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

Abstract

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.

Musashi1 expression is negatively correlated with numb expression in brain metastases

“…A large number of experiments have proved that the lack of numb may induce the activation of Notch signaling, which may lead to the occurrence, invasion and metastasis of tumor. [ 23 , 24 ] Hence, low expression of numb may be related to brain metastasis of primary tumor. Numb is a tumor suppressor gene and the low expression of numb may lose its inhibitory effect on tumor.…”

Notch Transduction in Non-Small Cell Lung Cancer

“…Although not extensively explored, endosome acidification inhibition is another attractive approach to block Notch signaling activity [141][142][143]. Endocytosis of Notch receptors in the signal-receiving cell is currently considered also a critical step in signaling modulation, downregulating Notch receptors that have not been activated through ligand binding-mediated proteolysis and, in aberrant contexts, abnormally triggering Notch cleavage through increased gamma secretase activity due to endosome acidification [141][142][143][144][145].…”

Notch3 in Development, Health and Disease

“…This releases Notch intracellular domain (ICD) to translocate to the nucleus where it forms a complex with the transcription factor CBF-1/Suppressor of Hairless/Lag1 (CSL), along with additional cofactors that activate gene transcription ( Figure 2). Additional routes to activation have also been described in both invertebrate and vertebrate models, which are independent of ligand binding [12][13][14][15][16][17][18]. These ligand-independent mechanisms, best characterised in Drosophila, depend on endocytosis of full-length Notch and proteolytic activation in the endosomal and lysosomal membranes ( Figure 2) [13,14,19,20].…”