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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-J
-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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