title: WW domain-containing proteins, WWOX and YAP, compete for interaction with ErbB-4 and modulate its transcriptional function.
abstract: 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-2gamma 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.
authors.affiliation: Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, Ohio State University, Columbus, Ohio 43220, USA. rami.aqeilan@osumc.edu
authors.forename: Rami I
authors.initials: RI
authors.lastname: Aqeilan
authors.forename: Valentina
authors.initials: V
authors.lastname: Donati
authors.forename: Alexey
authors.initials: A
authors.lastname: Palamarchuk
authors.forename: Francesco
authors.initials: F
authors.lastname: Trapasso
authors.forename: Mohamed
authors.initials: M
authors.lastname: Kaou
authors.forename: Yuri
authors.initials: Y
authors.lastname: Pekarsky
authors.forename: Marius
authors.initials: M
authors.lastname: Sudol
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
mesh_terms: D000595:Amino Acid Sequence; D001667:Binding, Competitive; D018797:Cell Cycle Proteins; D003593:Cytoplasm / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D010088:Oxidoreductases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D066247:Receptor, ErbB-4; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D015533:Transcriptional Activation / Q000502:physiology; D025521:Tumor Suppressor Proteins; D000074584:WW Domain-Containing Oxidoreductase
chemical_list: D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C456659:YY1AP1 protein, human; D010088:Oxidoreductases; D000074584:WW Domain-Containing Oxidoreductase; C486071:WWOX protein, human; C587689:ERBB4 protein, human; D066246:ErbB Receptors; D066247:Receptor, ErbB-4