WW Domains

ErbB-4 is the newest identified member of the epidermal growth-factor-receptor family and seems to be a good tumor marker for certain types of malignancies, such as prostate, lung or breast cancer (Starr et al. 2006; Ben et al. 2007; Junttila et al. 2005). The C-terminal fragment (CTF) of ErbB-4 is cleaved by y-secretase and shuttles to the nucleus of stimulated cells (Ni et al. 2001). The two WW-domain-containing proteins WWOX and YAP (Yes kinase associated protein) were shown to compete for interaction with the PPXY motifs of the cytosplamic tail of the ErbB-4 receptor (Komuro et al. 2003; Aqeilan et al. 2005). YAP acts as a transcriptional coactivator, while WWOX, which was described as a tumor suppressor gene (Paige et al. 2001), binds to ErbB-4 in the cytoplasm, thereby acting as an inhibitor of CTF nuclear translocation. For future drug development, the challenge will be to develop an inhibitor that targets the WW domain of YES, but leaves the interaction of WWOX and ErbB-4 unaffected. Since both WW domains converge on the same recognition motifs, amino acids outside the conserved proline-binding pocket have to be addressed as differentiating epitopes for the binding of chemical moieties (see discussion below). The power of negative selection, for example, implemented as a pre-clearing step in the screening process, might be employed in order to gain predominant inhibition of the desired WW domain.

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