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J. Biol. Chem., Vol. 281, Issue 41, 31164-31172, October 13, 2006

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Nardilysin Enhances Ectodomain Shedding of Heparin-binding Epidermal Growth Factor-like Growth Factor through Activation of Tumor Necrosis Factor--converting Enzyme^*

Eiichiro Nishi¹, Yoshinori Hiraoka, Kazuhiro Yoshida, Katsuya Okawa^¶, and Toru Kita

From the Molecular Pathology and ^¶Biomolecular Characterization Unit, Horizontal Medical Research Organization, and the Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan

Like other members of the epidermal growth factor family, heparin-binding epidermal growth factor-like growth factor (HB-EGF) is synthesized as a transmembrane protein that can be shed enzymatically to release a soluble growth factor. Ectodomain shedding is essential to the biological functions of HB-EGF and is strictly regulated. However, the mechanism that induces the shedding remains unclear. We have recently identified nardilysin (N-arginine dibasic convertase (NRDc)), a metalloendopeptidase of the M16 family, as a protein that specifically binds HB-EGF (Nishi, E., Prat, A., Hospital, V., Elenius, K., and Klagsbrun, M. (2001) EMBO J. 20, 3342-3350). Here, we show that NRDc enhances ectodomain shedding of HB-EGF. When expressed in cells, NRDc enhanced the shedding in cooperation with tumor necrosis factor--converting enzyme (TACE; ADAM17). NRDc formed a complex with TACE, a process promoted by phorbol esters, general activators of ectodomain shedding. NRDc enhanced TACE-induced HB-EGF cleavage in a peptide cleavage assay, indicating that the interaction with NRDc potentiates the catalytic activity of TACE. The metalloendopeptidase activity of NRDc was not required for the enhancement of HB-EGF shedding. Notably, a reduction in the expression of NRDc caused by RNA interference was accompanied by a decrease in ectodomain shedding of HB-EGF. These results indicate the essential role of NRDc in HB-EGF ectodomain shedding and reveal how the shedding is regulated by the modulation of sheddase activity.

Received for publication, February 10, 2006 , and in revised form, August 4, 2006.

^* This work was supported by Special Coordination Funds for Promoting Science and Technology Research Grants 16590680 and 18590809 from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, by a Japan Heart Foundation research grant, by the Takeda Science Foundation, and by the Kanae Foundation for Life & Socio-Medical Science. 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 To whom correspondence should be addressed: Molecular Pathology Unit, Horizontal Medical Research Organization, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-Cho, Sakyo-Ku, Kyoto 606-8507, Japan. Tel.: 81-75-751-3187; Fax: 81-75-751-3203; E-mail: nishi{at}kuhp.kyoto-u.ac.jp.

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