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Molecular and Cellular Biology, September 2000, p. 6913-6922, Vol. 20, No. 18
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Binding of Delta1, Jagged1, and Jagged2 to Notch2 Rapidly Induces Cleavage, Nuclear Translocation, and Hyperphosphorylation of Notch2

Kiyoshi Shimizu,1,2 Shigeru Chiba,1,2 Noriko Hosoya,1,2 Keiki Kumano,1,2 Toshiki Saito,1,2 Mineo Kurokawa,1,2 Yoshinobu Kanda,1,2 Yoshio Hamada,3 and Hisamaru Hirai1,2,*

Departments of Hematology and Oncology1 and Cell Therapy and Transplantation Medicine,2 Graduate School of Medicine, University of Tokyo, Tokyo, and National Institute of Basic Biology, Okazaki,3 Japan

Received 22 February 2000/Returned for modification 21 March 2000/Accepted 30 May 2000

Delta1, Jagged1, and Jagged2, commonly designated Delta/Serrate/LAG-2 (DSL) proteins, are known to be ligands for Notch1. However, it has been less understood whether they are ligands for Notch receptors other than Notch1. Meanwhile, ligand-induced cleavage and nuclear translocation of the Notch protein are considered to be fundamental for Notch signaling, yet direct observation of the behavior of the Notch molecule after ligand binding, including cleavage and nuclear translocation, has been lacking. In this report, we investigated these issues for Notch2. All of the three DSL proteins bound to endogenous Notch2 on the surface of BaF3 cells, although characteristics of Jagged2 for binding to Notch2 apparently differed from that of Delta1 and Jagged1. After binding, the three DSL proteins induced cleavage of the membrane-spanning subunit of Notch2 (Notch2TM), which occurred within 15 min. In a simultaneous time course, the cleaved fragment of Notch2TM was translocated into the nucleus. Interestingly, the cleaved Notch2 fragment was hyperphosphorylated also in a time-dependent manner. Finally, binding of DSL proteins to Notch2 also activated the transcription of reporter genes driven by the RBP-Jkappa -responsive promoter. Together, these data indicate that all of these DSL proteins function as ligands for Notch2. Moreover, the findings of rapid cleavage, nuclear translocation, and phosphorylation of Notch2 after ligand binding facilitate the understanding of the Notch signaling.

* Corresponding author. Mailing address: Department of Cell Therapy and Transplantation Medicine, University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Phone: 81-3-5804-6690. Fax: 81-3-5689-7286. E-mail: hhirai-tky{at}umin.ac.jp.

Molecular and Cellular Biology, September 2000, p. 6913-6922, Vol. 20, No. 18
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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