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Endocytosis pulls Notch apart

Delta cells (blue) pull on the Notch cell to remove and take up the Notch extracellular domain (green).

Notch'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 intracellular domain that can travel to the nucleus to activate gene expression. Three proteases are known to trim Notch. The first, 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 -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 -secretase and can activate signaling in its own cell.

Nichols et al. prove for the first 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.

Nicole LeBrasseur

lebrasn{at}rockefeller.edu

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DSL ligand endocytosis physically dissociates Notch1 heterodimers before activating proteolysis can occur

James T. Nichols, Alison Miyamoto, Samantha L. Olsen, Brendan D'Souza, Christine Yao, and Gerry Weinmaster
J. Cell Biol. 2007 176: 445-458. [Abstract] [Full Text] [PDF]

This Article Full Text (PDF, 1054K) PPT slides of all figures Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by LeBrasseur, N. Search for Related Content PubMed Articles by LeBrasseur, N. Related Collections Related Article Social Bookmarking                            What's this?