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Molecular and Cellular Biology, October 2002, p. 6788-6796, Vol. 22, No. 19
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.19.6788-6796.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Nuclear Targeting by the Growth Factor Midkine

Yoshihisa Shibata,1,2 Takashi Muramatsu,1 Makoto Hirai,2 Tatsuya Inui,3 Terutoshi Kimura,3 Hidehiko Saito,2,4 Lynn M. McCormick,5 Guojun Bu,5 and Kenji Kadomatsu1*

Department of Biochemistry,1 Department of Internal Medicine, Nagoya University School of Medicine, Showa-ku, Nagoya 466-8550,2 Peptide Institute Inc., Minoh, Osaka 562-0015,3 Nagoya National Hospital, Naka-ku, Nagoya 460-0001, Japan,4 Departments of Pediatrics and Cell Biology and Physiology, Washington University School of Medicine and St. Louis Children's Hospital, St. Louis, Missouri 631105

Received 14 May 2002/ Accepted 17 June 2002

Ligand-receptor internalization has been traditionally regarded as part of the cellular desensitization system. Low-density lipoprotein receptor-related protein (LRP) is a large endocytosis receptor with a diverse array of ligands. We recently showed that LRP binds heparin-binding growth factor midkine. Here we demonstrate that LRP mediates nuclear targeting by midkine and that the nuclear targeting is biologically important. Exogenous midkine reached the nucleus, where intact midkine was detected, within 20 min. Midkine was not internalized in LRP-deficient cells, whereas transfection of an LRP expression vector restored midkine internalization and subsequent nuclear translocation. Internalized midkine in the cytoplasm bound to nucleolin, a nucleocytoplasmic shuttle protein. The midkine-binding sites were mapped to acidic stretches in the N-terminal domain of nucleolin. When the nuclear localization signal located next to the acidic stretches was deleted, we found that the mutant nucleolin not only accumulated in the cytoplasm but also suppressed the nuclear translocation of midkine. By using cells that overexpressed the mutant nucleolin, we further demonstrated that the nuclear targeting was necessary for the full activity of midkine in the promotion of cell survival. This study therefore reveals a novel role of LRP in intracellular signaling by its ligand and the importance of nucleolin in this process.

* Corresponding author. Mailing address: Department of Biochemistry, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. Phone: 81-52-744-2064. Fax: 81-52-744-2065. E-mail: kkadoma{at}med.nagoya-u.ac.jp.

Molecular and Cellular Biology, October 2002, p. 6788-6796, Vol. 22, No. 19
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.19.6788-6796.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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