The Translation Initiation Factor 3f (eIF3f) Exhibits a Deubiquitinase Activity Regulating Notch Activation

Moretti, Julien; Chastagner, Patricia; Gastaldello, Stefano; Heuss, Sara Farrah; Dirac, Annette M.G.; Bernards, René; Masucci, Maria G.; Israël, Alain; Brou, Christel

doi:10.1371/journal.pbio.1000545

Cited by 78 publications

(92 citation statements)

References 57 publications

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“…Notch receptor endocytosis requires mono-ubiquitylation of the receptor at lysine 1749 (Gupta-Rossi et al, 2004), and, recently, this mono-ubiquitylation event has been shown to be followed by deubiquitylation mediated by elF3f, previously thought to solely constitute a subunit of translation initiation factor E74-like factor 3 (Elf3), which is required for Notch to be processed by -secretase (Moretti et al, 2010). The putative E3 ubiquitin ligase Deltex, which has been implicated in the regulation of Notch processing and internalization in several studies (Diederich et al, 1994;Hori et al, 2004;Matsuno et al, 1995;Wilkin et al, 2008;Yamada et al, 2011), serves as a bridging protein between elF3f and Notch in early endosomes (Moretti et al, 2010). Deltex has been described as both a positive (Fuwa et al, 2006;Matsuno et al, 1995;Matsuno et al, 2002;Wilkin et al, 2008) and a negative (Sestan et al, 1999;Mukherjee et al, 2005) regulator of Notch signaling, and Deltex appears to be required for Notch signaling in some, but not all, developmental processes in Drosophila (Fuwa et al, 2006).…”

Section: Endocytosis and Trafficking Of Processed Notch Receptorsmentioning

confidence: 99%

“…It is thus possible that the localization of Notch cleavage is variable and constitutes another level of signal fine-tuning that is dependent on cell context (Tagami et al, 2008). Notch receptor endocytosis requires mono-ubiquitylation of the receptor at lysine 1749 (Gupta-Rossi et al, 2004), and, recently, this mono-ubiquitylation event has been shown to be followed by deubiquitylation mediated by elF3f, previously thought to solely constitute a subunit of translation initiation factor E74-like factor 3 (Elf3), which is required for Notch to be processed by -secretase (Moretti et al, 2010). The putative E3 ubiquitin ligase Deltex, which has been implicated in the regulation of Notch processing and internalization in several studies (Diederich et al, 1994;Hori et al, 2004;Matsuno et al, 1995;Wilkin et al, 2008;Yamada et al, 2011), serves as a bridging protein between elF3f and Notch in early endosomes (Moretti et al, 2010).…”

Section: Endocytosis and Trafficking Of Processed Notch Receptorsmentioning

confidence: 99%

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Notch signaling: simplicity in design, versatility in function

2011

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Notch signaling is evolutionarily conserved and operates in many cell types and at various stages during development. Notch signaling must therefore be able to generate appropriate signaling outputs in a variety of cellular contexts. This need for versatility in Notch signaling is in apparent contrast to the simple molecular design of the core pathway. Here, we review recent studies in nematodes, Drosophila and vertebrate systems that begin to shed light on how versatility in Notch signaling output is generated, how signal strength is modulated, and how cross-talk between the Notch pathway and other intracellular signaling systems, such as the Wnt, hypoxia and BMP pathways, contributes to signaling diversity.Key words: Cis-inhibition, Delta-like, Signaling diversity, Jagged, Notch, Notch intracellular domain Introduction Cells need to sense cues from their extracellular environment and integrate this information into appropriate developmental or physiological responses. Although there are a number of mechanisms that relay information from the exterior of the cell to the interior, a relatively small set of highly evolutionarily conserved signaling pathways stand out as playing particularly crucial roles in this transmission of information. In this roster of 'elite' intracellular signaling mechanisms are the Wnt pathway, the sonic hedgehog (Shh) pathway, the bone morphogenetic protein/transforming growth factor  (BMP/TGF) pathway, phosphatidylinositol 3-kinase/thymoma viral proto-oncogene (PI3K/AKT) and Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling, and, the subject of this review, the Notch signaling pathway. Each of these pathways converts information about the concentration of extracellular ligands into specific transcriptional responses in the nucleus. In most cases, the signaling mechanism consists of the 'core' signaling pathway, i.e. the minimal set of protein components required for transducing the signal, and a more elaborate set of 'auxiliary' proteins, which, in various ways, impinge upon the core pathway and modify the signal but are not intrinsically necessary for relaying the signal.Among these highly conserved pathways (Gazave et al., 2009;Richards and Degnan, 2009), the Notch signaling pathway scores highly with regard to simplicity in molecular design, as it contains only a small number of core signaling components (Fig. 1). Despite this, Notch signaling affects cell differentiation decisions not only across a wide spectrum of metazoan species, but also across a broad range of cell types in a single organism and at different steps during cell lineage progression. The pleiotropic actions of Notch in different cell types and organs have recently been reviewed and are summarized in Table 1. In keeping with its important role in many cell types, the mutation of Notch genes leads to diseases in various organs and tissues (Table 2). These studies highlight the fact that the Notch pathway must be able to elicit appropriate responses in many spatially and temporally...

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Section: Endocytosis and Trafficking Of Processed Notch Receptorsmentioning

confidence: 99%

Section: Endocytosis and Trafficking Of Processed Notch Receptorsmentioning

confidence: 99%

Notch signaling: simplicity in design, versatility in function

2011

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“…These cells are devoid of any active Notch ligand and stably express low levels of full-length human Notch, Notch-FL, which remains transcriptionally inactive unless it is activated by its ligands. In this case, it is tagged in the extracellular domain with an HA epitope (9).…”

Section: Identification Of Usp12 As a Candidate Dub Acting Onmentioning

confidence: 99%

The Ubiquitin-specific Protease 12 (USP12) Is a Negative Regulator of Notch Signaling Acting on Notch Receptor Trafficking toward Degradation

Moretti

Chastagner

Liang

et al. 2012

Journal of Biological Chemistry

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“…Proper routing of the internalized Notch receptor may also be important for preventing ligand-independent activation, and Notch signaling defects are indeed linked to impaired endocytic trafficking and endosome acidification [4,16]. The internalization step appears to be controlled by monoubiquitylation of the Notch receptor at the cell surface [4], followed by a deubiquitylation event, which is required for signaling activation [17]. Deltex, an E3 ubiquitin ligase, is a regulator of Notch internalization and processing, although whether it functions to enhance or reduce Notch signaling appears to be cell context-dependent [18][19][20].…”

Section: Introductionmentioning

confidence: 99%

PKCζ regulates Notch receptor routing and activity in a Notch signaling-dependent manner

et al. 2014

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Activation of Notch signaling requires intracellular routing of the receptor, but the mechanisms controlling the distinct steps in the routing process is poorly understood. We identify PKCζ as a key regulator of Notch receptor intracellular routing. When PKCζ was inhibited in the developing chick central nervous system and in cultured myoblasts, Notch-stimulated cells were allowed to undergo differentiation. PKCζ phosphorylates membrane-tethered forms of Notch and regulates two distinct routing steps, depending on the Notch activation state. When Notch is activated, PKCζ promotes re-localization of Notch from late endosomes to the nucleus and enhances production of the Notch intracellular domain, which leads to increased Notch activity. In the non-activated state, PKCζ instead facilitates Notch receptor internalization, accompanied with increased ubiquitylation and interaction with the endosomal sorting protein Hrs. Collectively, these data identify PKCζ as a key regulator of Notch trafficking and demonstrate that distinct steps in intracellular routing are differentially modulated depending on Notch signaling status.

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The Translation Initiation Factor 3f (eIF3f) Exhibits a Deubiquitinase Activity Regulating Notch Activation

Abstract: The translation initiation factor complex eIF3f has an intrinsic deubiquitinase activity and regulates the Notch signaling pathway.

Cited by 78 publications

References 57 publications

Notch signaling: simplicity in design, versatility in function

Notch signaling: simplicity in design, versatility in function

The Ubiquitin-specific Protease 12 (USP12) Is a Negative Regulator of Notch Signaling Acting on Notch Receptor Trafficking toward Degradation

PKCζ regulates Notch receptor routing and activity in a Notch signaling-dependent manner

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