**2. Notch signaling**

The human Notch receptor family comprises four members, Notch1 through Notch4, ex‐ pressed as transmembrane molecules on the cell surface of neighboring cells that enable canonical signaling in a contact-dependent manner (Bray, 2006; Kopan and Ilagan, 2009). Canonical Notch signaling describes the 'classic' interaction between membrane-bound receptors and ligands expressed on the surface of neighboring (signaling and receiving) cells, whereas non-canonical signaling encompasses a diverse group of structurally unrelated ligands that contribute to the pleiotropic effect of Notch signaling (Kopan and Ilagan, 2009). In mammals, five members of the Delta-Serrate-LAG-2 (DSL) family have the capacity to activate or modify canonical Notch signaling — Delta-like 1 (Dll1), Dll3, Dll4, Jagged1, and Jagged2. Interaction between Notch receptor and ligand is tightly controlled, and the signaling outcome is determined by the receptor:ligand ratio (Artavanis-Tsakonas and Muskavitch, 2010; Gibert and Simpson, 2003; Heitzler and Simpson, 1991; Wilkinson et al., 1994) that critically determines asymmetry in cell fate and development of neighboring cells. This interaction between receptor and ligand can be modified posttranslationally through Notch glycosylation by lunatic, manic and radical glycosyltransferases (Bray, 2006). The receptor:li‐ gand ratio is dependent on the differential expression of competing ligands on neighboring cells in *trans*, as opposed to *cis* interaction through which receptor and ligand expressed on the same cell can also modulate Notch signaling. The complexity of receptor–ligand interaction is further increased by the requirement of heterodimerization of the receptor (Kopan and Ilagan, 2009). Canonical interaction between Notch receptor and ligand leads to two sequential cleavage events at site 2 (S2) and S3. S2 is a 'permissive' extracellular juxtamembrane cleavage by a disintegrin and metalloprotease 17 (ADAM17, known also as tumor necrosis factor-α converting enzyme/TACE) and/or ADAM10 (Artavanis-Tsakonas and Muskavitch, 2010; Bray, 2006), whereas S3 is executed by γ-secretase, a protease with many substrates (McCarthy et al., 2009; Wakabayashi and De Strooper, 2008). S1 cleavage is carried out by a furin-like convertase occurring posttranslationally in the trans-Golgi apparatus before translocation of the nascent Notch receptor to the cell surface (Bray, 2006; Kopan and Ilagan, 2009). Following S3 cleavage, the Notch intracellular domain is liberated and enters the nucleus to form a transcription activational complex with the transcriptional factor RBP-Jκ, and the transcrip‐ tional coactivator Mastermind to promote target gene transcription (Bray, 2006; Kopan and Ilagan, 2009). Targets indicative of Notch activity include the basic-helix-loop-helix genes of the hairy and enhancer of split (HES) and the hairy-related (HRT or Hey) family (Bray, 2006; Kopan and Ilagan, 2009).

Functionality of Notch signaling components is highly context-dependent and conventionally requires cell-to-cell contact to specify cell fate, differentiation, growth, proliferation, survival and apoptosis (Bray, 2006; Fiuza and Arias, 2007; Guruharsha et al., 2012). Interaction between Notch receptor and ligand on adjacent cells results in asymmetric signal transduction, leading to potentially divergent cell fate decision, phenotypic development and growth (Bray, 2006; Kopan and Ilagan, 2009).
