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J. Biol. Chem., Vol. 282, Issue 16, 12341-12352, April 20, 2007

This Article Full Text Full Text (PDF) All Versions of this Article: 282/16/12341    most recent M610948200v1 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 Miki, T. Articles by Takahashi, C. Search for Related Content PubMed PubMed Citation Articles by Miki, T. Articles by Takahashi, C. Social Bookmarking                      What's this?

The Reversion-inducing Cysteine-rich Protein with Kazal Motifs (RECK) Interacts with Membrane Type 1 Matrix Metalloproteinase and CD13/Aminopeptidase N and Modulates Their Endocytic Pathways^*

Takao Miki¹, Yujiro Takegami, Katsuya Okawa, Teruyuki Muraguchi, Makoto Noda, and Chiaki Takahashi^¶2

From the Department of Molecular Oncology, Horizontal Medical Research Organization, ^¶the 21st Century Center of Excellence Formation, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan

The reversion-inducing cysteine-rich protein with Kazal motifs (RECK) is anchored to the cell surface via glycosylphosphatidylinositol. This molecule antagonizes the function of membrane type 1 matrix metalloproteinase (MT1-MMP) to promote proMMP-2 maturation. Here, we attempt to clarify the mechanism underlying RECK functions. First, we found that RECK forms a complex with MT1-MMP and inhibits its proteolytic activity. Notably, RECK increases the amount of MT1-MMP that associates with detergent-resistant membranes during sucrose gradient ultracentrifugation. Furthermore, perturbation of membrane cholesterol significantly affected the function of RECK in suppressing MT1-MMP function. These findings indicate that RECK possibly regulates MT1-MMP function by modulating its behavior on the cell surface as well as by enzymatic action; this prompted us to find another molecule whose behavior in detergent-resistant membranes is influenced by RECK. Subsequently, we found that RECK interacts with CD13/aminopeptidase N. Further, we found that RECK inhibits the proteolytic activity of CD13 in a cholesterol perturbation-sensitive manner. Finally, we examined whether RECK influences the behavior of MT1-MMP and CD13 during their internalization from the cell surface. In the absence of RECK, MT1-MMP and CD13 were internalized along with the markers of clathrin- or caveolae-dependent endocytosis. However, interestingly, in the presence of RECK these molecules were internalized preferentially with an endocytic marker that is neither clathrinnor caveolae-dependent, indicating that RECK modulates endocytic pathways of MT1-MMP and CD13. This modulation was correlated with the accelerated internalization and decay of MT1-MMP and CD13. This study unveils the novel function and target molecules of RECK.

Received for publication, November 28, 2006 , and in revised form, February 26, 2007.

^* This work was supported by funds from The 21st Century COE Formation, Mitsubishi Pharma Research Foundation, and Public Trust Haraguchi Memorial Cancer Research Fund, a research grant from the Princess Taka-matsu Cancer Research Fund (to C. T.), and by the Ministry of Education, Culture, Sports, Science and Technology (to C. T. and M. N.). 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.

¹ Supported by the Japan Student Services Organization.

² To whom correspondence should be addressed: The 21st Century COE Formation, Kyoto University Graduate School of Medicine, Yoshida-Konoecho, Sakyo-ku, Kyoto 606-8501, Japan. Tel.: 81-75-751-4151; Fax: 81-75-751-4159; E-mail: chtakaha{at}virus.kyoto-u.ac.jp.

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