HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 279, Issue 17, 17785-17791, April 23, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/17/17785    most recent M310772200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Suzuki, N. Articles by Kadomatsu, K. Search for Related Content PubMed PubMed Citation Articles by Suzuki, N. Articles by Kadomatsu, K. Social Bookmarking                      What's this?

Proteasomal Degradation of the Nuclear Targeting Growth Factor Midkine^*

Noriyuki Suzuki, Yoshihisa Shibata, Takeshi Urano¶, Toyoaki Murohara, Takashi Muramatsu, and Kenji Kadomatsu||

From the Departments of Biochemistry, Cardiology, and ^¶Biochemistry II, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan

It is widely held that growth factor signaling is terminated by lysosomal degradation of its activated receptor and the endocytosed growth factor is transported to lysosomes. Nuclear targeting is another important pathway through which signals of growth factors are mediated. However, mechanisms underlying desensitization of nuclear targeting growth factors are poorly understood. Here we report that the nuclear targeting pathway is down-regulated by the proteasome system. Degradation of endocytosed midkine, a heparin-binding growth factor, was suppressed by both proteasome and lysosome inhibitors to similar extents. By contrast, a proteasome inhibitor, but not lysosome ones, accelerated the nuclear accumulation of midkine. An expression vector of signal sequence-less midkine, which is produced in the cytosol, was constructed because endocytosed midkine may be translocated to the cytosol from cellular compartments before entering the nucleus. The cytosol-produced midkine underwent proteasomal degradation and accumulated in the nucleus as did the endocytosed midkine. It was polyubiquitinated, and its nuclear accumulation was enhanced by a proteasome inhibitor. We further dissected the midkine molecule to investigate roles in degradation and trafficking. The N-terminal half-domain of midkine was significantly more susceptible to proteasomal degradation, whereas the C-terminal half-domain was sufficient for nuclear localization. Together, these data highlight the desensitization of nuclear targeting by growth factors and indicate a critical role of the proteasome system in it.

Received for publication, September 30, 2003 , and in revised form, January 29, 2004.

^* This work was supported by Grants-in-aid 15390103 and 14580647 from the Ministry of Education, Science, Sports and Culture of Japan and the Suzuken Memorial Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed. Tel.: 81-52-744-2064; Fax: 81-52-744-2065; E-mail: kkadoma{at}med.nagoya-u.ac.jp.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?