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J. Biol. Chem., Vol. 280, Issue 35, 30783-30787, September 2, 2005

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Secretase-dependent Tyrosine Phosphorylation of Mdm2 by the ErbB-4 Intracellular Domain Fragment^*

Rajeswara Rao Arasada and Graham Carpenter

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

Heregulin activation of the endogenous receptor tyrosine kinase ErbB-4 in ZR-75–1 breast cancer cells provokes tyrosine phosphorylation of Hdm2 in a manner that is sensitive to inhibition of or -secretase activity, indicating that liberation of the tyrosine kinase intracellular domain (ICD) fragment is required. Similar results are obtained when Erbb-4 is exogenously expressed in 32D cells, which do not otherwise express any ErbB family members. Expression of the ErbB-4 ICD fragment leads to its constitutive association with Mdm2 and tyrosine phosphorylation of Mdm2, a protein that is predominantly localized in the nucleus and that regulates p53 levels. When the ErbB-4 ICD fragment was expressed in H1299 cells, it promoted Hdm2 ubiquitination and increased the levels of p53 and p21, a transcriptional target of p53. In addition, expression of the ICD fragment increased p53 activity toward the p21 promoter in a luciferase reporter assay.

Received for publication, June 2, 2005

^* This work was supported by National Institutes of Health Grant CA97456. 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.: 615-322-6678; Fax: 615-322-2931; E-mail: graham.carpenter{at}vanderbilt.edu.

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