin ligand in “in trans” [101, 102]. By contrast, Paneth cell-specific ADAM10 deletion did not cause mislocalization of Paneth cells[91] (Table 1). Thus, ADAM10 warrants for further investigation to test its importance in regulating other substrate signaling events in differentiated post-mitotic intestinal epithelial cell types in vivo .…”

Section: Adam10 and Intestinal Homeostasissupporting

confidence: 64%

“…Interestingly, previous Notch inhibition studies have reported impaired crypt regeneration following radiation-induced injury [28, 89, 90]. Our own preliminary studies indicate that reduced crypt regeneration occurs in the ADAM10-deficient intestine following either radiation- or doxorubicin-induced injury[91] (Jones, J.C. and Dempsey, P.J, personal observation) (Table 1). These findings suggest that ADAM10-mediated Notch signaling likely contributes to crypt regeneration post-injury.…”

Section: Adam10 and Intestinal Homeostasismentioning

confidence: 77%

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Role of ADAM10 in intestinal crypt homeostasis and tumorigenesis

Dempsey

2017

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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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.

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