Figure 1

WWOX signaling. The full-length WWOX or WOX1 has two N-terminal WW domains and a C-terminal short-chain alcohol dehydrogenase/reductase (ADH/SDR) domain [1–5]. A nuclear localization signal (NLS) is located between the WW domains. Sex steroid hormones may interact with the NSYK motif in the ADH/SDR domain [4, 5]. Under stress stimuli, tyrosine kinase SRC and probably other kinases induce WWOX activation via Tyr33 phosphorylation. Activated WWOX binds Ser46-phosphorylated p53, and relocates to the mitochondria and nuclei to induce apoptosis. JNK1 and Zfra bind WWOX and counteract its-mediated apoptosis. The first WW domain of WWOX interacts with PPxY motif-containing transcription factors, including AP-2γ, p73, ERBB4, c-Jun and RUNX2. The binding allows transiently overexpressed WWOX to prevent relocation of transcription factors to the nucleus in vitro. However, the event does not work in vivo[6]. Phosphorylated Ezrin binds and anchors WWOX to the membrane/cytoskeleton area. Activated tyrosine kinase ACK1 phosphorylates WWOX at Tyr287 for polyubiquitination and proteosomal degradation.