Epidermal ADAM17 Is Dispensable for Notch Activation

Groot, Arjan J.; Cobzaru, Cristina; Weber, Silvio; Säftig, Paul; Blobel, Carl P.; Kopan, Raphael; Vooijs, Marc; Franzke, Claus‐Werner

doi:10.1038/jid.2013.162

Cited by 25 publications

(18 citation statements)

References 15 publications

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“…Previously, both our group and others have established that the Adam10 metalloprotease, but not Adam17, is essential in ligandinduced extracellular cleavage of Notch1 in cellular models and in vivo (2,14,49,50). While much knowledge on Notch1 regulation in many different systems exists, relatively little is known about the activation mechanisms of the NOTCH2, NOTCH3, and NOTCH4 receptors in mammalian cells.…”

Section: Discussionmentioning

confidence: 99%

Regulated Proteolysis of NOTCH2 and NOTCH3 Receptors by ADAM10 and Presenilins

Groot

Habets

Yahyanejad

et al. 2014

Molecular and Cellular Biology

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cIn mammals, there are four NOTCH receptors and five Delta-Jagged-type ligands regulating many aspects of embryonic development and adult tissue homeostasis. NOTCH proteins are type I transmembrane receptors that interact with ligands on adjacent cells and are activated by regulated intramembrane proteolysis (RIP). The activation mechanism of NOTCH1 receptors upon ligand binding is well understood and requires cleavage by ADAM10 metalloproteases prior to intramembranous cleavage by ␥-secretase. How the other human NOTCH receptor homologues are activated upon ligand binding is not known. Here, we dissect the proteolytic activation mechanism of the NOTCH2 and NOTCH3 receptors. We show that NOTCH2 and NOTCH3 signaling can be triggered by both Delta-Jagged-type ligands and requires ADAM10 and presenilin-1 or -2. Importantly, we did not find any role for the highly related ADAM17/TACE (tumor necrosis factor alpha-converting enzyme) protease in ligand-induced NOTCH2 or NOTCH3 signaling. These results demonstrate that canonical ligand-induced proteolysis of the NOTCH1, -2, and -3 receptors strictly depends on consecutive cleavage of these receptors by ADAM10 and the presenilin-containing ␥-secretase complex, leading to transcriptional activation.

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Section: Discussionmentioning

confidence: 99%

Regulated Proteolysis of NOTCH2 and NOTCH3 Receptors by ADAM10 and Presenilins

Groot

Habets

Yahyanejad

et al. 2014

Molecular and Cellular Biology

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“…Mice lacking ADAM17 resemble mice lacking the EGFR or specific EGFR ligands, in that they have open eyes at birth and wavy and stunted hair, as well as defects in lung and heart development (14)(15)(16)(17)(18)(19). Moreover, targeted deletion of Adam17 in keratinocytes gives rise to skin barrier defects that resemble those observed in mice lacking the EGFR in keratinocytes (20,21). Mice with strongly reduced overall ADAM17 activity develop skin defects and intestinal inflammation that most likely are caused by a lack of TGF␣/EGFR signaling (22).…”

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confidence: 99%

ADAM17 Controls Endochondral Ossification by Regulating Terminal Differentiation of Chondrocytes

Hall

Hill

Otero

et al. 2013

Molecular and Cellular Biology

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f Endochondral ossification is a highly regulated process that relies on properly orchestrated cell-cell interactions in the developing growth plate. This study is focused on understanding the role of a crucial regulator of cell-cell interactions, the membrane-anchored metalloproteinase ADAM17, in endochondral ossification. ADAM17 releases growth factors, cytokines, and other membrane proteins from cells and is essential for epidermal growth factor receptor (EGFR) signaling and for processing tumor necrosis factor alpha. Here, we report that mice lacking ADAM17 in chondrocytes (A17⌬Ch) have a significantly expanded zone of hypertrophic chondrocytes in the growth plate and retarded growth of long bones. This abnormality is caused by an accumulation of the most terminally differentiated type of chondrocytes that produces a calcified matrix. Inactivation of ADAM17 in osteoclasts or endothelial cells does not affect the zone of hypertrophic chondrocytes, suggesting that the main role of ADAM17 in the growth plate is in chondrocytes. This notion is further supported by in vitro experiments showing enhanced hypertrophic differentiation of primary chondrocytes lacking Adam17. The enlarged zone of hypertrophic chondrocytes in A17⌬Ch mice resembles that described in mice with mutant EGFR signaling or lack of its ligand transforming growth factor ␣ (TGF␣), suggesting that ADAM17 regulates terminal differentiation of chondrocytes during endochondral ossification by activating the TGF␣/EGFR signaling axis. Skeletal development is crucial to ensure optimal mobility and breathing, as well as protection of vital organs, such as the brain, spinal cord, lung, and heart. The axial and appendicular skeletons are formed through the generation of a cartilage intermediate, a process known as endochondral ossification, whereas the skull and clavicles are formed through intramembranous ossification (1-3). In the limb bud, which can be used as a model, endochondral ossification is initiated when mesenchymal precursor cells condense and the most central chondrocytes begin to differentiate. Eventually, this gives rise to different zones of chondrocytes in the growth plate, beginning with the resting zone, followed by the proliferating zone and the hypertrophic zone, in which chondrocytes secrete a type X collagen-rich matrix (1, 2). Once the hypertrophic chondrocytes mature into a terminally differentiated state and the lowermost cell layer becomes surrounded by mineral, the hypertrophic chondrocytes undergo apoptosis. This area in the developing long bone is directly adjacent to the primary center of ossification and is remodeled into trabecular bone as the invading vasculature supports the influx of osteoblasts and osteoclasts. In this process, the calcified matrix laid down by the hypertrophic chondrocytes is thought to be degraded through proteolytic activities, including MMP13 and MMP9 (4), while the remaining matrix provides a scaffold for the formation of trabecular bone. A secondary center of ossification develops after birth in m...

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“…The binding of a ligand to a Notch receptor triggers the unfolding of a juxtamembrane negative regulatory region (NRR), which exposes it to cleavage by the ADAM10 protease (a disintegrin and metalloprotease) at an extracellular sequence termed S2 (Groot et al, 2013;Mumm et al, 2000;van Tetering et al, 2009). S2 cleavage leads to the shedding of the extracellular domain and allows γ-secretase to cleave Notch within its transmembrane domain at S3, releasing the intracellular domain of Notch (NICD) from the membrane.…”

Section: Introductionmentioning

confidence: 99%