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J. Biol. Chem., Vol. 281, Issue 35, 25373-25380, September 1, 2006

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ErbB-4 s80 Intracellular Domain Abrogates ETO2-dependent Transcriptional Repression^*

From the Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146

ErbB-4 is cleaved by - and -secretases to release a soluble 80-kDa intracellular domain, termed s80, which translocates to the nucleus. s80 is present in the nucleus of normal and cancerous mammary cells and is predicted to have a role in cell differentiation. To further investigate the mechanism by which s80 may mediate differentiation, we tested whether s80 regulates Eto2, a transcriptional corepressor that is involved in erythrocyte differentiation and is also implicated in human breast cancer. Here we show that ligand binding to ErbB-4 causes s80 translocation to the nucleus, where it colocalizes and interacts with Eto2. Expression of s80 blocks Eto2-mediated transcriptional repression of a heterologous promoter. This effect on Eto2 does not require s80 kinase activity and is mediated by the carboxyl-terminal region of s80. Although other cell surface receptors regulate transcription by activating signal transduction cascades, these data present a novel mechanism of corepressor regulation and suggest a role for Eto2 in ErbB-4-dependent differentiation.

Received for publication, April 26, 2006 , and in revised form, June 26, 2006.

^* This work was supported by the Department of Defense Grant BC040357 (to B. L.), National Institutes of Health Grant CA97456 (to G. C.), and both the Vanderbilt Ingram Cancer Center Grant P30 CA6845 and the Vanderbilt Diabetes Center Grant P30 DK20593 for core resources. 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: Vanderbilt University School of Medicine, Dept. of Biochemistry, 647 Light Hall, Nashville, TN 37232-0146. Tel.: 615-322-6678; Fax: 615-322-2931; E-mail: graham.carpenter{at}vanderbilt.edu.

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