Notch signaling in hepatocellular carcinoma: guilty in association!

Notch signaling is a complex, highly conserved mechanism, originally discovered as critical regulator of cell fate determination during development in several tissues and organs.1,2 Activation of Notch may stimulate cells either to undergo a phenotypic switch or to maintain the original cell phenotype by preventing further differentiation,3 Notch is also involved in establishing organ-specific stem cell niches necessary for epithelial tissue homeostasis.3,4 The Notch system encompasses 4 genes encoding for different membrane receptors (Notch 1, 2, 3, and 4), which are activated by their binding to 5 ligands (Jagged-1, Jagged-2, and Delta-like 1, 3, and 4).4 Cell-to-cell contact is a prerequisite for the activation of Notch signaling.3,4 Whereas Notch receptors are expressed by the “receiver” cell, ligands are expressed by the “transmitter” cell. This interaction leads to the proteolytic cleavage and subsequent nuclear translocation of the intracellular domain of Notch receptors (NICD). Once migrated into the nucleus, NICD associates with the nuclear protein of the RBP-Jκ family and transcriptionally activates several other transcriptional activators or repressors that act as critical regulators of cell differentiation, apoptosis, and proliferation4 (see drawing on the left side of Figure 1). NICD is then rapidly deactivated by phosphorylation and by proteosomal degradation. The signal is maintained through ligand-induced proteolytic supply of new NICD.