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. Phosphorylated Ezrin binds and anchors WWOX to the membrane/cytoskeleton area. Activated tyrosine kinase ACK1 phosphorylates WWOX at Tyr287 for polyubiquitination and proteosomal degradation.