Notch Signaling

The Notch gene family encodes transmembrane receptors that are involved in cell fate choices in vertebrates and invertebrates. Notch signaling is an evolutionarily conserved mechanism for cell-cell interaction.The Notch receptor is a single transmembrane-spanning protein with a large extracellular domain, which requires to be proteolytically processed in order to be functional. The first cleavage of the receptor occurs at the extracellular side and takes place constitutively in the Golgi apparatus by a furin-like convertase. Only the cleaved fragments are presented at the cell surface. At the cell surface, the processed receptor interacts with ligand, Jagged or Delta, which are transmembrane proteins expressed on the signal sending cell. Ligand interaction leads to a second cleavage of the receptor close to the plasma membrane at the extracellular side, most likely catalyzed by TNFalpha-converting enzyme (TACE). The cleavage by TACE is a prerequisite for a final cleavage by gamma secretase, which releases the intracellular (IC) domain of the Notch receptor.The intracellular domain of the Notch receptor translocates to the nucleus and acts in conjunction with other DNA binding proteins like Mastermind (MAM) and Lag-1 (CSL) to regulate the transcription of the hairy/enhancer of split (Hes) and HES-related repressor protein (Herp) genes. The HES and HERP family of transcriptional repressors are the primary targets of Notch signaling. In addition to Jagged/Delta, Contactin (CNTN) also acts as a functional ligand of Notch. Interaction of CNTN with Notch triggers the gamma-secretase mediated nuclear translocation of the Notch IC domain. In the nucleus, Notch in conjunction with the trans factor Deltex (DTX) result in the up regulation of the myelin-associated glycoprotein (MAG) leading to oligodendrocyte maturation and myelination.This pathway highlights the important aspects of Notch signaling.