JLK isocoumarin inhibitors: Selective γ‐secretase inhibitors that do not interfere with notch pathway in vitro or in vivo

Petit, Agnès; Pasini, Andrea; Costa, Cristine Alves da; Ayral, Erwan; Hernandez, Jean‐François; Dumanchin-Njock, Cécile; Phiel, Christopher J.; Marambaud, Philippe; Wilk, Sherwin; Farzan, Michael; Fulcrand, Pierre; Martinez, Jean; Andrau, D.; Checler, Frédéric

doi:10.1002/jnr.10747

Cited by 43 publications

(30 citation statements)

References 64 publications

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“…Control explants consisted of medium containing DMSO (1 l/ml). In addition, we tested three other ␥-secretase inhibitors: JLK6 (5, 10, and 25 M) (27), L685458 (L6; 1, 10, 25, and 50 M) (28), and Compound 1 (C1; 25, 50, and 100 M) (4).…”

Section: Methodsmentioning

confidence: 99%

“…8C). Finally, we compared the DAPT effects in the lung with that of JLK6, an isocoumarin-based serine protease known to inhibit ␥-secretase activity of other substrates but not of Notch (27). Analysis of NICD, Sox2, and Titf1 expression confirmed that Notch cleavage was preserved and that proximal-distal patterning was undisturbed in JLK6 -treated explants (5-25 M) (supplemental Fig.…”

Section: Fgf10 Induces Expression Of Notch1 and Jag Ligands But Not mentioning

confidence: 97%

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γ-Secretase Activation of Notch Signaling Regulates the Balance of Proximal and Distal Fates in Progenitor Cells of the Developing Lung

Tsao

Chen

Izvolsky

et al. 2008

Journal of Biological Chemistry

103

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Little is known about the mechanisms by which the lung epithelial progenitors are initially patterned and how proximaldistal boundaries are established and maintained when the lung primordium forms and starts to branch. Here we identified a number of Notch pathway components in respiratory progenitors of the early lung, and we investigated the role of Notch in lung pattern formation. By preventing ␥-secretase cleavage of Notch receptors, we have disrupted global Notch signaling in the foregut and in the lung during the initial stages of murine lung morphogenesis. We demonstrate that Notch signaling is not necessary for lung bud initiation; however, Notch is required to maintain a balance of proximal-distal cell fates at these early stages. Disruption of Notch signaling dramatically expands the population of distal progenitors, altering morphogenetic boundaries and preventing formation of proximal structures. Our data suggest a novel mechanism in which Notch and fibroblast growth factor signaling interact to control the proximaldistal pattern of forming airways in the mammalian lung.The mammalian respiratory system arises from the ventral foregut endoderm. Studies in mice show that at around embryonic day 9 (E9) 2 respiratory progenitors are collectively identified in the ventral foregut as a group of endodermal cells expressing Titf1 (thyroid transcription factor-1, or Nkx2.1). Besides being the earliest known marker of respiratory progenitors, Titf1 appears to be required to regulate lung epithelial cell fate (1). By E9.5, major morphogenetic changes occur in the respiratory field, leading to Fgf10 (fibroblast growth factor 10)-mediated expansion of these progenitors to form the lung primordia. Once primary lung buds have formed, lateral buds arise at stereotyped positions from these tubules (the main bronchi) and undergo branching morphogenesis and differentiation to give rise to the bronchial tree (2, 3).Little is known about the mechanisms by which the lung epithelial progenitors are expanded and patterned into proximal and distal compartments during the early stages of lung morphogenesis. Furthermore, it is still unclear how proximaldistal boundaries are established and maintained when lung epithelial buds form and start to branch. Studies in other foregut derivatives, such as the pancreas and stomach implicate signaling by Notch as a critical regulator of pattern during organ formation (4, 5).The Notch pathway orchestrates a highly evolutionarily conserved mechanism of control of cell fate decisions, which plays a prominent role in establishing asymmetries or differences in signaling between two cells. During development, Notch-mediated mechanisms give rise to cellular diversity while also serving to generate compartments and to establish tissue boundaries (6 -8). Notch signaling results from cell-cell contact via interactions of Notch receptors (in mammalians, Notch1 to -4) with ligands (Delta-like 1, 3, and 4 and Jagged1 and -2) in adjacent cells. Ligand-receptor engagement results in shedding of the Not...

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Section: Methodsmentioning

confidence: 99%

Section: Fgf10 Induces Expression Of Notch1 and Jag Ligands But Not mentioning

confidence: 97%

γ-Secretase Activation of Notch Signaling Regulates the Balance of Proximal and Distal Fates in Progenitor Cells of the Developing Lung

Tsao

Chen

Izvolsky

et al. 2008

Journal of Biological Chemistry

103

View full text Add to dashboard Cite

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“…This is best illustrated by the lack of spreading of the plasma membrane that characterizes multinucleated macrophages. In contrast, JLK2, a PS inhibitor that inhibits the cleavage of APP but not Notch, 21 failed to inhibit the fusion of rat alveolar macrophages (data not shown). This confirmed that JLK2, unlike DAPT and DupE, affects ␥-secretase activity differently, and suggested that it might target different substrates, or different domains of the same substrates within the ␥-secretase complex.…”

Section: Resultsmentioning

confidence: 94%

The intracellular domain of CD44 promotes the fusion of macrophages

Cui

Zhang

et al. 2006

Blood

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Macrophages seed all tissues in which they have the ability, in specific and rare instances, to fuse with themselves and to differentiate into osteoclasts in bone or into giant cells in chronic inflammatory reactions. Although these cells play a central role in osteoporosis and in foreign body rejection, respectively, the molecular mechanism used by macrophages to fuse remains poorly understood. Macrophages might also fuse with somatic and tumor cells to promote tissue repair and metastasis, respectively. We reported that CD44 expression is highly induced in macrophages at the onset of fusion in which it plays a role. We report now that the intracellular domain of CD44 (CD44ICD) is cleaved in macrophages undergoing fusion and that presenilin inhibitors prevent the release of CD44ICD and fusion. We also show that CD44ICD promotes the fusion of tissue macrophages and bone marrow-derived macrophages. IntroductionMacrophages seed all tissues and have the capacity, in specific and rare instances, to undergo homotypic fusion and to differentiate into multinucleate osteoclasts or giant cells, in bone or in chronic inflammatory reactions, respectively. Multinucleation endows macrophages with the ability to resorb components located extracellularly such as bone and foreign bodies, respectively. 1,2 In as much as osteoclasts are essential for the remodeling of bone, they are chiefly responsible for the loss of bone that leads to osteoporosis. Osteoclasts are also responsible for the local loss of bone that results from inflammation, such as in rheumatoid arthritis and in periodontal disease. Giant cells differentiate around foreign bodies such as pathogens, implants, and transplants that they resorb.Increasing evidence suggests that macrophages possess the ability to fuse also with somatic cells to repair tissues and organs and with tumor cells to trigger the metastatic process. 2 So macrophages, which are ubiquitously present in tissues where they perform a wide array of functions, might be endowed with a larger repertoire of biologic activities than originally anticipated. 3 The molecular mechanisms used by macrophages to adhere to, and to fuse with each other, and possibly with other cells, is an essential step that remains to be characterized. Indeed, cell-to-cell fusion itself, whether it concerns that of sperm cells with oocytes or myoblasts with myoblasts, leading to fertilization and muscle development, respectively, remains unclear. 4 To gain insight into the fusion mechanism of macrophages, we had subjected fusing rat alveolar macrophages to genome-wide oligonucleotide microarray, an approach that revealed the transiently induced expression of presenilin 2 (PS2), a protein associated with Alzheimer disease (for a review, see Hutton and Hardy 5 ). The fact that the deletion of the ps1 gene in mice leads to severe skeletal defects, 6 and that the deletion of the ps2 gene enhances the embryonic lethal phenotype of ps1 deletion, 7 triggered our interest in PS.Presenilins (PS1 and PS2) are transmembrane proteins ide...

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“…Therefore, the pro-apoptotic signal by the secretase inhibitor may be more potent in the modulation of neutrophil apoptosis than the anti-apoptotic signal of Aβ. It was found that the direct addition of Aβ (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) to the cultured neutrophils failed to exert an anti-apoptotic effect on the neutrophils even though it has been shown that Aβ (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) in fibrillary state induces O 2 − and Aβ(1-42) production [3]. Therefore, it is possible that Aβ(1-40) can inhibit neutrophil apoptosis in the monomer state.…”

Section: Discussionmentioning

confidence: 99%

“…Aβ (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35), Aβ(1-40), Aβ(1-42), Aβ , and Aβ(40-1) were purchased from Bachem AG. The zVADfmk, zDEVD-fmk, zIETD-fmk, β-secretase inhibitor II (z-VLL-CHO), β-secretase inhibitor III (H-EVNstatineVAEF-NH 2 ), γ-secretase inhibitor I ( Z -Leu-Leu-NorLeue-CHO), γ-secretase inhibitor II (Boc-VI-NHCH(CH 3 )-COCF 2 -CO-NHVI-OCH 3 ), γ-secretase inhibitor XI (7-amino-4-chlroro-3-methylisocoumarin), phosphoinositide 3-kinase (PI 3-K) inhibitor (LY294002), phospholipase C (PLC) inhibitor (U73122), phospholipase A 2 (PLA 2 ) inhibitor (MAFP), and protein kinase C (PKC) inhibitor (calphostin C and Go6976) were obtained from Calbiochem.…”

Section: Reagentsmentioning

confidence: 99%