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J. Biol. Chem., Vol. 280, Issue 18, 17694-17700, May 6, 2005

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Molecular Dissection of the Interaction between p27 and Kip1 Ubiquitylation-promoting Complex, the Ubiquitin Ligase That Regulates Proteolysis of p27 in G₁ Phase^*

Shuhei Kotoshiba, Takumi Kamura, Taichi Hara, Noriko Ishida¶, and Keiichi I. Nakayama||

From the Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, CREST, the Japan Science and Technology Corporation, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, and the ^¶Department of Developmental Biology, Center for Translational and Advanced Animal Research on Human Disease, Graduate School of Medicine, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan

The cyclin-dependent kinase (CDK) inhibitor p27 is degraded at the G₀-G₁ transition of the cell cycle by the ubiquitin-proteasome pathway in a Skp2-independent manner. We recently identified a novel ubiquitin ligase, KPC (Kip1 ubiquitylation-promoting complex), consisting of KPC1 and KPC2, which regulates the ubiquitin-dependent degradation of p27 at G₁ phase. We have now investigated the structural requirements for the interactions of KPC1 with KPC2 and p27. The NH₂-terminal region of KPC1 was found to be responsible for binding to KPC2 and to p27. KPC1 mutants that lack this region failed to mediate polyubiquitylation of p27 in vitro and expression of one such mutant delayed p27 degradation in vivo. We also generated a series of deletion mutants of p27 and found that KPC failed to polyubiquitylate a p27 mutant that lacks the CDK inhibitory domain. Interestingly, the cyclin E·CDK2 complex prevented both the interaction of KPC with p27 as well as KPC-mediated polyubiquitylation of p27. A complex of cyclin E with a kinase-negative mutant of CDK2 also exhibited these inhibitory effects, suggesting that cyclin E·CDK2 competes with KPC1 for access to the CDK inhibitory domain of p27. These results suggest that free p27 is recognized by the NH₂-terminal region of KPC1, which also associates with KPC2, and that p27 is then polyubiquitylated by the COOH-terminal RING-finger domain of KPC1.

Received for publication, January 24, 2005 , and in revised form, March 2, 2005.

^* 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.: 81-92-642-6815; Fax: 81-92-642-6819; E-mail: nakayak1{at}bioreg.kyushu-u.ac.jp.

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