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Cell and Tumor Biology |
1 Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, Ohio State University, Columbus, Ohio; 2 Weis Center for Research, Geisinger Clinic, Danville, Pennsylvania; and 3 Department of Medicine, Mt. Sinai School of Medicine, New York, New York
Requests for reprints: Rami I. Aqeilan, Department of Human Cancer Genomics, The Ohio State University, Room 455E, Wiseman Hall, 410 West 12th Avenue, Columbus, OH 43220. Phone: 614-292-3120; Fax: 614-292-4053; E-mail: rami.aqeilan{at}osumc.edu.
The WW domain–containing oxidoreductase, WWOX, is a tumor suppressor that is deleted or altered in several cancer types. We recently showed that WWOX interacts with p73 and AP-2
and suppresses their transcriptional activity. Yes-associated protein (YAP), also containing WW domains, was shown to associate with p73 and enhance its transcriptional activity. In addition, YAP interacts with ErbB-4 receptor tyrosine kinase and acts as transcriptional coactivator of the COOH-terminal fragment (CTF) of ErbB-4. Stimulation of ErbB-4–expressing cells with 12-O-tetradecanoylphorbol-13-acetate (TPA) results in the proteolytic cleavage of its cytoplasmic domain and translocation of this domain to the nucleus. Here we report that WWOX physically associates with the full-length ErbB-4 via its first WW domain. Coexpression of WWOX and ErbB-4 in HeLa cells followed by treatment with TPA results in the retention of ErbB-4 in the cytoplasm. Moreover, in MCF-7 breast carcinoma cells, expressing high levels of endogenous WWOX, endogenous ErbB-4 is also retained in the cytoplasm. In addition, our results show that interaction of WWOX and ErbB-4 suppresses transcriptional coactivation of CTF by YAP in a dose-dependent manner. A mutant form of WWOX lacking interaction with ErbB-4 has no effect on this coactivation of ErbB-4. Furthermore, WWOX is able to inhibit coactivation of p73 by YAP. In summary, our data indicate that WWOX antagonizes the function of YAP by competing for interaction with ErbB-4 and other targets and thus affect its transcriptional activity.
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