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J. Biol. Chem., Vol. 282, Issue 50, 36744-36754, December 14, 2007

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Ebp1 Association with Nucleophosmin/B23 Is Essential for Regulating Cell Proliferation and Suppressing Apoptosis^*

From the Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 30322

Ebp1 and NPM/B23 are essential for cell proliferation and survival. Ebp1 possesses p42 and p48 isoforms. Whereas p42 exclusively resides in the cytoplasm, p48 localizes in both the cytoplasm and the nucleolus. Here, we show that Ebp1 forms a complex with B23, and this complex plays a critical role in cell proliferation and survival. p42 specifically associates with B23 upon epidermal growth factor stimulation, while p48 constantly binds B23. Moreover, Ser³⁶⁰ phosphorylation in p42, but not p48, is critical for the interaction. p48 constitutively binds B23 in the nucleolus, for which B23 Lys²⁶³ sumoylation is indispensable. By contrast, p42 selectively binds unsumoylated B23 mutants. Interestingly, B23 K263R, an unsumoylated mutant, triggers p42 nuclear translocation and interacts with it in the nucleus even in the absence of epidermal growth factor. In contrast, the nucleolar residency of p48 is abolished in B23 K263R cells. During the cell cycle, p42 selectively colocalizes with B23 in the mitotic cells, correlating with its phosphorylation status in mitosis. Knocking down of B23 or Ebp1 substantially decreases ribosome biogenesis and cell survival. Thus, B23 distinctively binds Ebp1 isoforms and regulates cell proliferation and survival through p42 and p48, respectively.

Received for publication, July 26, 2007 , and in revised form, October 18, 2007.

^* This work was supported by Grant R01, NS045627 from the National Institutes of Health (to K. Y.). 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. Tel.: 404-712-2814; E-mail: kye{at}emory.edu.

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