Chapter Three - Canonical and Non-Canonical Notch Ligands

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Abstract

Notch signaling induced by canonical Notch ligands is critical for normal embryonic development and tissue homeostasis through the regulation of a variety of cell fate decisions and cellular processes. Activation of Notch signaling is normally tightly controlled by direct interactions with ligand-expressing cells, and dysregulated Notch signaling is associated with developmental abnormalities and cancer. While canonical Notch ligands are responsible for the majority of Notch signaling, a diverse group of structurally unrelated noncanonical ligands has also been identified that activate Notch and likely contribute to the pleiotropic effects of Notch signaling. Soluble forms of both canonical and noncanonical ligands have been isolated, some of which block Notch signaling and could serve as natural inhibitors of this pathway. Ligand activity can also be indirectly regulated by other signaling pathways at the level of ligand expression, serving to spatiotemporally compartmentalize Notch signaling activity and integrate Notch signaling into a molecular network that orchestrates developmental events. Here, we review the molecular mechanisms underlying the dual role of Notch ligands as activators and inhibitors of Notch signaling. Additionally, evidence that Notch ligands function independent of Notch is presented. We also discuss how ligand posttranslational modification, endocytosis, proteolysis, and spatiotemporal expression regulate their signaling activity.

Introduction

The Notch pathway functions as a core signaling system during embryonic development and is also required for the regulation of tissue homeostasis and stem cell maintenance in the adult (Artavanis-Tsakonas et al., 1999, Gridley, 1997, Gridley, 2003). Ligand-induced Notch signaling directs the specification of a variety of cell types and contributes to tissue patterning and morphogenesis through effects on cellular differentiation, proliferation, survival, and apoptosis (Bray, 2006, Fiuza and Arias, 2007). Given the widespread usage of the Notch pathway in different cell types and cellular processes, it is not surprising that defects in Notch ligands are associated with hereditary diseases such as Alagille syndrome and spondylocostal dysostosis and that aberrant ligand expression is detected in several cancers (Koch and Radtke, 2007, Leong and Karsan, 2006, Piccoli and Spinner, 2001, Turnpenny et al., 2007).

The canonical ligands that bind and activate Notch receptors are integral cell surface proteins, and thus activation of Notch signaling is dependent on direct cell-to-cell interactions. The transmembrane nature of Notch ligands serves to limit signaling to local cell interactions and additionally provides a signaling system for cells to communicate directly with their neighbors. Interestingly, during certain developmental processes, ligands have been found to activate Notch expressed on the surface of distantly located cells. Such long range signaling may utilize actin-based cellular projections to deliver activating signals to Notch at distant sites (de Joussineau et al., 2003). In support of such a model, the ligand Delta appears to concentrate in filopodia-like projections, possibly inducing and stabilizing these structures to facilitate long-range signaling (de Joussineau et al., 2003, Renaud and Simpson, 2001). Similarly, the Caenorhabditis elegans, distal tip cell has long cellular processes that contain the ligand Lag2 and appear to extend all the way to the mitotic/meiotic border where they regulate proliferation of the germ line through activation of the Notch homolog Glp1 (Fitzgerald and Greenwald, 1995).

Signaling induced by Notch cells following engagement with ligand cells involves a series of proteolytic cleavages in Notch to release the intracellular domain (ICD) that functions directly as the biologically active signal transducer (Kopan and Ilagan, 2009). During maturation and trafficking to the cell surface, the Notch receptor is processed by a furin-like protease to produce an intramolecular heterodimer that predisposes Notch to proteolytic activation by ligand. Interactions with ligand cells result in an extracellular juxtamembrane cleavage in Notch catalyzed by an A-Disintegrin-And-Metalloprotease (ADAM), which is followed by an intramembrane cleavage by γ-secretase to release the Notch intracellular domain (NICD) from the membrane (Fig. 3.1). NICD translocates to the nucleus where it functions directly in signal transduction through complexing with the CSL (CBF1, Su(H), LAG1) DNA binding protein and transcriptional coactivators to switch on expression of Notch target genes such as hairy and enhancer of split (HES) family. The mechanism and details of Notch transcriptional activation are covered extensively in Chapter 8. In addition to the well-characterized role for the activation of Notch signaling through cell–cell interactions (trans-interactions), ligands can also interact with Notch cell autonomously (cis-interactions) leading to inhibition of Notch signaling. The nature and mechanisms underlying the inhibitory role of Notch ligands will be discussed in Section 3 of this review. Additional characteristics of canonical and noncanonical Notch ligands required to activate signaling are discussed below.

Section snippets

Canonical Notch Ligand Structure

The majority of Notch signaling is induced by a family of DSL ligands that are characterized by the presence of a DSL (Delta, Serrate, and Lag2) domain (Henderson et al., 1994, Tax et al., 1994). The mammalian DSL ligands are classified as either Delta-like (Dll1, Dll3, and Dll4) or Serrate (Jagged)-like (Jagged1 and Jagged2) based on homology to their Drosophila prototypes Delta and Serrate (Kopan and Ilagan, 2009). DSL ligands are type 1 transmembrane proteins that share a common modular

Canonical Ligands as Inhibitors of Notch Signaling

The Notch receptors and DSL ligands are widely expressed during development, and in many cases, interacting cells express both ligands and receptors. Cells take on distinct fates because Notch signaling is consistently activated in only one of the two interacting cells, indicating that the signaling polarity must be highly regulated. The relative levels of Notch and its ligands present on interacting cells are thought to establish the signaling polarity necessary to ensure that the correct cell

Glycosylation

The Notch ligands and receptors undergo O- and N-linked glycan modifications at conserved sequences within specific EGF repeats; however, only O-fucose and O-glucose additions to Notch have so far been reported to affect signaling. N-glycan modifications of Notch, on the other hand, do not appear to alter Notch-dependent development in mice (Haltiwanger and Lowe, 2004). Glycosylation of Notch both positively and negatively regulates signaling induced by ligands, presumably through modulating

Ligand Endocytosis in Activation of Notch Signaling

A requirement for direct cell-to-cell interactions is a hallmark of Notch signaling; however, the transmembrane property of the ligands may underlie the basic mechanism of Notch activation that is dependent on ligand endocytosis. Specifically, in the absence of endocytosis, ligands accumulate at the cell surface but fail to activate signaling (Itoh et al., 2003, Nichols et al., 2007a, Parks et al., 2000). That ligands need to be internalized by the signal-sending cell to activate Notch on the

Regulation of DSL Ligand Activity by Proteolysis

DSL ligands undergo proteolytic cleavage by ADAMs and γ-secretase as described for Notch; however, in contrast to signaling induced by Notch proteolysis, proteolytic removal of cell surface ligand can either inhibit or enhance Notch signaling. Although Notch proteolysis generates an intracellular fragment that acts as the signal transducer, it is less clear if the cleavage products generated by ligand proteolysis have intrinsic activity (Fig. 3.4). A detailed review describing the proteases

DSL Ligand Interactions with PDZ-Domain Containing Proteins

The vertebrate DSL ligands Dll1, Dll4, and Jagged1 have PDZ-binding motifs at their carboxy-termini (Pintar et al., 2007), which mediate interactions with PDZ-containing scaffold/adaptor proteins (Ascano et al., 2003, Estrach et al., 2007, Mizuhara et al., 2005, Pfister et al., 2003, Six et al., 2004, Wright et al., 2004). While being dispensable for both ligand activation (Ascano et al., 2003, Mizuhara et al., 2005, Six et al., 2004, Wright et al., 2004) and inhibition of Notch signaling (

Regulation of DSL Ligand Expression Patterns

Notch signaling can both positively and negatively regulate DSL ligand expression, such that defects in Notch signaling are associated with increased expression of Dll1 (Barrantes et al., 1999, de la Pompa et al., 1997) or Dll4 (Suchting et al., 2007). On the other hand, Notch inductive signals upregulate DSL ligand expression, which is necessary for proper wing margin formation in flies (Doherty et al., 1996) as well as somite formation and patterning in vertebrates (Barrantes et al., 1999,

Noncanonical Ligands

In contrast to other signaling systems that employ a large number of activating ligands, there are only four mammalian ligands known to activate Notch receptors. It is difficult to account for the pleiotropic affects of Notch given this limited number of DSL ligands; however, the identification of noncanonical ligands expands the repertoire of ligands reported to activate signaling. Unlike the activating canonical ligands that contain a DSL domain required to interact with Notch (Fig. 3.2),

Conclusions and Future Directions

Although unique ligand–receptor combinations have been identified that induce specific cellular responses, the molecular mechanisms underlying ligand-specific signaling remains an outstanding question in the field. Moreover, given the direct and somewhat simple signaling mechanism ascribed to Notch, it is unclear how different Notch ligands could induce distinct signaling responses. It will be important to determine if different ligand–Notch complexes recruit unique signaling effectors and

Acknowledgments

We thank Abdiwahab Musse and Jason Tchieu for help with the illustrations and Alison Miyamoto for contributions to the material previously published in Oncogene (2008) 27, 5148–5167. The authors acknowledge the National Institute of Health NIH (GW), Jonsson Comprehensive Cancer Center (JCCF) (LMK), and Association of International Cancer Research (AICR) (BD) for financial support.

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