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Molecular and Cellular Biology, November 2009, p. 5679-5695, Vol. 29, No. 21
0270-7306/09/$08.00+0     doi:10.1128/MCB.00406-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Selective Use of ADAM10 and ADAM17 in Activation of Notch1 Signaling{triangledown}

Esra Cagavi Bozkulak1 and Gerry Weinmaster1,2,3*

Department of Biological Chemistry, David Geffen School of Medicine,1 Molecular Biology Institute,2 Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California 900953

Received 28 March 2009/ Returned for modification 2 July 2009/ Accepted 11 August 2009

Notch signaling requires a series of proteolytic cleavage events to release the Notch intracellular domain (NICD) that functions directly in signal transduction. The Notch receptor is locked down in a protease-resistant state by a negative regulatory region (NRR) that protects an ADAM (a disintegrin and metalloprotease) cleavage site. Engagement with ligand-bearing cells induces global conformational movements in Notch that unfold the NRR structure to expose the ADAM cleavage site and initiate proteolytic activation. Although both ADAM10 and ADAM17 have been reported to cleave Notch to facilitate NICD release by {gamma}-secretase, the relevant ADAM has remained controversial. Our study provides new insight into this conflict, as we find that although Notch1 (N1) is a substrate for both ADAM10 and ADAM17, the particular ADAM required for receptor activation is context dependent. Specifically, ADAM10 was absolutely required for N1 signaling induced by ligands, while signaling independent of ligands required ADAM17. In contrast to the strict and differential use of ADAM10 and ADAM17 in normal and dysregulated signaling, respectively, both proteases participated in signaling intrinsic to N1 mutations associated with leukemia. We propose that in addition to exposing the ADAM cleavage site, activating N1 conformational changes facilitate selective cleavage by specific proteases.

* Corresponding author. Mailing address: 615 Charles Young Drive South, BSRB-390A, Box 951737, Los Angeles, CA 90095-1737. Phone: (310) 206-9446. Fax: (310) 206-5272. E-mail: gweinmaster{at}mednet.ucla.edu

{triangledown} Published ahead of print on 24 August 2009.

Molecular and Cellular Biology, November 2009, p. 5679-5695, Vol. 29, No. 21
0270-7306/09/$08.00+0     doi:10.1128/MCB.00406-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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