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J. Biol. Chem., Vol. 281, Issue 47, 36391-36400, November 24, 2006

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Neuralized-2 Regulates a Notch Ligand in Cooperation with Mind Bomb-1^*

Ran Song¹, Bon-Kyoung Koo¹, Ki-Jun Yoon, Mi-Jeong Yoon, Kyeong-Won Yoo, Hyun-Taek Kim, Hyeon-Jeong Oh, Yoon-Young Kim, Jin-Kwan Han, Cheol-Hee Kim, and Young-Yun Kong²

From the Division of Molecular and Life Sciences, Pohang University of Science and Technology, Pohang, Kyungbuk 790-784, South Korea and the Department of Biology, Chungnam National University, Daejeon 305-764, South Korea

Mutations in Drosophila neuralized (Dneur) result in a variety of developmental defects that closely resemble those of Notch mutants and other Notch pathway mutants. However, mice with disrupted neur1 do not show any aberrant cell fate specifications in neurogenesis and somitogenesis. Thus, we speculated that other vertebrate neur homolog(s) might compensate for loss of the neur gene. Here, we report the paralog of mouse Neur1, named Neuralized-2 (Neur2), which is a ubiquitin-protein isopeptide ligase (E3) that interacts with and ubiquitinates Delta. Both murine Neur1 and Neur2 have similar degrees of homology to DNeur, and neur2 is expressed in patterns similar to those of neur1 in embryos, suggesting potential functional redundancy. Interestingly, two distinct classes of E3 ligases, Mind bomb-1 (Mib1) and Neur2, have cooperative but distinct roles in Delta endocytosis to Hrs-positive vesicles, i.e. Mib1 functions in the initial step of Delta endocytosis, and Neur2 is required for targeting endocytosed Delta to Hrs-positive vesicles. Thus, our study provides a new insight into how distinct E3 ligases work together in the endocytic pathways for Notch signaling.

Received for publication, July 11, 2006 , and in revised form, September 15, 2006.

^* This work was supported by 21C Frontier Functional Human Genome Project Grant FG04-22-05 from the Ministry of Science and Technology of Korea and by Basic Research Program Grant R02-2003-000-10057-0 and a Vascular System Research Center grant from the Korea Science and Engineering 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 and 2.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed. Tel.: 82-54-279-2287; Fax: 82-54-279-2199; E-mail: ykong{at}postech.ac.kr.

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