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Molecular and Cellular Biology, January 2008, p. 165-176, Vol. 28, No. 1
0270-7306/08/$08.00+0     doi:10.1128/MCB.00863-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Regulation of Notch Signaling by Dynamic Changes in the Precision of S3 Cleavage of Notch-1 ^,

Shinji Tagami,^1, Masayasu Okochi,^1*, Kanta Yanagida,¹ Akiko Ikuta,¹ Akio Fukumori,¹ Naohiko Matsumoto,¹ Yoshiko Ishizuka-Katsura,¹ Taisuke Nakayama,¹ Naohiro Itoh,¹ Jingwei Jiang,¹ Kouhei Nishitomi,¹ Kouzin Kamino,¹ Takashi Morihara,¹ Ryota Hashimoto,¹ Toshihisa Tanaka,¹ Takashi Kudo,¹ Shigeru Chiba,² and Masatoshi Takeda¹

Department of Post-Genomics and Diseases, Division of Psychiatry and Behavioral Proteomics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan,¹ Department of Cell Therapy and Transplantation Medicine, University of Tokyo Hospital, Bunkyo-ku, Tokyo 113-8655, Japan²

Received 16 May 2007/ Returned for modification 19 July 2007/ Accepted 11 October 2007

Intramembrane proteolysis by presenilin-dependent -secretase produces the Notch intracellular cytoplasmic domain (NCID) and Alzheimer disease-associated amyloid-β. Here, we show that upon Notch signaling the intracellular domain of Notch-1 is cleaved into two distinct types of NICD species due to diversity in the site of S3 cleavage. Consistent with the N-end rule, the S3-V cleavage produces stable NICD with Val at the N terminus, whereas the S3-S/S3-L cleavage generates unstable NICD with Ser/Leu at the N terminus. Moreover, intracellular Notch signal transmission with unstable NICDs is much weaker than that with stable NICD. Importantly, the extent of endocytosis in target cells affects the relative production ratio of the two types of NICD, which changes in parallel with Notch signaling. Surprisingly, substantial amounts of unstable NICD species are generated from the ValGly and the LysArg mutants, which have been reported to decrease S3 cleavage efficiency in cultured cells. Thus, we suggest that the existence of two distinct types of NICD points to a novel aspect of the intracellular signaling and that changes in the precision of S3 cleavage play an important role in the process of conversion from extracellular to intracellular Notch signaling.

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* Corresponding author. Mailing address: Department of Post-Genomics and Diseases, Division of Psychiatry and Behavioral Proteomics, Osaka University Graduate School of Medicine, D3, Yamada-oka 2-2, Suita, Osaka 565-0871, Japan. Phone: 81-6-6879-3053. Fax: 81-6-6879-3059. E-mail: mokochi{at}psy.med.osaka-u.ac.jp

Published ahead of print on 29 October 2007.

Supplemental material for this article may be found at http://mcb.asm.org/.

These authors contributed equally to this work.

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Molecular and Cellular Biology, January 2008, p. 165-176, Vol. 28, No. 1
0270-7306/08/$08.00+0     doi:10.1128/MCB.00863-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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