The Notch 'gospel'

Abstract

Workshop on Notch Signalling in Development and Cancer

Figure 1

Notch receptors and their ligands. Drosophila contains one Notch receptor (dNotch) that is bound by two transmembrane DSL-ligands (Delta and Serrate). Mammalians possess four Notch receptors (Notch1–4) and five ligands (Jagged1 and 2, which are homologous to Serrate, and Delta-like (Dll) 1, 3 and 4, which are homologous to Delta). Notch receptors are expressed on the cell surface as heterodimeric proteins. Their extracellular portion contains 29–36 epidermal growth factor (EGF)-like repeats that are associated with ligand binding, followed by three cysteine-rich LIN repeats that prevent ligand-independent signalling, and a heterodimerization domain. The intracellular portion of the receptor harbours two protein interaction domains, the RAM domain (R) and six ankyrin repeats (ANK), two nuclear localizations signals (NLS) and a transactivation domain (TAD, which has not yet been defined for Notch3 and 4), and a PEST (P) sequence. Notch ligands are also expressed as membrane-bound proteins. They all contain an amino-terminal DSL domain (Delta, Serrate and Lag2) followed by EGF-like repeats. Ligands of the Serrate family also harbour a cysteine-rich (CR) domain downstream of the EGF-like repeats. PM, plasma membrane.

Figure 2

Notch signalling. Notch receptors are synthesized as single precursor proteins that are cleaved in the Golgi by a Furin-like convertase during their transport to the cell surface where they are expressed as heterodimers. Fringe glycosyltransferases modify EGF-like repeats by adding N-acetylglucosamine within the Golgi. Notch signalling is initiated after ligand-receptor interaction, which induces two sequential proteolytic cleavages. The first cleavage within the extracellular domain is mediated by the metalloprotease TACE (tumor necrosis factor α-converting enzyme). The cleaved extracellular subunit of the receptor is ‘trans-endocytosed' by the neighbouring ligand-expressing cell. This process seems to be controlled by Neuralized and/or Mindbomb E3 ubiqutin ligases. The second cleavage occurs within the transmembrane domain and is mediated by the γ-secretase activity of the multi-protein complex of presenilins (PS), which includes Nicastrin, APH-1 and PEN-2. The liberated intracellular domain of Notch (NICD) translocates into the nucleus and binds to the transcription factor CSL (CBF1 in humans, Supressor of Hairless in Drosophila and LAG in C. elegans). This interaction leads to transcriptional activation by displacement of corepressors (CoR) and simultaneous recruitment of coactivators (CoA), including mastermind-like proteins (MAML1). Receptors modified by Fringe glycosyltransferases cannot mediate signalling via Jagged ligands, whereas Delta-mediated Notch signalling is still possible.

The EMBO Workshop on Notch Signalling in Development and Cancer was held between 22 and 25 April 2005 in Rome, Italy, and was organized by I. Screpanti, B. Osborne, L. Miele, S. Krishna and U. Lendahl.