SIGNAL-TRANSDUCTION BY ACTIVATED MNOTCH - IMPORTANCE OF PROTEOLYTIC PROCESSING AND ITS REGULATION BY THE EXTRACELLULAR DOMAIN

Previous studies imply that the intracellular domain of Notch1 must tr anslocate to the nucleus for its activity. In this study, we demonstra te that a mNotch 1 mutant protein that lacks its extracellular domain but retains its membrane-spanning region becomes proteolytically proce ssed on its intracellular surface and, as a result, the activated intr acellular domain (mNotchIC) is released and can move to the nucleus, P roteolytic cleavage at an intracellular site is blocked by protease in hibitors, Intracellular cleavage is not seen in cells transfected with an inactive variant, which includes the extracellular lin-Notch-glp r epeats. Collectively, the studies presented here support the model tha t mNotch1 is proteolytically processed and the cleavage product is tra nslocated to the nucleus for mNotch1 signal transduction.