INTRACELLULAR CLEAVAGE OF NOTCH LEADS TO A HETERODIMERIC RECEPTOR ON THE PLASMA-MEMBRANE

Previous models for signal transduction via the Notch pathway have dep icted the full-length Notch receptor expressed at the cell surface. We present evidence demonstrating that the Notch receptor on the plasma membrane is cleaved. This cleavage is an evolutionarily conserved, gen eral property of Notch and occurs in the trans-Golgi network as the re ceptor traffics toward the plasma membrane. Although full-length Notch is detectable in the cell, it does not reach the surface. Cleavage re sults in a C-terminal fragment, N(TM), that appears to be cleaved N-te rminal to the transmembrane domain, and an N-terminal fragment, N-EC, that contains most of the extracellular region. We provide evidence th at these fragments are tethered together on the plasma membrane by a l ink that is sensitive to reducing conditions, forming a heterodimeric receptor.