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Published online February 12, 2007
doi:10.1083/jcb.200609014
The Journal of Cell Biology, Vol. 176, No. 4, 445-458
The Rockefeller University Press, 0021-9525 $30.00
© 2007 Nichols et al.
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Article

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

James T. Nichols1, Alison Miyamoto1, Samantha L. Olsen1, Brendan D'Souza1, Christine Yao1, and Gerry Weinmaster1,2,3

1 Department of Biological Chemistry, David Geffen School of Medicine, 2 Molecular Biology Institute, and 3 Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095

Correspondence to Gerry Weinmaster: gweinmaster{at}mednet.ucla.edu

Cleavage of Notch by furin is required to generate a mature, cell surface heterodimeric receptor that can be proteolytically activated to release its intracellular domain, which functions in signal transduction. Current models propose that ligand binding to heterodimeric Notch (hNotch) induces a disintegrin and metalloprotease (ADAM) proteolytic release of the Notch extracellular domain (NECD), which is subsequently shed and/or endocytosed by DSL ligand cells. We provide evidence for NECD release and internalization by DSL ligand cells, which, surprisingly, did not require ADAM activity. However, losses in either hNotch formation or ligand endocytosis significantly decreased NECD transfer to DSL ligand cells, as well as signaling in Notch cells. Because endocytosis-defective ligands bind hNotch, but do not dissociate it, additional forces beyond those produced through ligand binding must function to disrupt the intramolecular interactions that keep hNotch intact and inactive. Based on our findings, we propose that mechanical forces generated during DSL ligand endocytosis function to physically dissociate hNotch, and that dissociation is a necessary step in Notch activation.

Abbreviations used in this paper: ADAM, a disintegrin and metalloprotease; CSL, CBF1, SuH, LAG-1; DIC, differential interference contrast; DSL, Delta/Serrate/Lag-2; hNotch, heterodimeric Notch; NECD, Notch extracellular domain; NICD, Notch intracellular domain; RIP, regulated intramembrane proteolysis.


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