Endocytosis in Notch Signaling Activation

Sala, Elisa; Ruggiero, Luca; Giacomo, Giuseppina Di; Cremona, Ottavio

doi:10.5772/48767

Cited by 6 publications

(4 citation statements)

References 309 publications

(393 reference statements)

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“…The requirement for endocytosis of Notch ligands during (and even prior to) receptor engagement is well characterized [Figure 2 ; ( 86 )]. However, the need for internalization of Notch itself on the signal-receiving cell as a prerequisite for signal transduction is less well established.…”

Section: The Role Of Receptor Endocytosis In Notch Activationmentioning

confidence: 99%

A Review of Notch Processing With New Insights Into Ligand-Independent Notch Signaling in T-Cells

Steinbuck

Winandy

2018

Front. Immunol.

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The Notch receptor is an evolutionarily highly conserved transmembrane protein essential to a wide spectrum of cellular systems, and its deregulation has been linked to a vast number of developmental disorders and malignancies. Regulated Notch function is critical for the generation of T-cells, in which abnormal Notch signaling results in leukemia. Notch activation through trans-activation of the receptor by one of its ligands expressed on adjacent cells has been well defined. In this canonical ligand-dependent pathway, Notch receptor undergoes conformational changes upon ligand engagement, stimulated by a pulling-force on the extracellular fragment of Notch that results from endocytosis of the receptor-bound ligand into the ligand-expressing cell. These conformational changes in the receptor allow for two consecutive proteolytic cleavage events to occur, which release the intracellular region of the receptor into the cytoplasm. It can then travel to the nucleus, where it induces gene transcription. However, there is accumulating evidence that other pathways may induce Notch signaling. A ligand-independent mechanism of Notch activation has been described in which receptor processing is initiated via cell-internal signals. These signals result in the internalization of Notch into endosomal compartments, where chemical changes existing in this microenvironment result in the conformational modifications required for receptor processing. This review will present mechanisms underlying both canonical ligand-dependent and non-canonical ligand-independent Notch activation pathways and discuss the latter in the context of Notch signaling in T-cells.

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Section: The Role Of Receptor Endocytosis In Notch Activationmentioning

confidence: 99%

A Review of Notch Processing With New Insights Into Ligand-Independent Notch Signaling in T-Cells

Steinbuck

Winandy

2018

Front. Immunol.

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“…Given that Notch signaling in worms, like that in flies and mammals, is γ secretase dependent (Francis et al, 2002), this finding provides in vivo evidence against the idea that Notch internalization is absolutely essential for signaling. Unfortunately, this work remains largely unnoticed in the literature where the relationship between Notch and endocytic transport is discussed (Baron, 2012;Fortini and Bilder, 2009;Le Bras et al, 2011;Moretti and Brou, 2013;Pratt et al, 2010;Sala et al, 2012;Tien et al, 2009;Yamamoto et al, 2010).…”

Section: Internalization-independent Notch Signalingmentioning

confidence: 97%

Regulation of Notch Signaling Through Intracellular Transport

Conner

2016

International Review of Cell and Molecular Biology

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“…Multiple factors can influence the production of activated Notch and thereby fine-tune pathway activity. In ligand-induced signaling, the ligand/receptor abundance at cell surfaces (regulated by endocytosis) 21,27,28 , the specific ligand-receptor complex formed 7,26,29,30 , glycosylation of the receptor's EGF repeats [31][32][33] and lipid-ligand interactions 34 can all affect Notch activation and NICD release dynamics 25 . In ligand-independent signaling, residence of Notch at distinct endocytic/endosomal compartments can affect receptor activation and modify signaling levels 20, [35][36][37] .…”

Section: Introductionmentioning

confidence: 99%

The Abelson kinase and the Nedd4-family E3 ligases co-regulate Notch trafficking to limit signaling

Miranda-Alban,

Sanchez-Luege,

Valbuena

et al. 2024

Preprint

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Precise output from the conserved Notch signaling pathway governs a plethora of cellular processes and developmental transitions. Unlike other pathways that use a cytoplasmic relay, the Notch cell surface receptor transduces signaling directly to the nucleus, with endocytic trafficking providing critical regulatory nodes. Here we report that the cytoplasmic tyrosine kinase Abelson (Abl) facilitates Notch internalization into late endosomes/multivesicular bodies (LEs), thereby limiting signaling output in both ligand-dependent and -independent contexts. Abl phosphorylates the PPxY motif within Notch, a molecular target for its degradation via Nedd4-family ubiquitin ligases. We show that Su(dx), a family member, mediates the Abl-directed LE regulation of Notch via the PPxY, while another family member, Nedd4Lo, contributes to Notch internalization into LEs through both PPxY-dependent and independent mechanisms. Our findings demonstrate how a network of post-translational modifiers converging at LEs cooperatively modulate Notch signaling to ensure the precision and robustness of its cellular and developmental functions.

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Endocytosis in Notch Signaling Activation

Cited by 6 publications

References 309 publications

A Review of Notch Processing With New Insights Into Ligand-Independent Notch Signaling in T-Cells

A Review of Notch Processing With New Insights Into Ligand-Independent Notch Signaling in T-Cells

Regulation of Notch Signaling Through Intracellular Transport

The Abelson kinase and the Nedd4-family E3 ligases co-regulate Notch trafficking to limit signaling

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