Endocytosis pulls Notch apart

N otch's neighbors are tearing it apart. On page 445, Nichols et al. show that endocytosis of a ligand on one cell pulls apart its Notch receptor on an adjacent cell, leaving behind an activation-susceptible receptor remnant. Dormant Notch on the cell surface must be cleaved into a free intra-cellular domain that can travel to the nucleus to activate gene expression. Three proteases are known to trim Notch. The fi rst, furin, cleaves before the receptor reaches the plasma membrane and leaves Notch in two pieces that are held together by noncovalent bonds. The next two cleavages, by ADAM and then γ-secretase, occur after Notch binds a ligand such as Delta on an adjacent cell. Endocytosis in the Delta cell is necessary to activate Notch signaling in the neighboring cell. One model proposes that Delta endocytosis makes the ADAM cleavage possible, thus allowing the extracellular portion of Notch to be taken in along with the ligand into the adjacent cell. The remaining piece of Notch is then accessible to γ-secretase and can activate signaling in its own cell. Nichols et al. prove for the fi rst time that part of Notch is indeed taken into the adjacent Delta cell. ADAM cleavage, however, was not necessary for the Notch transendocytosis. Instead, endocytosis itself provides a force that tears Notch apart at its furin cleavage site. ADAM was needed, however, for the remaining Notch to be activated. The authors propose that removing the extracellular portion by endocytosis is like pulling the pin from a grenade: it leaves behind a protease-accessible piece of Notch that soon explodes with activity. In the Delta cell, the " pin " is simply degraded. Because Notch regulates so many different processes, cells strictly prevent its inadvertent activation. In that case, the noncovalent bonds at the furin cleavage site must be strong. Endocytosis—and the bond between Delta and Notch—must be even stronger. Pinched off membrane C ells slough off extra membrane by pinching it off into the extra-cellular space, say Dubreuil et al. on page 483. The discarded membrane can be released by either cilia or midbodies, with potentially distinct outcomes. Membrane particles can be seen fl oat-ing in the extracellular space of the developing neural tube. These particles are distinct from signaling exosomes, leaving their origin in question. The authors now show that one origin of these particles is the midbody—the membrane structure that transiently connects two …