Notch signaling at a glance

Abstract

Cell–cell interactions define a quintessential aspect of multicellular development. Metazoan morphogenesis depends on a handful of fundamental, conserved cellular interaction mechanisms, one of which is defined by the Notch signaling pathway. Signals transmitted through the Notch surface receptor have a unique developmental role: Notch signaling links the fate of one cell with that of a cellular neighbor through physical interactions between the Notch receptor and the membrane-bound ligands that are expressed in an apposing cell. The developmental outcome of Notch signals is strictly dependent on the cellular context and can influence differentiation, proliferation and apoptotic cell fates. The Notch pathway is conserved across species (Artavanis-Tsakonas et al., 1999; Bray, 2006; Kopan and Ilagan, 2009). In humans, Notch malfunction has been associated with a diverse range of diseases linked to changes in cell fate and cell proliferation including cancer (Louvi and Artavanis-Tsakonas, 2012). In this Cell Science at a Glance article and the accompanying poster we summarize the molecular biology of Notch signaling, its role in development and its relevance to disease.

Selective regulation of Notch ligands during angiogenesis is mediated by vimentin

“…Vimentin interacts with membrane-tethered proteins through PDZ motifs (48) and Jagged and Dll carry distinct PDZ sequences in their ICDs (49)(50)(51). Whereas the ECDs are important for receptor binding, the ICDs play important roles in signal activation through posttranslational modifications (37,52) and interactions with endocytic regulators (41)(42)(43). To elucidate whether the ICDs of Dll4 and Jagged 1 influence vimentin binding and Notch signaling, we swapped the ICDs of Dll4 and Jagged 1 (53) to generate the chimeric variants: JaggedECDDll4ICD and Dll4ECDJaggedICD.…”

“…In contrast to Dll4, Jagged-Notch signaling promotes tip cell selection and sprouting by antagonizing Dll4-Notch signaling (31,(33)(34)(35)(36). How the competition between the ligands is balanced and how ligand-receptor signaling specificity is achieved is under intense investigation (31,33,34,37,38). Modification of the Notch receptor by the Fringe family of glycosaminyltransferases has been shown to enhance Dll4-Notch signaling and to suppress sprouting (31).…”

“…However, other mechanisms that balance the competition between Jagged and Dll4 signaling are still to be elucidated. Notch signaling is elicited by ligand binding to the Notch receptor on neighboring cells, which leads to proteolytic processing of the receptor and release of the Notch intracellular domain (NICD), which translocates to the nucleus and regulates transcription of target genes (37,39,40). Notch signaling is critically regulated Significance Angiogenesis, the formation of new blood vessels from existing ones, is essential for embryonic development and necessary for tumor growth and invasion.…”

Mapping Sites of O-Glycosylation and Fringe Elongation on Drosophila Notch

“…The Notch signaling pathway is evolutionarily conserved in all metazoans and controls a number of critical developmental processes (1)(2)(3)(4). Consequently, defects in Notch signaling are linked to several diseases in humans (5).…”

Notch Signaling in Cell–Cell Communication Pathways

“…In mammals, there are four different receptors (Notch1-4), and all are able to respond to the four different ligands: Jagged (Jag)1-2, and Delta-like (Dll) 1, 4 [5]. These ligands generally interact with neighboring cells (in trans), but can also inhibit Notch in cis.…”